WorldWideScience

Sample records for additional susceptibility loci

  1. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2.

    Science.gov (United States)

    Orr, Nick; Dudbridge, Frank; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Ghoussaini, Maya; Hopper, John L; Southey, Melissa C; Apicella, Carmel; Stone, Jennifer; Schmidt, Marjanka K; Broeks, Annegien; Van't Veer, Laura J; Hogervorst, Frans B; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Gibson, Lorna; Aitken, Zoe; Warren, Helen; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Chistof; Guénel, Pascal; Truong, Thérèse; Cordina-Duverger, Emilie; Sanchez, Marie; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Benitez, Javier; Zamora, Maria Pilar; Arias Perez, Jose Ignacio; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan L; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Hamann, Ute; Brauch, Hiltrud; Justenhoven, Christina; Brüning, Thomas; Ko, Yon-Dschun; Nevanlinna, Heli; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Bogdanova, Natalia; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Chenevix-Trench, Georgia; Beesley, Jonathan; Lambrechts, Diether; Moisse, Matthieu; Floris, Guiseppe; Beuselinck, Benoit; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Peissel, Bernard; Pensotti, Valeria; Couch, Fergus J; Olson, Janet E; Slettedahl, Seth; Vachon, Celine; Giles, Graham G; Milne, Roger L; McLean, Catriona; Haiman, Christopher A; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Kristensen, Vessela; Alnæs, Grethe Grenaker; Nord, Silje; Borresen-Dale, Anne-Lise; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Tchatchou, Sandrine; Devilee, Peter; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Van Asperen, Christi J; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Klevebring, Daniel; Hooning, Maartje J; Hollestelle, Antoinette; van Deurzen, Carolien H M; Kriege, Mieke; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Pharoah, Paul D P; Dunning, Alison M; Shah, Mitul; Perkins, Barbara J; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Ashworth, Alan; Swerdlow, Anthony; Jones, Michael; Schoemaker, Minouk J; Meindl, Alfons; Schmutzler, Rita K; Olswold, Curtis; Slager, Susan; Toland, Amanda E; Yannoukakos, Drakoulis; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Matsuo, Keitaro; Ito, Hidema; Iwata, Hiroji; Ishiguro, Junko; Wu, Anna H; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Teo, Soo Hwang; Yip, Cheng Har; Kang, Peter; Ikram, Mohammad Kamran; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Noh, Dong-Young; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Lee, Soo Chin; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; Mckay, James; Wu, Pei-Ei; Hou, Ming-Feng; Yu, Jyh-Cherng; Shen, Chen-Yang; Blot, William; Cai, Qiuyin; Signorello, Lisa B; Luccarini, Craig; Bayes, Caroline; Ahmed, Shahana; Maranian, Mel; Healey, Catherine S; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Hunter, David J; Lindstrom, Sara; Dennis, Joe; Michailidou, Kyriaki; Bolla, Manjeet K; Easton, Douglas F; dos Santos Silva, Isabel; Fletcher, Olivia; Peto, Julian

    2015-05-15

    We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. © The Author 2015. Published by Oxford University Press.

  2. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

    NARCIS (Netherlands)

    N. Orr (Nick); F. Dudbridge (Frank); N. Dryden (Nicola); S. Maguire (Sarah); D. Novo (Daniela); E. Perrakis (Eleni); N. Johnson (Nichola); M. Ghoussaini (Maya); J. Hopper (John); M.C. Southey (Melissa); C. Apicella (Carmel); J. Stone (Jennifer); M.K. Schmidt (Marjanka); A. Broeks (Annegien); L.J. van 't Veer (Laura); F.B.L. Hogervorst (Frans); P.A. Fasching (Peter); L. Haeberle (Lothar); A.B. Ekici (Arif); M.W. Beckmann (Matthias W.); L.J. Gibson (Lorna); A. Aitken; H. Warren (Helen); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); B. Burwinkel (Barbara); F. Marme (Federick); A. Schneeweiss (Andreas); C. Sohn (Chistof); P. Guénel (Pascal); T. Truong (Thérèse); E. Cordina-Duverger (Emilie); M. Sanchez (Marie); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); S.F. Nielsen (Sune); H. Flyger (Henrik); J. Benítez (Javier); M.P. Zamora (Pilar); J.I.A. Perez (Jose Ignacio Arias); P. Menéndez (Primitiva); H. Anton-Culver (Hoda); S.L. Neuhausen (Susan); H. Brenner (Hermann); A.K. Dieffenbach (Aida Karina); V. Arndt (Volker); C. Stegmaier (Christa); U. Hamann (Ute); H. Brauch (Hiltrud); C. Justenhoven (Christina); T. Brüning (Thomas); Y.-D. Ko (Yon-Dschun); H. Nevanlinna (Heli); K. Aittomäki (Kristiina); C. Blomqvist (Carl); S. Khan (Sofia); N.V. Bogdanova (Natalia); T. Dörk (Thilo); A. Lindblom (Annika); S. Margolin (Sara); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); G. Chenevix-Trench (Georgia); J. Beesley (Jonathan); D. Lambrechts (Diether); M. Moisse (Matthieu); O.A.M. Floris; B. Beuselinck (B.); J. Chang-Claude (Jenny); A. Rudolph (Anja); P. Seibold (Petra); D. Flesch-Janys (Dieter); P. Radice (Paolo); P. Peterlongo (Paolo); B. Peissel (Bernard); V. Pensotti (Valeria); F.J. Couch (Fergus); J.E. Olson (Janet); S. Slettedahl (Seth); C. Vachon (Celine); G.G. Giles (Graham G.); R.L. Milne (Roger L.); C.A. McLean (Catriona Ann); C.A. Haiman (Christopher); B.E. Henderson (Brian); F.R. Schumacher (Fredrick); L. Le Marchand (Loic); J. Simard (Jacques); M.S. Goldberg (Mark); F. Labrèche (France); M. Dumont (Martine); V. Kristensen (Vessela); G.G. Alnæs (Grethe); S. Nord (Silje); A.-L. Borresen-Dale (Anne-Lise); W. Zheng (Wei); S.L. Deming-Halverson (Sandra); M. Shrubsole (Martha); J. Long (Jirong); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); S. Tchatchou (Sandrine); P. Devilee (Peter); R.A.E.M. Tollenaar (Robertus A. E. M.); C.M. Seynaeve (Caroline); C.J. van Asperen (Christi); M. García-Closas (Montserrat); J.D. Figueroa (Jonine); S.J. Chanock (Stephen); J. Lissowska (Jolanta); K. Czene (Kamila); H. Darabi (Hatef); M. Eriksson (Mikael); D. Klevebring (Daniel); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); C.H.M. van Deurzen (Carolien); M. Kriege (Mieke); P. Hall (Per); J. Li (Jingmei); J. Liu (Jianjun); M.K. Humphreys (Manjeet); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); P.D.P. Pharoah (Paul); A.M. Dunning (Alison); M. Shah (Mitul); B. Perkins (Barbara); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska-Bieniek (Katarzyna); K. Durda (Katarzyna); A. Ashworth (Alan); A.J. Swerdlow (Anthony ); M. Jones (Michael); M. Schoemaker (Minouk); A. Meindl (Alfons); R.K. Schmutzler (Rita); C. Olswold (Curtis); S. Slager (Susan); A.E. Toland (Amanda); D. Yannoukakos (Drakoulis); K.R. Muir (K.); A. Lophatananon (Artitaya); S. Stewart-Brown (Sarah); P. Siriwanarangsan (Pornthep); K. Matsuo (Keitaro); H. Ito (Hidema); H. Iwata (Hisato); J. Ishiguro (Junko); A.H. Wu (Anna H.); C.-C. Tseng (Chiu-chen); D. Van Den Berg (David); D.O. Stram (Daniel O.); S.-H. Teo; C.H. Yip (Cheng Har); P. Kang (Peter); M.K. Ikram (Kamran); X.-O. Shu (Xiao-Ou); W. Lu (Wei); Y. Gao; H. Cai (Hui); D. Kang (Daehee); J.-Y. Choi (J.); S.K. Park (Sue); D-Y. Noh (Dong-Young); J.M. Hartman (Joost); X. Miao; W.-Y. Lim (Wei-Yen); S.C. Lee (Soo Chin); S. Sangrajrang (Suleeporn); V. Gaborieau (Valerie); P. Brennan (Paul); J.D. McKay (James); P.-E. Wu (Pei-Ei); M.-F. Hou (Ming-Feng); J-C. Yu (Jyh-Cherng); C-Y. Shen (Chen-Yang); W.J. Blot (William); Q. Cai (Qiuyin); L.B. Signorello (Lisa B.); C. Luccarini (Craig); C. Bayes (Caroline); S. Ahmed (Shahana); M. Maranian (Melanie); S. Healey (Sue); A. González-Neira (Anna); G. Pita (G.); M. Rosario Alonso; N. Álvarez (Nuria); D. Herrero (Daniel); D.C. Tessier (Daniel C.); D. Vincent (Daniel); F. Bacot (Francois); D. Hunter (David); S. Lindstrom (Stephen); J. Dennis (Joe); K. Michailidou (Kyriaki); M.K. Bolla (Manjeet); D.F. Easton (Douglas); I. dos Santos Silva (Isabel); O. Fletcher (Olivia); J. Peto (Julian)

    2015-01-01

    textabstractWe recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and

  3. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

    OpenAIRE

    Orr, Nick; Dudbridge, Frank; Dryden, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Ghoussaini, Maya; Hopper, John L.; Southey, Melissa C.; Apicella, Carmel; Stone, Jennifer; Schmidt, Marjanka K.; Broeks, Annegien; Van't Veer, Laura J.

    2015-01-01

    We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92...

  4. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

    OpenAIRE

    Orr, N; Dudbridge, F; Dryden, N; Maguire, S; Novo, D; Perrakis, E; Johnson, N.; Ghoussaini, M; Hopper, J L; Southey, M C; Apicella, C.; J. Stone(Boston University); Schmidt, M K; Broeks, A; van't Veer, L J

    2016-01-01

    We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios OR = 0.90 0.88-0.92; P...

  5. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

    National Research Council Canada - National Science Library

    ...; Orr, Nick; Dudbridge, Frank; den, Nicola; Maguire, Sarah; Novo, Daniela; Perrakis, Eleni; Johnson, Nichola; Ghoussaini, Maya; Hopper, John; Southey, Melissa; Apicella, Carmel; Stone, Jennifer; Schmidt, Marjanka; Broeks, Annegien; Veer, Laura; Hogervorst, Frans; Fasching, Peter; Haeberle, Lothar; Ekici, Arif; Beckmann, Matthias W; Gibson, Lorna; Aitken, A; Warren, Helen; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael; Miller, Nicola; Burwinkel, Barbara; Marme, Federick; Schneeweiss, Aneas; Sohn, Chistof; Guénel, Pascal; Truong, Thérèse; Cordina-Duverger, Emilie; Sanchez, Marie; Bojesen, Stig; Nordestgaard, Børge; Nielsen, Sune; Flyger, Henrik; Benítez, Javier; Zamora, Pilar; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Anton-Culver, Hoda; Neuhausen, Susan; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Hamann, Ute; Brauch, Hiltrud; Justenhoven, Christina; Brüning, Thomas; Ko, Yon-Dschun; Nevanlinna, Heli; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Bogdanova, Natalia; Dörk, Thilo; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, J; Chenevix-Trench, Georgia; Beesley, Jonathan; Lambrechts, Diether; Moisse, Matthieu; Floris, O.A.M; Beuselinck, B; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Peissel, Bernard; Pensotti, Valeria; Couch, Fergus; Olson, Janet; Slettedahl, Seth; Vachon, Celine; Giles, Graham G; Milne, Roger L; McLean, Catriona Ann; Haiman, Christopher; Henderson, Brian; Schumacher, Freick; Le Marchand, Loic; Simard, Jacques; Goldberg, Mark; Labrèche, France; Dumont, Martine; Kristensen, Vessela; Alnæs, Grethe Grenaker; Nord, Silje; Borresen-Dale, Anne-Lise; Zheng, Wei

    2015-01-01

    .... Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies...

  6. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

    DEFF Research Database (Denmark)

    Orr, Nick; Dudbridge, Frank; Dryden, Nicola

    2015-01-01

    5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs......We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further...... of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including...

  7. Novel susceptibility loci for Alzheimer's disease.

    Science.gov (United States)

    Reitz, Christiane

    2015-12-01

    Late-onset Alzheimer's disease (AD), a highly prevalent neurodegenerative disorder characterized by progressive deterioration in cognition, function and behavior terminating in incapacity and death, is a clinically and pathologically heterogeneous disease with a substantial heritable component. During the past 5 years, the technological developments in next-generation high-throughput genome technologies have led to the identification of more than 20 novel susceptibility loci for AD, and have implicated specific pathways in the disease, in particular intracellular trafficking/endocytosis, inflammation and immune response and lipid metabolism. These observations have significantly advanced our understanding of underlying pathogenic mechanisms and potential therapeutic targets. This review article summarizes these recent advances in AD genomics and discusses the value of identified susceptibility loci for diagnosis and prognosis of AD.

  8. Confirmation of five novel susceptibility loci for systemic lupus erythematosus (SLE) and integrated network analysis of 82 SLE susceptibility loci.

    Science.gov (United States)

    Molineros, Julio E; Yang, Wanling; Zhou, Xu-Jie; Sun, Celi; Okada, Yukinori; Zhang, Huoru; Heng Chua, Kek; Lau, Yu-Lung; Kochi, Yuta; Suzuki, Akari; Yamamoto, Kazuhiko; Ma, Jianyang; Bang, So-Young; Lee, Hye-Soon; Kim, Kwangwoo; Bae, Sang-Cheol; Zhang, Hong; Shen, Nan; Looger, Loren L; Nath, Swapan K

    2017-03-15

    We recently identified ten novel SLE susceptibility loci in Asians and uncovered several additional suggestive loci requiring further validation. This study aimed to replicate five of these suggestive loci in a Han Chinese cohort from Hong Kong, followed by meta-analysis (11,656 cases and 23,968 controls) on previously reported Asian and European populations, and to perform bioinformatic analyses on all 82 reported SLE loci to identify shared regulatory signatures. We performed a battery of analyses for these five loci, as well as joint analyses on all 82 SLE loci. All five loci passed genome-wide significance: MYNN (rs10936599, Pmeta = 1.92 × 10-13, OR = 1.14), ATG16L2 (rs11235604, Pmeta = 8.87 × 10 -12, OR = 0.78), CCL22 (rs223881, Pmeta = 5.87 × 10-16, OR = 0.87), ANKS1A (rs2762340, Pmeta = 4.93 × 10-15, OR = 0.87) and RNASEH2C (rs1308020, Pmeta = 2.96 × 10-19, OR = 0.84) and co-located with annotated gene regulatory elements. The novel loci share genetic signatures with other reported SLE loci, including effects on gene expression, transcription factor binding, and epigenetic characteristics. Most (56%) of the correlated (r2 > 0.8) SNPs from the 82 SLE loci were implicated in differential expression (9.81 × 10-198 SLE loci, consistent with apoptosis playing a critical role in SLE. Enrichment analysis revealed common pathways, gene ontology, protein domains, and cell type-specific expression. In summary, we provide evidence of five novel SLE susceptibility loci. Integrated bioinformatics using all 82 loci revealed that SLE susceptibility loci share many gene regulatory features, suggestive of conserved mechanisms of SLE etiopathogenesis. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  9. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

    Science.gov (United States)

    Zeggini, Eleftheria; Scott, Laura J.; Saxena, Richa; Voight, Benjamin F.; Marchini, Jonathan L; Hu, Tainle; de Bakker, Paul IW; Abecasis, Gonçalo R; Almgren, Peter; Andersen, Gitte; Ardlie, Kristin; Boström, Kristina Bengtsson; Bergman, Richard N; Bonnycastle, Lori L; Borch-Johnsen, Knut; Burtt, Noël P; Chen, Hong; Chines, Peter S; Daly, Mark J; Deodhar, Parimal; Ding, Charles; Doney, Alex S F; Duren, William L; Elliott, Katherine S; Erdos, Michael R; Frayling, Timothy M; Freathy, Rachel M; Gianniny, Lauren; Grallert, Harald; Grarup, Niels; Groves, Christopher J; Guiducci, Candace; Hansen, Torben; Herder, Christian; Hitman, Graham A; Hughes, Thomas E; Isomaa, Bo; Jackson, Anne U; Jørgensen, Torben; Kong, Augustine; Kubalanza, Kari; Kuruvilla, Finny G; Kuusisto, Johanna; Langenberg, Claudia; Lango, Hana; Lauritzen, Torsten; Li, Yun; Lindgren, Cecilia M; Lyssenko, Valeriya; Marvelle, Amanda F; Meisinger, Christa; Midthjell, Kristian; Mohlke, Karen L; Morken, Mario A; Morris, Andrew D; Narisu, Narisu; Nilsson, Peter; Owen, Katharine R; Palmer, Colin NA; Payne, Felicity; Perry, John RB; Pettersen, Elin; Platou, Carl; Prokopenko, Inga; Qi, Lu; Qin, Li; Rayner, Nigel W; Rees, Matthew; Roix, Jeffrey J; Sandbæk, Anelli; Shields, Beverley; Sjögren, Marketa; Steinthorsdottir, Valgerdur; Stringham, Heather M; Swift, Amy J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Timpson, Nicholas J; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Walker, Mark; Watanabe, Richard M; Weedon, Michael N; Willer, Cristen J; Illig, Thomas; Hveem, Kristian; Hu, Frank B; Laakso, Markku; Stefansson, Kari; Pedersen, Oluf; Wareham, Nicholas J; Barroso, Inês; Hattersley, Andrew T; Collins, Francis S; Groop, Leif; McCarthy, Mark I; Boehnke, Michael; Altshuler, David

    2009-01-01

    Genome-wide association (GWA) studies have identified multiple new genomic loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)1-11. Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to discover loci at which common alleles have modest effects, we performed meta-analysis of three T2D GWA scans encompassing 10,128 individuals of European-descent and ~2.2 million SNPs (directly genotyped and imputed). Replication testing was performed in an independent sample with an effective sample size of up to 53,975. At least six new loci with robust evidence for association were detected, including the JAZF1 (p=5.0×10−14), CDC123/CAMK1D (p=1.2×10−10), TSPAN8/LGR5 (p=1.1×10−9), THADA (p=1.1×10−9), ADAMTS9 (p=1.2×10−8), and NOTCH2 (p=4.1×10−8) gene regions. The large number of loci with relatively small effects indicates the value of large discovery and follow-up samples in identifying additional clues about the inherited basis of T2D. PMID:18372903

  10. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

    Science.gov (United States)

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo. PMID:26870082

  11. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

    DEFF Research Database (Denmark)

    Zeggini, Eleftheria; Scott, Laura J; Saxena, Richa

    2008-01-01

    Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published ...

  12. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Phelan, Catherine M; Kuchenbaecker, Karoline B; Tyrer, Jonathan P

    2017-01-01

    , including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low...

  13. Prognostic relevance of urinary bladder cancer susceptibility Loci

    NARCIS (Netherlands)

    Grotenhuis, A.J.; Dudek, A.M.D.; Verhaegh, G.W.C.T.; Witjes, J.A.; Aben, K.K.H.; Marel, S.L. van der; Vermeulen, S.; Kiemeney, L.A.L.M.

    2014-01-01

    In the last few years, susceptibility loci have been identified for urinary bladder cancer (UBC) through candidate-gene and genome-wide association studies. Prognostic relevance of most of these loci is yet unknown. In this study, we used data of the Nijmegen Bladder Cancer Study (NBCS) to perform a

  14. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.

    Science.gov (United States)

    Zeggini, Eleftheria; Scott, Laura J; Saxena, Richa; Voight, Benjamin F; Marchini, Jonathan L; Hu, Tianle; de Bakker, Paul I W; Abecasis, Gonçalo R; Almgren, Peter; Andersen, Gitte; Ardlie, Kristin; Boström, Kristina Bengtsson; Bergman, Richard N; Bonnycastle, Lori L; Borch-Johnsen, Knut; Burtt, Noël P; Chen, Hong; Chines, Peter S; Daly, Mark J; Deodhar, Parimal; Ding, Chia-Jen; Doney, Alex S F; Duren, William L; Elliott, Katherine S; Erdos, Michael R; Frayling, Timothy M; Freathy, Rachel M; Gianniny, Lauren; Grallert, Harald; Grarup, Niels; Groves, Christopher J; Guiducci, Candace; Hansen, Torben; Herder, Christian; Hitman, Graham A; Hughes, Thomas E; Isomaa, Bo; Jackson, Anne U; Jørgensen, Torben; Kong, Augustine; Kubalanza, Kari; Kuruvilla, Finny G; Kuusisto, Johanna; Langenberg, Claudia; Lango, Hana; Lauritzen, Torsten; Li, Yun; Lindgren, Cecilia M; Lyssenko, Valeriya; Marvelle, Amanda F; Meisinger, Christa; Midthjell, Kristian; Mohlke, Karen L; Morken, Mario A; Morris, Andrew D; Narisu, Narisu; Nilsson, Peter; Owen, Katharine R; Palmer, Colin N A; Payne, Felicity; Perry, John R B; Pettersen, Elin; Platou, Carl; Prokopenko, Inga; Qi, Lu; Qin, Li; Rayner, Nigel W; Rees, Matthew; Roix, Jeffrey J; Sandbaek, Anelli; Shields, Beverley; Sjögren, Marketa; Steinthorsdottir, Valgerdur; Stringham, Heather M; Swift, Amy J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Timpson, Nicholas J; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Walker, Mark; Watanabe, Richard M; Weedon, Michael N; Willer, Cristen J; Illig, Thomas; Hveem, Kristian; Hu, Frank B; Laakso, Markku; Stefansson, Kari; Pedersen, Oluf; Wareham, Nicholas J; Barroso, Inês; Hattersley, Andrew T; Collins, Francis S; Groop, Leif; McCarthy, Mark I; Boehnke, Michael; Altshuler, David

    2008-05-01

    Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.

  15. Genetic susceptibility loci, pesticide exposure and prostate cancer risk.

    Directory of Open Access Journals (Sweden)

    Stella Koutros

    Full Text Available Uncovering SNP (single nucleotide polymorphisms-environment interactions can generate new hypotheses about the function of poorly characterized genetic variants and environmental factors, like pesticides. We evaluated SNP-environment interactions between 30 confirmed prostate cancer susceptibility loci and 45 pesticides and prostate cancer risk in 776 cases and 1,444 controls in the Agricultural Health Study. We used unconditional logistic regression to estimate odds ratios (ORs and 95% confidence intervals (CIs. Multiplicative SNP-pesticide interactions were calculated using a likelihood ratio test. After correction for multiple tests using the False Discovery Rate method, two interactions remained noteworthy. Among men carrying two T alleles at rs2710647 in EH domain binding protein 1 (EHBP1 SNP, the risk of prostate cancer in those with high malathion use was 3.43 times those with no use (95% CI: 1.44-8.15 (P-interaction= 0.003. Among men carrying two A alleles at rs7679673 in TET2, the risk of prostate cancer associated with high aldrin use was 3.67 times those with no use (95% CI: 1.43, 9.41 (P-interaction= 0.006. In contrast, associations were null for other genotypes. Although additional studies are needed and the exact mechanisms are unknown, this study suggests known genetic susceptibility loci may modify the risk between pesticide use and prostate cancer.

  16. Expression QTL analysis of top loci from GWAS meta-analysis highlights additional schizophrenia candidate genes

    DEFF Research Database (Denmark)

    de Jong, Simone; van Eijk, Kristel R; Zeegers, Dave W L H

    2012-01-01

    of the Psychiatric GWAS consortium (PGC) yielded five novel loci for schizophrenia. In this study, we aim to highlight additional schizophrenia susceptibility loci from the PGC study by combining the top association findings from the discovery stage (9394 schizophrenia cases and 12 462 controls) with expression QTLs...

  17. Overlap of disease susceptibility loci for rheumatoid arthritis and juvenile idiopathic arthritis

    Science.gov (United States)

    Hinks, Anne; Eyre, Steve; Ke, Xiayi; Barton, Anne; Martin, Paul; Flynn, Edward; Packham, Jon; Worthington, Jane; Thomson, Wendy

    2010-01-01

    Background Genome-wide association studies (GWAS) have been extremely successful in the search for susceptibility risk factors for complex genetic autoimmune diseases. As more studies are published, evidence is emerging of considerable overlap of loci between these diseases. In juvenile idiopathic arthritis (JIA), another complex genetic autoimmune disease, the strategy of using information from autoimmune disease GWAS or candidate gene studies to help in the search for novel JIA susceptibility loci has been successful, with confirmed association with two genes, PTPN22 and IL2RA. Rheumatoid arthritis (RA) is an autoimmune disease that shares similar clinical and pathological features with JIA and, therefore, recently identified confirmed RA susceptibility loci are also excellent JIA candidate loci. Objective To determine the overlap of disease susceptibility loci for RA and JIA. Methods Fifteen single nucleotide polymorphisms (SNPs) at nine RA-associated loci were genotyped in Caucasian patients with JIA (n=1054) and controls (n=3531) and tested for association with JIA. Allele and genotype frequencies were compared between cases and controls using the genetic analysis software, PLINK. Results Two JIA susceptibility loci were identified, one of which was a novel JIA association (STAT4) and the second confirmed previously published associations of the TRAF1/C5 locus with JIA. Weak evidence of association of JIA with three additional loci (Chr6q23, KIF5A and PRKCQ) was also obtained, which warrants further investigation. Conclusion All these loci are good candidates in view of the known pathogenesis of JIA, as genes within these regions (TRAF1, STAT4, TNFAIP3, PRKCQ) are known to be involved in T-cell receptor signalling or activation pathways. PMID:19674979

  18. Identification of multiple independent susceptibility loci in the HLA region in Behcet's disease

    NARCIS (Netherlands)

    Hughes, Travis; Coit, Patrick; Adler, Adam; Yilmaz, Vuslat; Aksu, Kenan; Duzgun, Nursen; Keser, Gokhan; Cefle, Ayse; Yazici, Ayten; Ergen, Andac; Alpsoy, Erkan; Salvarani, Carlo; Casali, Bruno; Koetter, Ina; Gutierrez-Achury, Javier; Wijmenga, Cisca; Direskeneli, Haner; Saruhan-Direskeneli, Guher; Sawalha, Amr H.

    Behcet's disease is an inflammatory disease characterized by recurrent oral and genital ulcers and significant organ involvement. Localizing the genetic association between HLA-B*51 and Behcet's disease and exploring additional susceptibility loci in the human leukocyte antigen (HLA) region are

  19. Pancreatic cancer susceptibility loci and their role in survival.

    Directory of Open Access Journals (Sweden)

    Cosmeri Rizzato

    Full Text Available Pancreatic cancer has one of the worst mortality rates of all cancers. Little is known about its etiology, particularly regarding inherited risk. The PanScan project, a genome-wide association study, identified several common polymorphisms affecting pancreatic cancer susceptibility. Single nucleotide polymorphisms (SNPs in ABO, sonic hedgehog (SHH, telomerase reverse transcriptase (TERT, nuclear receptor subfamily 5, group A, member 2 (NR5A2 were found to be associated with pancreatic cancer risk. Moreover the scan identified loci on chromosomes 13q22.1 and 15q14, to which no known genes or other functional elements are mapped. We sought to replicate these observations in two additional, independent populations (from Germany and the UK, and also evaluate the possible impact of these SNPs on patient survival. We genotyped 15 SNPs in 690 cases of pancreatic ductal adenocarcinoma (PDAC and in 1277 healthy controls. We replicated several associations between SNPs and PDAC risk. Furthermore we found that SNP rs8028529 was weakly associated with a better overall survival (OS in both populations. We have also found that NR5A2 rs12029406_T allele was associated with a shorter survival in the German population. In conclusion, we found that rs8028529 could be, if these results are replicated, a promising marker for both risk and prognosis for this lethal disease.

  20. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium

    National Research Council Canada - National Science Library

    Broeks, A; Schmidt, M.K; Sherman, M.E; Couch, F.J; Hopper, J.L; Dite, G.S; Apicella, C; Smith, L.D; Hammet, F; Southey, M.C; Veer, L.J. van 't; Groot, R. de; Smit, V.T; Fasching, P.A; Beckmann, M.W; Jud, S; Ekici, A.B; Hartmann, A; Hein, A; Schulz-Wendtland, R; Burwinkel, B; Marme, F; Schneeweiss, A; Sinn, H.P; Sohn, C; Tchatchou, S; Bojesen, S.E; Nordestgaard, B.G; Flyger, H; Orsted, D.D; Kaur-Knudsen, D; Milne, R.L; Perez, J.I; Zamora, P; Roiguez, P.M; Benitez, J; Brauch, H; Justenhoven, C; Ko, Y.D; Hamann, U; Fischer, H.P; Bruning, T; Pesch, B; Chang-Claude, J; Wang-Gohrke, S; Bremer, M; Karstens, J.H; Hillemanns, P; Dork, T; Nevanlinna, H.A; Heikkinen, T; Heikkila, P; Blomqvist, C; Aittomaki, K; Aaltonen, K; Lindblom, A; Margolin, S; Mannermaa, A; Kosma, V.M; Kauppinen, J.M; Kataja, V; Auvinen, P; Eskelinen, M; Soini, Y; Chenevix-Trench, G; Spurdle, A.B; Beesley, J; Chen, X; Holland, H; Lambrechts, D; Claes, B; Vandorpe, T; Neven, P; Wildiers, H; Flesch-Janys, D; Hein, R; Loning, T; Kosel, M; Fredericksen, Z.S; Wang, X; Giles, G.G; Baglietto, L; Severi, G; McLean, C; Haiman, C.A; Henderson, B.E; Marchand, L. le; Kolonel, L.N; Alnaes, G.G; Kristensen, V; Borresen-Dale, A.L; Hunter, D.J; Hankinson, S.E; Anulis, I.L; Mulligan, A.M; O'Malley, F.P; Devilee, P; Huijts, P.E; Tollenaar, R.A.E.M; Asperen, C.J. van

    2011-01-01

    .... We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes...

  1. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

    Science.gov (United States)

    Couch, Fergus J.; Kuchenbaecker, Karoline B.; Michailidou, Kyriaki; Mendoza-Fandino, Gustavo A.; Nord, Silje; Lilyquist, Janna; Olswold, Curtis; Hallberg, Emily; Agata, Simona; Ahsan, Habibul; Aittomäki, Kristiina; Ambrosone, Christine; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K.; Arver, Brita; Barile, Monica; Barkardottir, Rosa B.; Barrowdale, Daniel; Beckmann, Lars; Beckmann, Matthias W.; Benitez, Javier; Blank, Stephanie V.; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S.; Caldes, Trinidad; Caligo, Maria A.; Canzian, Federico; Carpenter, Jane; Chang-Claude, Jenny; Chanock, Stephen J.; Chung, Wendy K.; Claes, Kathleen B. M.; Cox, Angela; Cross, Simon S.; Cunningham, Julie M.; Czene, Kamila; Daly, Mary B.; Damiola, Francesca; Darabi, Hatef; de la Hoya, Miguel; Devilee, Peter; Diez, Orland; Ding, Yuan C.; Dolcetti, Riccardo; Domchek, Susan M.; Dorfling, Cecilia M.; dos-Santos-Silva, Isabel; Dumont, Martine; Dunning, Alison M.; Eccles, Diana M.; Ehrencrona, Hans; Ekici, Arif B.; Eliassen, Heather; Ellis, Steve; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Försti, Asta; Fostira, Florentia; Foulkes, William D.; Friebel, Tara; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gammon, Marilie D.; Ganz, Patricia A.; Gapstur, Susan M.; Garber, Judy; Gaudet, Mia M.; Gayther, Simon A.; Gerdes, Anne-Marie; Ghoussaini, Maya; Giles, Graham G.; Glendon, Gord; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Greene, Mark H.; Gronwald, Jacek; Guénel, Pascal; Gunter, Marc; Haeberle, Lothar; Haiman, Christopher A.; Hamann, Ute; Hansen, Thomas V. O.; Hart, Steven; Healey, Sue; Heikkinen, Tuomas; Henderson, Brian E.; Herzog, Josef; Hogervorst, Frans B. L.; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Humphreys, Keith; Hunter, David J.; Huzarski, Tomasz; Imyanitov, Evgeny N.; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M.; Jones, Michael; Kabisch, Maria; Kar, Siddhartha; Karlan, Beth Y.; Khan, Sofia; Khaw, Kay-Tee; Kibriya, Muhammad G.; Knight, Julia A.; Ko, Yon-Dschun; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Lee, Eunjung; Le Marchand, Loic; Lester, Jenny; Lindblom, Annika; Lindor, Noralane; Lindstrom, Sara; Liu, Jianjun; Long, Jirong; Lubinski, Jan; Mai, Phuong L.; Makalic, Enes; Malone, Kathleen E.; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Martens, John W. M.; McGuffog, Lesley; Meindl, Alfons; Miller, Austin; Milne, Roger L.; Miron, Penelope; Montagna, Marco; Mazoyer, Sylvie; Mulligan, Anna M.; Muranen, Taru A.; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Nordestgaard, Børge G.; Nussbaum, Robert L.; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I.; Olson, Janet E.; Osorio, Ana; Park, Sue K.; Peeters, Petra H.; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M.; Pilarski, Robert; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Romieu, Isabelle; Rudolph, Anja; Rutgers, Emiel J.; Sanchez, Maria-Jose; Santella, Regina M.; Sawyer, Elinor J.; Schmidt, Daniel F.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Schumacher, Fredrick; Scott, Rodney; Senter, Leigha; Sharma, Priyanka; Simard, Jacques; Singer, Christian F.; Sinilnikova, Olga M.; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Swerdlow, Anthony; Szabo, Csilla I.; Tamimi, Rulla; Tapper, William; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Mary B.; Thomassen, Mads; Thompson, Deborah; Tihomirova, Laima; Toland, Amanda E.; Tollenaar, Robert A. E. M.; Tomlinson, Ian; Truong, Thérèse; Tsimiklis, Helen; Teulé, Alex; Tumino, Rosario; Tung, Nadine; Turnbull, Clare; Ursin, Giski; van Deurzen, Carolien H. M.; van Rensburg, Elizabeth J.; Varon-Mateeva, Raymonda; Wang, Zhaoming; Wang-Gohrke, Shan; Weiderpass, Elisabete; Weitzel, Jeffrey N.; Whittemore, Alice; Wildiers, Hans; Winqvist, Robert; Yang, Xiaohong R.; Yannoukakos, Drakoulis; Yao, Song; Zamora, M Pilar; Zheng, Wei; Hall, Per; Kraft, Peter; Vachon, Celine; Slager, Susan; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Monteiro, Alvaro A. N.; García-Closas, Montserrat; Easton, Douglas F.; Antoniou, Antonis C.

    2016-01-01

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. PMID:27117709

  2. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.

    Science.gov (United States)

    Couch, Fergus J; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Mendoza-Fandino, Gustavo A; Nord, Silje; Lilyquist, Janna; Olswold, Curtis; Hallberg, Emily; Agata, Simona; Ahsan, Habibul; Aittomäki, Kristiina; Ambrosone, Christine; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K; Arver, Brita; Barile, Monica; Barkardottir, Rosa B; Barrowdale, Daniel; Beckmann, Lars; Beckmann, Matthias W; Benitez, Javier; Blank, Stephanie V; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Canzian, Federico; Carpenter, Jane; Chang-Claude, Jenny; Chanock, Stephen J; Chung, Wendy K; Claes, Kathleen B M; Cox, Angela; Cross, Simon S; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Darabi, Hatef; de la Hoya, Miguel; Devilee, Peter; Diez, Orland; Ding, Yuan C; Dolcetti, Riccardo; Domchek, Susan M; Dorfling, Cecilia M; Dos-Santos-Silva, Isabel; Dumont, Martine; Dunning, Alison M; Eccles, Diana M; Ehrencrona, Hans; Ekici, Arif B; Eliassen, Heather; Ellis, Steve; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Försti, Asta; Fostira, Florentia; Foulkes, William D; Friebel, Tara; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Gaudet, Mia M; Gayther, Simon A; Gerdes, Anne-Marie; Ghoussaini, Maya; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Greene, Mark H; Gronwald, Jacek; Guénel, Pascal; Gunter, Marc; Haeberle, Lothar; Haiman, Christopher A; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Healey, Sue; Heikkinen, Tuomas; Henderson, Brian E; Herzog, Josef; Hogervorst, Frans B L; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Robert N; Hopper, John L; Humphreys, Keith; Hunter, David J; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M; Jones, Michael; Kabisch, Maria; Kar, Siddhartha; Karlan, Beth Y; Khan, Sofia; Khaw, Kay-Tee; Kibriya, Muhammad G; Knight, Julia A; Ko, Yon-Dschun; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Lee, Eunjung; Le Marchand, Loic; Lester, Jenny; Lindblom, Annika; Lindor, Noralane; Lindstrom, Sara; Liu, Jianjun; Long, Jirong; Lubinski, Jan; Mai, Phuong L; Makalic, Enes; Malone, Kathleen E; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Martens, John W M; McGuffog, Lesley; Meindl, Alfons; Miller, Austin; Milne, Roger L; Miron, Penelope; Montagna, Marco; Mazoyer, Sylvie; Mulligan, Anna M; Muranen, Taru A; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nordestgaard, Børge G; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Osorio, Ana; Park, Sue K; Peeters, Petra H; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M; Pilarski, Robert; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Romieu, Isabelle; Rudolph, Anja; Rutgers, Emiel J; Sanchez, Maria-Jose; Santella, Regina M; Sawyer, Elinor J; Schmidt, Daniel F; Schmidt, Marjanka K; Schmutzler, Rita K; Schumacher, Fredrick; Scott, Rodney; Senter, Leigha; Sharma, Priyanka; Simard, Jacques; Singer, Christian F; Sinilnikova, Olga M; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla; Tapper, William; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary B; Thomassen, Mads; Thompson, Deborah; Tihomirova, Laima; Toland, Amanda E; Tollenaar, Robert A E M; Tomlinson, Ian; Truong, Thérèse; Tsimiklis, Helen; Teulé, Alex; Tumino, Rosario; Tung, Nadine; Turnbull, Clare; Ursin, Giski; van Deurzen, Carolien H M; van Rensburg, Elizabeth J; Varon-Mateeva, Raymonda; Wang, Zhaoming; Wang-Gohrke, Shan; Weiderpass, Elisabete; Weitzel, Jeffrey N; Whittemore, Alice; Wildiers, Hans; Winqvist, Robert; Yang, Xiaohong R; Yannoukakos, Drakoulis; Yao, Song; Zamora, M Pilar; Zheng, Wei; Hall, Per; Kraft, Peter; Vachon, Celine; Slager, Susan; Chenevix-Trench, Georgia; Pharoah, Paul D P; Monteiro, Alvaro A N; García-Closas, Montserrat; Easton, Douglas F; Antoniou, Antonis C

    2016-04-27

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

  3. Lupus nephritis susceptibility loci in women with systemic lupus erythematosus.

    Science.gov (United States)

    Chung, Sharon A; Brown, Elizabeth E; Williams, Adrienne H; Ramos, Paula S; Berthier, Celine C; Bhangale, Tushar; Alarcon-Riquelme, Marta E; Behrens, Timothy W; Criswell, Lindsey A; Graham, Deborah Cunninghame; Demirci, F Yesim; Edberg, Jeffrey C; Gaffney, Patrick M; Harley, John B; Jacob, Chaim O; Kamboh, M Ilyas; Kelly, Jennifer A; Manzi, Susan; Moser-Sivils, Kathy L; Russell, Laurie P; Petri, Michelle; Tsao, Betty P; Vyse, Tim J; Zidovetzki, Raphael; Kretzler, Matthias; Kimberly, Robert P; Freedman, Barry I; Graham, Robert R; Langefeld, Carl D

    2014-12-01

    Lupus nephritis is a manifestation of SLE resulting from glomerular immune complex deposition and inflammation. Lupus nephritis demonstrates familial aggregation and accounts for significant morbidity and mortality. We completed a meta-analysis of three genome-wide association studies of SLE to identify lupus nephritis-predisposing loci. Through genotyping and imputation, >1.6 million markers were assessed in 2000 unrelated women of European descent with SLE (588 patients with lupus nephritis and 1412 patients with lupus without nephritis). Tests of association were computed using logistic regression adjusting for population substructure. The strongest evidence for association was observed outside the MHC and included markers localized to 4q11-q13 (PDGFRA, GSX2; P=4.5×10(-7)), 16p12 (SLC5A11; P=5.1×10(-7)), 6p22 (ID4; P=7.4×10(-7)), and 8q24.12 (HAS2, SNTB1; P=1.1×10(-6)). Both HLA-DR2 and HLA-DR3, two well established lupus susceptibility loci, showed evidence of association with lupus nephritis (P=0.06 and P=3.7×10(-5), respectively). Within the class I region, rs9263871 (C6orf15-HCG22) had the strongest evidence of association with lupus nephritis independent of HLA-DR2 and HLA-DR3 (P=8.5×10(-6)). Consistent with a functional role in lupus nephritis, intra-renal mRNA levels of PDGFRA and associated pathway members showed significant enrichment in patients with lupus nephritis (n=32) compared with controls (n=15). Results from this large-scale genome-wide investigation of lupus nephritis provide evidence of multiple biologically relevant lupus nephritis susceptibility loci. Copyright © 2014 by the American Society of Nephrology.

  4. Phenotypic associations of genetic susceptibility loci in systemic lupus erythematosus.

    Science.gov (United States)

    Sanchez, Elena; Nadig, Ajay; Richardson, Bruce C; Freedman, Barry I; Kaufman, Kenneth M; Kelly, Jennifer A; Niewold, Timothy B; Kamen, Diane L; Gilkeson, Gary S; Ziegler, Julie T; Langefeld, Carl D; Alarcón, Graciela S; Edberg, Jeffrey C; Ramsey-Goldman, Rosalind; Petri, Michelle; Brown, Elizabeth E; Kimberly, Robert P; Reveille, John D; Vilá, Luis M; Merrill, Joan T; Anaya, Juan-Manuel; James, Judith A; Pons-Estel, Bernardo A; Martin, Javier; Park, So-Yeon; Bang, So-Young; Bae, Sang-Cheol; Moser, Kathy L; Vyse, Timothy J; Criswell, Lindsey A; Gaffney, Patrick M; Tsao, Betty P; Jacob, Chaim O; Harley, John B; Alarcón-Riquelme, Marta E; Sawalha, Amr H

    2011-10-01

    Systemic lupus erythematosus is a clinically heterogeneous autoimmune disease. A number of genetic loci that increase lupus susceptibility have been established. This study examines if these genetic loci also contribute to the clinical heterogeneity in lupus. 4001 European-derived, 1547 Hispanic, 1590 African-American and 1191 Asian lupus patients were genotyped for 16 confirmed lupus susceptibility loci. Ancestry informative markers were genotyped to calculate and adjust for admixture. The association between the risk allele in each locus was determined and compared in patients with and without the various clinical manifestations included in the ACR criteria. Renal disorder was significantly correlated with the lupus risk allele in ITGAM (p=5.0 × 10(-6), OR 1.25, 95% CI 1.12 to 1.35) and in TNFSF4 (p=0.0013, OR 1.14, 95% CI 1.07 to 1.25). Other significant findings include the association between risk alleles in FCGR2A and malar rash (p=0.0031, OR 1.11, 95% CI 1.17 to 1.33), ITGAM and discoid rash (p=0.0020, OR 1.20, 95% CI 1.06 to 1.33), STAT4 and protection from oral ulcers (p=0.0027, OR 0.89, 95% CI 0.83 to 0.96) and IL21 and haematological disorder (p=0.0027, OR 1.13, 95% CI 1.04 to 1.22). All these associations are significant with a false discovery rate of manifestations and the FCGR2A, ITGAM, STAT4, TNSF4 and IL21 genes. The findings suggest that genetic profiling might be a useful tool to predict disease manifestations in lupus patients in the future.

  5. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study

    Science.gov (United States)

    Eeles, Rosalind A.; Kote-Jarai, Zsofia; Olama, Ali Amin Al; Giles, Graham G.; Guy, Michelle; Severi, Gianluca; Muir, Kenneth; Hopper, John L.; Henderson, Brian E.; Haiman, Christopher A.; Schleutker, Johanna; Hamdy, Freddie C.; Neal, David E.; Donovan, Jenny L.; Stanford, Janet L.; Ostrander, Elaine A.; Ingles, Sue A.; John, Esther M.; Thibodeau, Stephen N.; Schaid, Daniel; Park, Jong Y.; Spurdle, Amanda; Clements, Judith; Dickinson, Joanne L.; Maier, Christiane; Vogel, Walther; Dörk, Thilo; Rebbeck, Timothy R.; Cooney, Kathleen A.; Cannon-Albright, Lisa; Chappuis, Pierre O.; Hutter, Pierre; Zeegers, Maurice; Kaneva, Radka; Zhang, Hong-Wei; Lu, Yong-Jie; Foulkes, William D.; English, Dallas R.; Leongamornlert, Daniel A.; Tymrakiewicz, Malgorzata; Morrison, Jonathan; Ardern-Jones, Audrey T.; Hall, Amanda L.; O’Brien, Lynne T.; Wilkinson, Rosemary A.; Saunders, Edward J.; Page, Elizabeth C.; Sawyer, Emma J.; Edwards, Stephen M.; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas; Woodhouse, Christopher J.; Thompson, Alan; Christmas, Tim; Ogden, Chris; Cooper, Colin S.; Southey, Melissa C.; Lophatananon, Artitaya; Liu, Jo-Fen; Kolonel, Laurence N.; Le Marchand, Loic; Wahlfors, Tiina; Tammela, Teuvo L.; Auvinen, Anssi; Lewis, Sarah J.; Cox, Angela; FitzGerald, Liesel M.; Koopmeiners, Joseph S.; Karyadi, Danielle M.; Kwon, Erika M.; Stern, Mariana C.; Corral, Roman; Joshi, Amit D.; Shahabi, Ahva; McDonnell, Shannon K.; Sellers, Thomas A; Pow-Sang, Julio; Chambers, Suzanne; Aitken, Joanne; Gardiner, R.A. (Frank); Batra, Jyotsna; Kedda, Mary Anne; Lose, Felicity; Polanowski, Andrea; Patterson, Briony; Serth, Jürgen; Meyer, Andreas; Luedeke, Manuel; Stefflova, Klara; Ray, Anna M.; Lange, Ethan M.; Farnham, Jim; Khan, Humera; Slavov, Chavdar; Mitkova, Atanaska; Cao, Guangwen; Easton, Douglas F.

    2010-01-01

    Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10−8 to P=2.7×10−33). PMID:19767753

  6. Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2

    DEFF Research Database (Denmark)

    Ahmed, Shahana; Thomas, Gilles; Ghoussaini, Maya

    2009-01-01

    strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 x 10(-23)) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 x 10(-8)). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q....

  7. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

    Science.gov (United States)

    Reveille, John D; Sims, Anne-Marie; Danoy, Patrick; Evans, David M; Leo, Paul; Pointon, Jennifer J; Jin, Rui; Zhou, Xiaodong; Bradbury, Linda A; Appleton, Louise H; Davis, John C; Diekman, Laura; Doan, Tracey; Dowling, Alison; Duan, Ran; Duncan, Emma L; Farrar, Claire; Hadler, Johanna; Harvey, David; Karaderi, Tugce; Mogg, Rebecca; Pomeroy, Emma; Pryce, Karena; Taylor, Jacqueline; Savage, Laurie; Deloukas, Panos; Kumanduri, Vasudev; Peltonen, Leena; Ring, Sue M; Whittaker, Pamela; Glazov, Evgeny; Thomas, Gethin P; Maksymowych, Walter P; Inman, Robert D; Ward, Michael M; Stone, Millicent A; Weisman, Michael H; Wordsworth, B Paul; Brown, Matthew A

    2011-01-01

    To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility. PMID:20062062

  8. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

    DEFF Research Database (Denmark)

    Couch, Fergus J; Kuchenbaecker, Karoline B; Michailidou, Kyriaki

    2016-01-01

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci...

  9. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

    NARCIS (Netherlands)

    Couch, Fergus J; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Mendoza-Fandino, Gustavo A; Nord, Silje; Lilyquist, Janna; Olswold, Curtis; Hallberg, Emily; Agata, Simona; Ahsan, Habibul; Aittomäki, Kristiina; Ambrosone, Christine; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K; Arver, Brita; Barile, Monica; Barkardottir, Rosa B; Barrowdale, Daniel; Beckmann, Lars; Beckmann, Matthias W; Benitez, Javier; Blank, Stephanie V; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Canzian, Federico; Carpenter, Jane; Chang-Claude, Jenny; Chanock, Stephen J; Chung, Wendy K; Claes, Kathleen B M; Cox, Angela; Cross, Simon S; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Darabi, Hatef; de la Hoya, Miguel; Devilee, Peter; Diez, Orland; Ding, Yuan C; Dolcetti, Riccardo; Domchek, Susan M; Dorfling, Cecilia M; Dos-Santos-Silva, Isabel; Dumont, Martine; Dunning, Alison M; Eccles, Diana M; Ehrencrona, Hans; Ekici, Arif B; Eliassen, Heather; Ellis, Steve; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Försti, Asta; Fostira, Florentia; Foulkes, William D; Friebel, Tara; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Gaudet, Mia M; Gayther, Simon A; Gerdes, Anne-Marie; Ghoussaini, Maya; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Greene, Mark H; Gronwald, Jacek; Guénel, Pascal; Gunter, Marc; Haeberle, Lothar; Haiman, Christopher A; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Healey, Sue; Heikkinen, Tuomas; Henderson, Brian E; Herzog, Josef; Hogervorst, Frans B L; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Robert N; Hopper, John L; Humphreys, Keith; Hunter, David J; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M; Jones, Michael; Kabisch, Maria; Kar, Siddhartha; Karlan, Beth Y; Khan, Sofia; Khaw, Kay-Tee; Kibriya, Muhammad G; Knight, Julia A; Ko, Yon-Dschun; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Lee, Eunjung; Le Marchand, Loic; Lester, Jenny; Lindblom, Annika; Lindor, Noralane; Lindstrom, Sara; Liu, Jianjun; Long, Jirong; Lubinski, Jan; Mai, Phuong L; Makalic, Enes; Malone, Kathleen E; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Martens, John W M; McGuffog, Lesley; Meindl, Alfons; Miller, Austin; Milne, Roger L; Miron, Penelope; Montagna, Marco; Mazoyer, Sylvie; Mulligan, Anna M; Muranen, Taru A; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nordestgaard, Børge G; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Osorio, Ana; Park, Sue K; Peeters, Petra H; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M; Pilarski, Robert; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Romieu, Isabelle; Rudolph, Anja; Rutgers, Emiel J; Sanchez, Maria-Jose; Santella, Regina M; Sawyer, Elinor J; Schmidt, Daniel F; Schmidt, Marjanka K; Schmutzler, Rita K; Schumacher, Fredrick; Scott, Rodney; Senter, Leigha; Sharma, Priyanka; Simard, Jacques; Singer, Christian F; Sinilnikova, Olga M; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla; Tapper, William; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary B; Thomassen, Mads; Thompson, Deborah; Tihomirova, Laima; Toland, Amanda E; Tollenaar, Robert A E M; Tomlinson, Ian; Truong, Thérèse; Tsimiklis, Helen; Teulé, Alex; Tumino, Rosario; Tung, Nadine; Turnbull, Clare; Ursin, Giski; van Deurzen, Carolien H M; van Rensburg, Elizabeth J; Varon-Mateeva, Raymonda; Wang, Zhaoming; Wang-Gohrke, Shan; Weiderpass, Elisabete; Weitzel, Jeffrey N; Whittemore, Alice; Wildiers, Hans; Winqvist, Robert; Yang, Xiaohong R; Yannoukakos, Drakoulis; Yao, Song; Zamora, M Pilar; Zheng, Wei; Hall, Per; Kraft, Peter; Vachon, Celine; Slager, Susan; Chenevix-Trench, Georgia; Pharoah, Paul D P; Monteiro, Alvaro A N; García-Closas, Montserrat; Easton, Douglas F; Antoniou, Antonis C

    2016-01-01

    Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci,

  10. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

    Science.gov (United States)

    Phelan, Catherine M; Kuchenbaecker, Karoline B; Tyrer, Jonathan P; Kar, Siddhartha P; Lawrenson, Kate; Winham, Stacey J; Dennis, Joe; Pirie, Ailith; Riggan, Marjorie J; Chornokur, Ganna; Earp, Madalene A; Lyra, Paulo C; Lee, Janet M; Coetzee, Simon; Beesley, Jonathan; McGuffog, Lesley; Soucy, Penny; Dicks, Ed; Lee, Andrew; Barrowdale, Daniel; Lecarpentier, Julie; Leslie, Goska; Aalfs, Cora M; Aben, Katja K H; Adams, Marcia; Adlard, Julian; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia; Aravantinos, Gerasimos; Arnold, Norbert; Arun, Banu K; Arver, Brita; Azzollini, Jacopo; Balmaña, Judith; Banerjee, Susana N; Barjhoux, Laure; Barkardottir, Rosa B; Bean, Yukie; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Bernardini, Marcus Q; Birrer, Michael J; Bjorge, Line; Black, Amanda; Blankstein, Kenneth; Blok, Marinus J; Bodelon, Clara; Bogdanova, Natalia; Bojesen, Anders; Bonanni, Bernardo; Borg, Åke; Bradbury, Angela R; Brenton, James D; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Bruinsma, Fiona; Brunet, Joan; Buecher, Bruno; Butzow, Ralf; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Cannioto, Rikki; Carney, Michael E; Cescon, Terence; Chan, Salina B; Chang-Claude, Jenny; Chanock, Stephen; Chen, Xiao Qing; Chiew, Yoke-Eng; Chiquette, Jocelyne; Chung, Wendy K; Claes, Kathleen B M; Conner, Thomas; Cook, Linda S; Cook, Jackie; Cramer, Daniel W; Cunningham, Julie M; D'Aloisio, Aimee A; Daly, Mary B; Damiola, Francesca; Damirovna, Sakaeva Dina; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Davidson, Rosemarie; DeFazio, Anna; Delnatte, Capucine; Doheny, Kimberly F; Diez, Orland; Ding, Yuan Chun; Doherty, Jennifer Anne; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; Dossus, Laure; Duran, Mercedes; Dürst, Matthias; Dworniczak, Bernd; Eccles, Diana; Edwards, Todd; Eeles, Ros; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B; Ellis, Steve; Elvira, Mingajeva; Eng, Kevin H; Engel, Christoph; Evans, D Gareth; Fasching, Peter A; Ferguson, Sarah; Ferrer, Sandra Fert; Flanagan, James M; Fogarty, Zachary C; Fortner, Renée T; Fostira, Florentia; Foulkes, William D; Fountzilas, George; Fridley, Brooke L; Friebel, Tara M; Friedman, Eitan; Frost, Debra; Ganz, Patricia A; Garber, Judy; García, María J; Garcia-Barberan, Vanesa; Gehrig, Andrea; Gentry-Maharaj, Aleksandra; Gerdes, Anne-Marie; Giles, Graham G; Glasspool, Rosalind; Glendon, Gord; Godwin, Andrew K; Goldgar, David E; Goranova, Teodora; Gore, Martin; Greene, Mark H; Gronwald, Jacek; Gruber, Stephen; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hamann, Ute; Hansen, Thomas V O; Harrington, Patricia A; Harris, Holly R; Hauke, Jan; Hein, Alexander; Henderson, Alex; Hildebrandt, Michelle A T; Hillemanns, Peter; Hodgson, Shirley; Høgdall, Claus K; Høgdall, Estrid; Hogervorst, Frans B L; Holland, Helene; Hooning, Maartje J; Hosking, Karen; Huang, Ruea-Yea; Hulick, Peter J; Hung, Jillian; Hunter, David J; Huntsman, David G; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Iversen, Edwin S; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jernetz, Mats; Jensen, Allan; Jensen, Uffe Birk; John, Esther M; Johnatty, Sharon; Jones, Michael E; Kannisto, Päivi; Karlan, Beth Y; Karnezis, Anthony; Kast, Karin; Kennedy, Catherine J; Khusnutdinova, Elza; Kiemeney, Lambertus A; Kiiski, Johanna I; Kim, Sung-Won; Kjaer, Susanne K; Köbel, Martin; Kopperud, Reidun K; Kruse, Torben A; Kupryjanczyk, Jolanta; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Larrañaga, Nerea; Larson, Melissa C; Lazaro, Conxi; Le, Nhu D; Le Marchand, Loic; Lee, Jong Won; Lele, Shashikant B; Leminen, Arto; Leroux, Dominique; Lester, Jenny; Lesueur, Fabienne; Levine, Douglas A; Liang, Dong; Liebrich, Clemens; Lilyquist, Jenna; Lipworth, Loren; Lissowska, Jolanta; Lu, Karen H; Lubinński, Jan; Luccarini, Craig; Lundvall, Lene; Mai, Phuong L; Mendoza-Fandiño, Gustavo; Manoukian, Siranoush; Massuger, Leon F A G; May, Taymaa; Mazoyer, Sylvie; McAlpine, Jessica N; McGuire, Valerie; McLaughlin, John R; McNeish, Iain; Meijers-Heijboer, Hanne; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R; Merritt, Melissa A; Milne, Roger L; Mitchell, Gillian; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moffitt, Melissa; Montagna, Marco; Moysich, Kirsten B; Mulligan, Anna Marie; Musinsky, Jacob; Nathanson, Katherine L; Nedergaard, Lotte; Ness, Roberta B; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Nussbaum, Robert L; Odunsi, Kunle; Olah, Edith; Olopade, Olufunmilayo I; Olsson, Håkan; Olswold, Curtis; O'Malley, David M; Ong, Kai-Ren; Onland-Moret, N Charlotte; Orr, Nicholas; Orsulic, Sandra; Osorio, Ana; Palli, Domenico; Papi, Laura; Park-Simon, Tjoung-Won; Paul, James; Pearce, Celeste L; Pedersen, Inge Søkilde; Peeters, Petra H M; Peissel, Bernard; Peixoto, Ana; Pejovic, Tanja; Pelttari, Liisa M; Permuth, Jennifer B; Peterlongo, Paolo; Pezzani, Lidia; Pfeiler, Georg; Phillips, Kelly-Anne; Piedmonte, Marion; Pike, Malcolm C; Piskorz, Anna M; Poblete, Samantha R; Pocza, Timea; Poole, Elizabeth M; Poppe, Bruce; Porteous, Mary E; Prieur, Fabienne; Prokofyeva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pujol, Pascal; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rhiem, Kerstin; Rice, Patricia; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C; Rodríguez-Antona, Cristina; Romm, Jane; Rookus, Matti A; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Salvesen, Helga B; Sandler, Dale P; Schoemaker, Minouk J; Senter, Leigha; Setiawan, V Wendy; Severi, Gianluca; Sharma, Priyanka; Shelford, Tameka; Siddiqui, Nadeem; Side, Lucy E; Sieh, Weiva; Singer, Christian F; Sobol, Hagay; Song, Honglin; Southey, Melissa C; Spurdle, Amanda B; Stadler, Zsofia; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sucheston-Campbell, Lara E; Sukiennicki, Grzegorz; Sutphen, Rebecca; Sutter, Christian; Swerdlow, Anthony J; Szabo, Csilla I; Szafron, Lukasz; Tan, Yen Y; Taylor, Jack A; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Thomsen, Liv Cecilie Vestrheim; Thull, Darcy L; Tihomirova, Laima; Tinker, Anna V; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tone, Alicia; Trabert, Britton; Travis, Ruth C; Trichopoulou, Antonia; Tung, Nadine; Tworoger, Shelley S; van Altena, Anne M; Van Den Berg, David; van der Hout, Annemarie H; van der Luijt, Rob B; Van Heetvelde, Mattias; Van Nieuwenhuysen, Els; van Rensburg, Elizabeth J; Vanderstichele, Adriaan; Varon-Mateeva, Raymonda; Vega, Ana; Edwards, Digna Velez; Vergote, Ignace; Vierkant, Robert A; Vijai, Joseph; Vratimos, Athanassios; Walker, Lisa; Walsh, Christine; Wand, Dorothea; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Webb, Penelope M; Weinberg, Clarice R; Weitzel, Jeffrey N; Wentzensen, Nicolas; Whittemore, Alice S; Wijnen, Juul T; Wilkens, Lynne R; Wolk, Alicja; Woo, Michelle; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Yannoukakos, Drakoulis; Ziogas, Argyrios; Zorn, Kristin K; Narod, Steven A; Easton, Douglas F; Amos, Christopher I; Schildkraut, Joellen M; Ramus, Susan J; Ottini, Laura; Goodman, Marc T; Park, Sue K; Kelemen, Linda E; Risch, Harvey A; Thomassen, Mads; Offit, Kenneth; Simard, Jacques; Schmutzler, Rita Katharina; Hazelett, Dennis; Monteiro, Alvaro N; Couch, Fergus J; Berchuck, Andrew; Chenevix-Trench, Georgia; Goode, Ellen L; Sellers, Thomas A; Gayther, Simon A; Antoniou, Antonis C; Pharoah, Paul D P

    2017-05-01

    To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

  11. Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study

    DEFF Research Database (Denmark)

    Kote-Jarai, Zsofia; Olama, Ali Amin Al; Giles, Graham G

    2011-01-01

    Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results...... of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations...... in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10(-8) to P = 2.7 × 10(-24)). We also identified a SNP in TERT more strongly associated...

  12. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

    DEFF Research Database (Denmark)

    Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I

    2014-01-01

    Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer...

  13. Identification of twelve new susceptibility loci for different histotypes of epithelial ovarian cancer

    Science.gov (United States)

    Phelan, Catherine M.; Kuchenbaecker, Karoline B.; Tyrer, Jonathan P.; Kar, Siddhartha P.; Lawrenson, Kate; Winham, Stacey J.; Dennis, Joe; Pirie, Ailith; Riggan, Marjorie; Chornokur, Ganna; Earp, Madalene A.; Lyra, Paulo C.; Lee, Janet M.; Coetzee, Simon; Beesley, Jonathan; McGuffog, Lesley; Soucy, Penny; Dicks, Ed; Lee, Andrew; Barrowdale, Daniel; Lecarpentier, Julie; Leslie, Goska; Aalfs, Cora M.; Aben, Katja K.H.; Adams, Marcia; Adlard, Julian; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia; Aravantinos, Gerasimos; Arnold, Norbert; Arun, Banu K.; Arver, Brita; Azzollini, Jacopo; Balmaña, Judith; Banerjee, Susana N.; Barjhoux, Laure; Barkardottir, Rosa B.; Bean, Yukie; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Bernardini, Marcus Q.; Birrer, Michael J.; Bjorge, Line; Black, Amanda; Blankstein, Kenneth; Blok, Marinus J.; Bodelon, Clara; Bogdanova, Natalia; Bojesen, Anders; Bonanni, Bernardo; Borg, Åke; Bradbury, Angela R.; Brenton, James D.; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Bruinsma, Fiona; Brunet, Joan; Buecher, Bruno; Butzow, Ralf; Buys, Saundra S.; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Cannioto, Rikki; Carney, Michael E.; Cescon, Terence; Chan, Salina B.; Chang-Claude, Jenny; Chanock, Stephen; Chen, Xiao Qing; Chiew, Yoke-Eng; Chiquette, Jocelyne; Chung, Wendy K.; Claes, Kathleen B.M.; Conner, Thomas; Cook, Linda S.; Cook, Jackie; Cramer, Daniel W.; Cunningham, Julie M.; D’Aloisio, Aimee A.; Daly, Mary B.; Damiola, Francesca; Damirovna, Sakaeva Dina; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Davidson, Rosemarie; DeFazio, Anna; Delnatte, Capucine; Doheny, Kimberly F.; Diez, Orland; Ding, Yuan Chun; Doherty, Jennifer Anne; Domchek, Susan M.; Dorfling, Cecilia M.; Dörk, Thilo; Dossus, Laure; Duran, Mercedes; Dürst, Matthias; Dworniczak, Bernd; Eccles, Diana; Edwards, Todd; Eeles, Ros; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B.; Ellis, Steve; Elvira, Mingajeva; Eng, Kevin H.; Engel, Christoph; Evans, D. Gareth; Fasching, Peter A.; Ferguson, Sarah; Ferrer, Sandra Fert; Flanagan, James M.; Fogarty, Zachary C.; Fortner, Renée T.; Fostira, Florentia; Foulkes, William D.; Fountzilas, George; Fridley, Brooke L.; Friebel, Tara M.; Friedman, Eitan; Frost, Debra; Ganz, Patricia A.; Garber, Judy; García, María J.; Garcia-Barberan, Vanesa; Gehrig, Andrea; Gentry-Maharaj, Aleksandra; Gerdes, Anne-Marie; Giles, Graham G.; Glasspool, Rosalind; Glendon, Gord; Godwin, Andrew K.; Goldgar, David E.; Goranova, Teodora; Gore, Martin; Greene, Mark H.; Gronwald, Jacek; Gruber, Stephen; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hamann, Ute; Hansen, Thomas V.O.; Harrington, Patricia A.; Harris, Holly R; Hauke, Jan; Hein, Alexander; Henderson, Alex; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hodgson, Shirley; Høgdall, Claus K.; Høgdall, Estrid; Hogervorst, Frans B.L.; Holland, Helene; Hooning, Maartje J.; Hosking, Karen; Huang, Ruea-Yea; Hulick, Peter J.; Hung, Jillian; Hunter, David J.; Huntsman, David G.; Huzarski, Tomasz; Imyanitov, Evgeny N.; Isaacs, Claudine; Iversen, Edwin S.; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jernetz, Mats; Jensen, Allan; Jensen, Uffe Birk; John, Esther M.; Johnatty, Sharon; Jones, Michael E.; Kannisto, Päivi; Karlan, Beth Y.; Karnezis, Anthony; Kast, Karin; Kennedy, Catherine J.; Khusnutdinova, Elza; Kiemeney, Lambertus A.; Kiiski, Johanna I.; Kim, Sung-Won; Kjaer, Susanne K.; Köbel, Martin; Kopperud, Reidun K.; Kruse, Torben A.; Kupryjanczyk, Jolanta; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Larrañaga, Nerea; Larson, Melissa C.; Lazaro, Conxi; Le, Nhu D.; Le Marchand, Loic; Lee, Jong Won; Lele, Shashikant B.; Leminen, Arto; Leroux, Dominique; Lester, Jenny; Lesueur, Fabienne; Levine, Douglas A.; Liang, Dong; Liebrich, Clemens; Lilyquist, Jenna; Lipworth, Loren; Lissowska, Jolanta; Lu, Karen H.; Lubiński, Jan; Luccarini, Craig; Lundvall, Lene; Mai, Phuong L.; Mendoza-Fandiño, Gustavo; Manoukian, Siranoush; Massuger, Leon F.A.G.; May, Taymaa; Mazoyer, Sylvie; McAlpine, Jessica N.; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Meijers-Heijboer, Hanne; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R.; Merritt, Melissa A.; Milne, Roger L.; Mitchell, Gillian; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moffitt, Melissa; Montagna, Marco; Moysich, Kirsten B.; Mulligan, Anna Marie; Musinsky, Jacob; Nathanson, Katherine L.; Nedergaard, Lotte; Ness, Roberta B.; Neuhausen, Susan L.; Nevanlinna, Heli; Niederacher, Dieter; Nussbaum, Robert L.; Odunsi, Kunle; Olah, Edith; Olopade, Olufunmilayo I.; Olsson, Håkan; Olswold, Curtis; O’Malley, David M.; Ong, Kai-ren; Onland-Moret, N. Charlotte; Orr, Nicholas; Orsulic, Sandra; Osorio, Ana; Palli, Domenico; Papi, Laura; Park-Simon, Tjoung-Won; Paul, James; Pearce, Celeste L.; Pedersen, Inge Søkilde; Peeters, Petra H.M.; Peissel, Bernard; Peixoto, Ana; Pejovic, Tanja; Pelttari, Liisa M.; Permuth, Jennifer B.; Peterlongo, Paolo; Pezzani, Lidia; Pfeiler, Georg; Phillips, Kelly-Anne; Piedmonte, Marion; Pike, Malcolm C.; Piskorz, Anna M.; Poblete, Samantha R.; Pocza, Timea; Poole, Elizabeth M.; Poppe, Bruce; Porteous, Mary E.; Prieur, Fabienne; Prokofyeva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pujol, Pascal; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rhiem, Kerstin; Rice, Patricia; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C.; Rodríguez-Antona, Cristina; Romm, Jane; Rookus, Matti A.; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Salvesen, Helga B.; Sandler, Dale P.; Schoemaker, Minouk J.; Senter, Leigha; Setiawan, V. Wendy; Severi, Gianluca; Sharma, Priyanka; Shelford, Tameka; Siddiqui, Nadeem; Side, Lucy E.; Sieh, Weiva; Singer, Christian F.; Sobol, Hagay; Song, Honglin; Southey, Melissa C.; Spurdle, Amanda B.; Stadler, Zsofia; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sucheston-Campbell, Lara E.; Sukiennicki, Grzegorz; Sutphen, Rebecca; Sutter, Christian; Swerdlow, Anthony J.; Szabo, Csilla I.; Szafron, Lukasz; Tan, Yen Y.; Taylor, Jack A.; Tea, Muy-Kheng; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Thomsen, Liv Cecilie Vestrheim; Thull, Darcy L.; Tihomirova, Laima; Tinker, Anna V.; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tone, Alicia; Trabert, Britton; Travis, Ruth C.; Trichopoulou, Antonia; Tung, Nadine; Tworoger, Shelley S.; van Altena, Anne M.; Van Den Berg, David; van der Hout, Annemarie H.; van der Luijt, Rob B.; Van Heetvelde, Mattias; Van Nieuwenhuysen, Els; van Rensburg, Elizabeth J.; Vanderstichele, Adriaan; Varon-Mateeva, Raymonda; Ana, Vega; Edwards, Digna Velez; Vergote, Ignace; Vierkant, Robert A.; Vijai, Joseph; Vratimos, Athanassios; Walker, Lisa; Walsh, Christine; Wand, Dorothea; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Webb, Penelope M.; Weinberg, Clarice R.; Weitzel, Jeffrey N.; Wentzensen, Nicolas; Whittemore, Alice S.; Wijnen, Juul T.; Wilkens, Lynne R.; Wolk, Alicja; Woo, Michelle; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Yannoukakos, Drakoulis; Ziogas, Argyrios; Zorn, Kristin K.; Narod, Steven A.; Easton, Douglas F.; Amos, Christopher I.; Schildkraut, Joellen M.; Ramus, Susan J.; Ottini, Laura; Goodman, Marc T.; Park, Sue K.; Kelemen, Linda E.; Risch, Harvey A.; Thomassen, Mads; Offit, Kenneth; Simard, Jacques; Schmutzler, Rita Katharina; Hazelett, Dennis; Monteiro, Alvaro N.; Couch, Fergus J.; Berchuck, Andrew; Chenevix-Trench, Georgia; Goode, Ellen L.; Sellers, Thomas A.; Gayther, Simon A.; Antoniou, Antonis C.; Pharoah, Paul D.P.

    2017-01-01

    To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3, 9q31.1) and one for endometrioid EOC (5q12.3). We then meta-analysed the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified an additional three loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a novel susceptibility gene for low grade/borderline serous EOC. PMID:28346442

  14. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

    NARCIS (Netherlands)

    Pharoah, P.D.; Tsai, Y.Y.; Ramus, S.J.; Phelan, C.M.; Goode, E.L.; Lawrenson, K.; Buckley, M.; Fridley, B.L.; Tyrer, J.P.; Shen, H.; Weber, R.; Karevan, R.; Larson, M.C.; Song, H.; Tessier, D.C.; Bacot, F.; Vincent, D.; Cunningham, J.M.; Dennis, J.; Dicks, E.; Aben, K.K.H.; Anton-Culver, H.; Antonenkova, N.; Armasu, S.M.; Baglietto, L.; Bandera, E.V.; Beckmann, M.W.; Birrer, M.J.; Bloom, G.; Bogdanova, N.; Brenton, J.D.; Brinton, L.A.; Brooks-Wilson, A.; Brown, R.; Butzow, R.; Campbell, I.; Carney, M.E.; Carvalho, R.S.; Chang-Claude, J.; Chen, Y.A.; Chen, Z.; Chow, W.H.; Cicek, M.S.; Coetzee, G.; Cook, L.S.; Cramer, D.W; Cybulski, C.; Dansonka-Mieszkowska, A.; Despierre, E.; Doherty, J.A.; Dork, T.; Bois, A. du; Durst, M.; Eccles, D.; Edwards, R.; Ekici, A.B.; Fasching, P.A.; Fenstermacher, D.; Flanagan, J.; Gao, Y.T.; Garcia-Closas, M.; Gentry-Maharaj, A.; Giles, G.; Gjyshi, A.; Gore, M.; Gronwald, J.; Guo, Q.; Halle, M.K.; Harter, P.; Hein, A.; Heitz, F.; Hillemanns, P.; Hoatlin, M.; Hogdall, E.; Hogdall, C.K.; Hosono, S.; Jakubowska, A.; Jensen, A.; Kalli, K.R.; Karlan, B.Y.; Kelemen, L.E.; Kiemeney, L.A.L.M.; Kjaer, S.K.; Konecny, G.E.; Krakstad, C.; Kupryjanczyk, J.; Lambrechts, D.; Lambrechts, S.; Le, N.D.; Lee, N.; Lee, J. van der; Leminen, A.; Lim, B.K.; Lissowska, J.; Lubinski, J.; Lundvall, L.; Lurie, G.; Massuger, L.F.A.G.; Altena, A.M. van

    2013-01-01

    Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top

  15. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

    DEFF Research Database (Denmark)

    Pharoah, Paul D P; Tsai, Ya-Yu; Ramus, Susan J

    2013-01-01

    Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24...

  16. Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

    DEFF Research Database (Denmark)

    Kar, Siddhartha P; Adler, Emily; Tyrer, Jonathan

    2017-01-01

    BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription facto...

  17. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.

    Science.gov (United States)

    Nakayama, Akiyoshi; Nakaoka, Hirofumi; Yamamoto, Ken; Sakiyama, Masayuki; Shaukat, Amara; Toyoda, Yu; Okada, Yukinori; Kamatani, Yoichiro; Nakamura, Takahiro; Takada, Tappei; Inoue, Katsuhisa; Yasujima, Tomoya; Yuasa, Hiroaki; Shirahama, Yuko; Nakashima, Hiroshi; Shimizu, Seiko; Higashino, Toshihide; Kawamura, Yusuke; Ogata, Hiraku; Kawaguchi, Makoto; Ohkawa, Yasuyuki; Danjoh, Inaho; Tokumasu, Atsumi; Ooyama, Keiko; Ito, Toshimitsu; Kondo, Takaaki; Wakai, Kenji; Stiburkova, Blanka; Pavelka, Karel; Stamp, Lisa K; Dalbeth, Nicola; Sakurai, Yutaka; Suzuki, Hiroshi; Hosoyamada, Makoto; Fujimori, Shin; Yokoo, Takashi; Hosoya, Tatsuo; Inoue, Ituro; Takahashi, Atsushi; Kubo, Michiaki; Ooyama, Hiroshi; Shimizu, Toru; Ichida, Kimiyoshi; Shinomiya, Nariyoshi; Merriman, Tony R; Matsuo, Hirotaka

    2017-05-01

    A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (pgout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10-8). Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  18. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

    Science.gov (United States)

    Nakayama, Akiyoshi; Nakaoka, Hirofumi; Yamamoto, Ken; Sakiyama, Masayuki; Shaukat, Amara; Toyoda, Yu; Okada, Yukinori; Kamatani, Yoichiro; Nakamura, Takahiro; Takada, Tappei; Inoue, Katsuhisa; Yasujima, Tomoya; Yuasa, Hiroaki; Shirahama, Yuko; Nakashima, Hiroshi; Shimizu, Seiko; Higashino, Toshihide; Kawamura, Yusuke; Ogata, Hiraku; Kawaguchi, Makoto; Ohkawa, Yasuyuki; Danjoh, Inaho; Tokumasu, Atsumi; Ooyama, Keiko; Ito, Toshimitsu; Kondo, Takaaki; Wakai, Kenji; Stiburkova, Blanka; Pavelka, Karel; Stamp, Lisa K; Dalbeth, Nicola; Sakurai, Yutaka; Suzuki, Hiroshi; Hosoyamada, Makoto; Fujimori, Shin; Yokoo, Takashi; Hosoya, Tatsuo; Inoue, Ituro; Takahashi, Atsushi; Kubo, Michiaki; Ooyama, Hiroshi; Shimizu, Toru; Ichida, Kimiyoshi; Shinomiya, Nariyoshi; Merriman, Tony R; Matsuo, Hirotaka

    2017-01-01

    Objective A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. Methods Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. Results In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (pgout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (pmeta=3.58×10−8). Conclusions Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia. PMID:27899376

  19. Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

    OpenAIRE

    Kuchenbaecker, Karoline B; Ramus, Susan J.; Tyrer, Jonathan; Lee, Andrew; Shen, Howard C; Beesley, Jonathan; Lawrenson, Kate; McGuffog, Lesley; Healey, Sue; Janet M Lee; Spindler, Tassja J.; Lin, Yvonne G.; Pejovic, Tanja; Bean, Yukie; Li, Qiyuan

    2015-01-01

    This is the Author Accepted Manuscript of 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer' which was published in Nature Genetics 47, 164–171 (2015) © Nature Publishing Group - content may only be used for academic research. Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of ...

  20. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

    Science.gov (United States)

    McKay, James D; Hung, Rayjean J; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C; Caporaso, Neil E; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A; Qian, David C; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N; Bojesen, Stig E; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C; Bush, William S; Tardon, Adonina; Rennert, Gad; Teare, M Dawn; Field, John K; Kiemeney, Lambertus A; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B; Andrew, Angeline S; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A; Wilkens, Lynne R; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F M; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael P A; Marcus, Michael W; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A; Barnett, Matt P; Chen, Chu; Goodman, Gary E; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H-Erich; Manz, Judith; Muley, Thomas R; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A; Tsao, Ming-Sound; Arnold, Susanne M; Haura, Eric B; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J; Butler, Lesley M; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S; McLaughlin, John; Stevens, Victoria L; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C; Obeidat, Ma'en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D; Wain, Louise V; Rafnar, Thorunn; Thorgeirsson, Thorgeir E; Reginsson, Gunnar W; Stefansson, Kari; Hancock, Dana B; Bierut, Laura J; Spitz, Margaret R; Gaddis, Nathan C; Lutz, Sharon M; Gu, Fangyi; Johnson, Eric O; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I

    2017-07-01

    Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

  1. The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility.

    Science.gov (United States)

    Castaldi, Peter J; Cho, Michael H; Litonjua, Augusto A; Bakke, Per; Gulsvik, Amund; Lomas, David A; Anderson, Wayne; Beaty, Terri H; Hokanson, John E; Crapo, James D; Laird, Nan; Silverman, Edwin K

    2011-12-01

    Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV(1) and FEV(1)/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. Thirty-two single-nucleotide polymorphisms (SNPs) in or near 17 genes in 11 previously identified GWS spirometric genomic regions were tested for association with COPD status in four COPD case-control study samples (NETT/NAS, the Norway case-control study, ECLIPSE, and the first 1,000 subjects in COPDGene; total sample size, 3,456 cases and 1,906 controls). In addition to testing the 32 spirometric GWS SNPs, we tested a dense panel of imputed HapMap2 SNP markers from the 17 genes located near the 32 GWS SNPs and in a set of 21 well studied COPD candidate genes. Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate.

  2. Further evidence of subphenotype association with systemic lupus erythematosus susceptibility loci: a European cases only study.

    Directory of Open Access Journals (Sweden)

    Elisa Alonso-Perez

    Full Text Available INTRODUCTION: Systemic Lupus Erythematosus (SLE shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question. METHODS: European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR classification criteria (except ANAs and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication. RESULTS: THERE WERE THREE NEW ASSOCIATIONS: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR=0.76 and 1.30, P(corr =0.007 and 0.03, respectively and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci. CONCLUSION: Some of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component.

  3. Further Evidence of Subphenotype Association with Systemic Lupus Erythematosus Susceptibility Loci: A European Cases Only Study

    Science.gov (United States)

    Alonso-Perez, Elisa; Suarez-Gestal, Marian; Calaza, Manuel; Ordi-Ros, Josep; Balada, Eva; Bijl, Marc; Papasteriades, Chryssa; Carreira, Patricia; Skopouli, Fotini N.; Witte, Torsten; Endreffy, Emöke; Marchini, Maurizio; Migliaresi, Sergio; Sebastiani, Gian Domenico; Santos, Maria Jose; Suarez, Ana; Blanco, Francisco J.; Barizzone, Nadia; Pullmann, Rudolf; Ruzickova, Sarka; Lauwerys, Bernard R.; Gomez-Reino, Juan J.; Gonzalez, Antonio

    2012-01-01

    Introduction Systemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question. Methods European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication. Results There were three new associations: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR = 0.76 and 1.30, Pcorr = 0.007 and 0.03, respectively) and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci. Conclusion Some of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component. PMID:23049788

  4. Genome-wide association study identifies novel breast cancer susceptibility loci

    Science.gov (United States)

    Easton, Douglas F.; Pooley, Karen A.; Dunning, Alison M.; Pharoah, Paul D. P.; Thompson, Deborah; Ballinger, Dennis G.; Struewing, Jeffery P.; Morrison, Jonathan; Field, Helen; Luben, Robert; Wareham, Nicholas; Ahmed, Shahana; Healey, Catherine S.; Bowman, Richard; Meyer, Kerstin B.; Haiman, Christopher A.; Kolonel, Laurence K.; Henderson, Brian E.; Marchand, Loic Le; Brennan, Paul; Sangrajrang, Suleeporn; Gaborieau, Valerie; Odefrey, Fabrice; Shen, Chen-Yang; Wu, Pei-Ei; Wang, Hui-Chun; Eccles, Diana; Evans, D. Gareth; Peto, Julian; Fletcher, Olivia; Johnson, Nichola; Seal, Sheila; Stratton, Michael R.; Rahman, Nazneen; Chenevix-Trench, Georgia; Bojesen, Stig E.; Nordestgaard, Børge G.; Axelsson, Christen K.; Garcia-Closas, Montserrat; Brinton, Louise; Chanock, Stephen; Lissowska, Jolanta; Peplonska, Beata; Nevanlinna, Heli; Fagerholm, Rainer; Eerola, Hannaleena; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Ahn, Sei-Hyun; Hunter, David J.; Hankinson, Susan E.; Cox, David G.; Hall, Per; Wedren, Sara; Liu, Jianjun; Low, Yen-Ling; Bogdanova, Natalia; Schürmann, Peter; Dörk, Thilo; Tollenaar, Rob A. E. M.; Jacobi, Catharina E.; Devilee, Peter; Klijn, Jan G. M.; Sigurdson, Alice J.; Doody, Michele M.; Alexander, Bruce H.; Zhang, Jinghui; Cox, Angela; Brock, Ian W.; MacPherson, Gordon; Reed, Malcolm W. R.; Couch, Fergus J.; Goode, Ellen L.; Olson, Janet E.; Meijers-Heijboer, Hanne; van den Ouweland, Ans; Uitterlinden, André; Rivadeneira, Fernando; Milne, Roger L.; Ribas, Gloria; Gonzalez-Neira, Anna; Benitez, Javier; Hopper, John L.; McCredie, Margaret; Southey, Melissa; Giles, Graham G.; Schroen, Chris; Justenhoven, Christina; Brauch, Hiltrud; Hamann, Ute; Ko, Yon-Dschun; Spurdle, Amanda B.; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana; Day, Nicholas E.; Cox, David R.; Ponder, Bruce A. J.; Luccarini, Craig; Conroy, Don; Shah, Mitul; Munday, Hannah; Jordan, Clare; Perkins, Barbara; West, Judy; Redman, Karen; Driver, Kristy; Aghmesheh, Morteza; Amor, David; Andrews, Lesley; Antill, Yoland; Armes, Jane; Armitage, Shane; Arnold, Leanne; Balleine, Rosemary; Begley, Glenn; Beilby, John; Bennett, Ian; Bennett, Barbara; Berry, Geoffrey; Blackburn, Anneke; Brennan, Meagan; Brown, Melissa; Buckley, Michael; Burke, Jo; Butow, Phyllis; Byron, Keith; Callen, David; Campbell, Ian; Chenevix-Trench, Georgia; Clarke, Christine; Colley, Alison; Cotton, Dick; Cui, Jisheng; Culling, Bronwyn; Cummings, Margaret; Dawson, Sarah-Jane; Dixon, Joanne; Dobrovic, Alexander; Dudding, Tracy; Edkins, Ted; Eisenbruch, Maurice; Farshid, Gelareh; Fawcett, Susan; Field, Michael; Firgaira, Frank; Fleming, Jean; Forbes, John; Friedlander, Michael; Gaff, Clara; Gardner, Mac; Gattas, Mike; George, Peter; Giles, Graham; Gill, Grantley; Goldblatt, Jack; Greening, Sian; Grist, Scott; Haan, Eric; Harris, Marion; Hart, Stewart; Hayward, Nick; Hopper, John; Humphrey, Evelyn; Jenkins, Mark; Jones, Alison; Kefford, Rick; Kirk, Judy; Kollias, James; Kovalenko, Sergey; Lakhani, Sunil; Leary, Jennifer; Lim, Jacqueline; Lindeman, Geoff; Lipton, Lara; Lobb, Liz; Maclurcan, Mariette; Mann, Graham; Marsh, Deborah; McCredie, Margaret; McKay, Michael; McLachlan, Sue Anne; Meiser, Bettina; Milne, Roger; Mitchell, Gillian; Newman, Beth; O'Loughlin, Imelda; Osborne, Richard; Peters, Lester; Phillips, Kelly; Price, Melanie; Reeve, Jeanne; Reeve, Tony; Richards, Robert; Rinehart, Gina; Robinson, Bridget; Rudzki, Barney; Salisbury, Elizabeth; Sambrook, Joe; Saunders, Christobel; Scott, Clare; Scott, Elizabeth; Scott, Rodney; Seshadri, Ram; Shelling, Andrew; Southey, Melissa; Spurdle, Amanda; Suthers, Graeme; Taylor, Donna; Tennant, Christopher; Thorne, Heather; Townshend, Sharron; Tucker, Kathy; Tyler, Janet; Venter, Deon; Visvader, Jane; Walpole, Ian; Ward, Robin; Waring, Paul; Warner, Bev; Warren, Graham; Watson, Elizabeth; Williams, Rachael; Wilson, Judy; Winship, Ingrid; Young, Mary Ann; Bowtell, David; Green, Adele; deFazio, Anna; Chenevix-Trench, Georgia; Gertig, Dorota; Webb, Penny

    2009-01-01

    Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2>0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P<10−7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P<0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. PMID:17529967

  5. A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci.

    Directory of Open Access Journals (Sweden)

    Eimear E Kenny

    Full Text Available Crohn's disease (CD is a complex disorder resulting from the interaction of intestinal microbiota with the host immune system in genetically susceptible individuals. The largest meta-analysis of genome-wide association to date identified 71 CD-susceptibility loci in individuals of European ancestry. An important epidemiological feature of CD is that it is 2-4 times more prevalent among individuals of Ashkenazi Jewish (AJ descent compared to non-Jewish Europeans (NJ. To explore genetic variation associated with CD in AJs, we conducted a genome-wide association study (GWAS by combining raw genotype data across 10 AJ cohorts consisting of 907 cases and 2,345 controls in the discovery stage, followed up by a replication study in 971 cases and 2,124 controls. We confirmed genome-wide significant associations of 9 known CD loci in AJs and replicated 3 additional loci with strong signal (p<5×10⁻⁶. Novel signals detected among AJs were mapped to chromosomes 5q21.1 (rs7705924, combined p = 2×10⁻⁸; combined odds ratio OR = 1.48, 2p15 (rs6545946, p = 7×10⁻⁹; OR = 1.16, 8q21.11 (rs12677663, p = 2×10⁻⁸; OR = 1.15, 10q26.3 (rs10734105, p = 3×10⁻⁸; OR = 1.27, and 11q12.1 (rs11229030, p = 8×10⁻⁹; OR = 1.15, implicating biologically plausible candidate genes, including RPL7, CPAMD8, PRG2, and PRG3. In all, the 16 replicated and newly discovered loci, in addition to the three coding NOD2 variants, accounted for 11.2% of the total genetic variance for CD risk in the AJ population. This study demonstrates the complementary value of genetic studies in the Ashkenazim.

  6. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

    DEFF Research Database (Denmark)

    McKay, James D; Hung, Rayjean J; Han, Younghun

    2017-01-01

    Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association ...

  7. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

    NARCIS (Netherlands)

    Mckay, James D.; Hung, Rayjean J; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C.; Caporaso, Neil E.; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A.; Qian, David C.; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N.; Bojesen, Stig E.; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeboeller, Heike; Aldrich, Melinda C.; Bush, William S.; Tardon, Adonina; Rennert, Gad; Teare, M. Dawn; Field, John K.; Kiemeney, Lambertus A.; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B.; Andrew, Angeline S.; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C.; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S.; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A.; Wilkens, Lynne R.; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F. M.; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael P. A.; Marcus, Michael W.; Brunnstrom, Hans; Manjer, Jonas; Melander, Olle; Muller, David C.; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A.; Barnett, Matt P.; Chen, Chu; Goodman, Gary E.; Cox, Angela; Taylor, Fiona; Woll, Penella J.; Brueske, Irene; Wichmann, H. -Erich; Manz, Judith; Muley, Thomas R.; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A.; Tsao, Ming Sound; Arnold, Susanne M.; Haura, Eric B.; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M.; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J.; Butler, Lesley M.; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S.; McLaughlin, John; Stevens, Victoria L.; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C.; Obeidat, Ma'en; Timens, Wim; Zhu, BL; Song, Lei; Kachuri, Linda; Artigas, Maria Soler; Tobin, Martin D.; Wain, Louise V.; Rafnar, Thorunn; Thorgeirsson, Thorgeir E.; Reginsson, Gunnar W.; Stefansson, Kari; Hancock, Dana B.; Bierut, Laura J.; Spitz, Margaret R.; Gaddis, Nathan C.; Lutz, Sharon M.; Gu, Fangyi; Johnson, Eric O.; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindstroem, Sara; Jiang, Xia; Tyndale, Rachel F.; Chenevix-Trench, Georgia; Beesley, Jonathan; Bosse, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I.

    Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association

  8. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array

    Science.gov (United States)

    Eeles, Rosalind A; Olama, Ali Amin Al; Benlloch, Sara; Saunders, Edward J; Leongamornlert, Daniel A; Tymrakiewicz, Malgorzata; Ghoussaini, Maya; Luccarini, Craig; Dennis, Joe; Jugurnauth-Little, Sarah; Dadaev, Tokhir; Neal, David E; Hamdy, Freddie C; Donovan, Jenny L; Muir, Ken; Giles, Graham G; Severi, Gianluca; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A; Schumacher, Fredrick; Henderson, Brian; Le Marchand, Loic; Lindstrom, Sara; Kraft, Peter; Hunter, David J; Gapstur, Susan; Chanock, Stephen J; Berndt, Sonja I; Albanes, Demetrius; Andriole, Gerald; Schleutker, Johanna; Weischer, Maren; Canzian, Federico; Riboli, Elio; Key, Tim J; Travis, Ruth; Campa, Daniele; Ingles, Sue A; John, Esther M; Hayes, Richard B; Pharoah, Paul DP; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet; Ostrander, Elaine A; Signorello, Lisa B; Thibodeau, Stephen N; Schaid, Dan; Maier, Christiane; Vogel, Walther; Kibel, Adam S; Cybulski, Cezary; Lubinski, Jan; Cannon-Albright; Brenner, Hermann; Park, Jong Y; Kaneva, Radka; Batra, Jyotsna; Spurdle, Amanda B; Clements, Judith A; Teixeira, Manuel R; Dicks, Ed; Lee, Andrew; Dunning, Alison; Baynes, Caroline; Conroy, Don; Maranian, Melanie J; Ahmed, Shahana; Govindasami, Koveela; Guy, Michelle; Wilkinson, Rosemary A; Sawyer, Emma J; Morgan, Angela; Dearnaley, David P; Horwich, Alan; Huddart, Robert A; Khoo, Vincent S; Parker, Christopher C; Van As, Nicholas J; Woodhouse, J; Thompson, Alan; Dudderidge, Tim; Ogden, Chris; Cooper, Colin; Lophatananon, Artitaya; Cox, Angela; Southey, Melissa; Hopper, John L; English, Dallas R; Aly, Markus; Adolfsson, Jan; Xu, Jiangfeng; Zheng, Siqun; Yeager, Meredith; Kaaks, Rudolf; Diver, W Ryan; Gaudet, Mia M; Stern, Mariana; Corral, Roman; Joshi, Amit D; Shahabi, Ahva; Wahlfors, Tiina; Tammela, Teuvo J; Auvinen, Anssi; Virtamo, Jarmo; Klarskov, Peter; Nordestgaard, Børge G; Røder, Andreas; Nielsen, Sune F; Bojesen, Stig E; Siddiq, Afshan; FitzGerald, Liesel; Kolb, Suzanne; Kwon, Erika; Karyadi, Danielle; Blot, William J; Zheng, Wei; Cai, Qiuyin; McDonnell, Shannon K; Rinckleb, Antje; Drake, Bettina; Colditz, Graham; Wokolorczyk, Dominika; Stephenson, Robert A; Teerlink, Craig; Muller, Heiko; Rothenbacher, Dietrich; Sellers, Thomas A; Lin, Hui-Yi; Slavov, Chavdar; Mitev, Vanio; Lose, Felicity; Srinivasan, Srilakshmi; Maia, Sofia; Paulo, Paula; Lange, Ethan; Cooney, Kathleen A; Antoniou, Antonis; Vincent, Daniel; Bacot, François; Tessier; Kote-Jarai, Zsofia; Easton, Douglas F

    2013-01-01

    Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining ~30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies. PMID:23535732

  9. Evaluation of 19 susceptibility loci of breast cancer in women of African ancestry.

    Science.gov (United States)

    Huo, Dezheng; Zheng, Yonglan; Ogundiran, Temidayo O; Adebamowo, Clement; Nathanson, Katherine L; Domchek, Susan M; Rebbeck, Timothy R; Simon, Michael S; John, Esther M; Hennis, Anselm; Nemesure, Barbara; Wu, Suh-Yuh; Leske, M Cristina; Ambs, Stefan; Niu, Qun; Zhang, Jing; Cox, Nancy J; Olopade, Olufunmilayo I

    2012-04-01

    Multiple breast cancer susceptibility loci have been identified in genome-wide association studies (GWAS) in populations of European and Asian ancestry using array chips optimized for populations of European ancestry. It is important to examine whether these loci are associated with breast cancer risk in women of African ancestry. We evaluated 25 single nucleotide polymorphisms (SNPs) at 19 loci in a pooled case-control study of breast cancer, which included 1509 cases and 1383 controls. Cases and controls were enrolled in Nigeria, Barbados and the USA; all women were of African ancestry. We found significant associations for three SNPs, which were in the same direction and of similar magnitude as those reported in previous fine-mapping studies in women of African ancestry. The allelic odds ratios were 1.24 [95% confidence interval (CI): 1.04-1.47; P = 0.018] for the rs2981578-G allele (10q26/FGFR2), 1.34 (95% CI: 1.10-1.63; P = 0.0035) for the rs9397435-G allele (6q25) and 1.12 (95% CI: 1.00-1.25; P = 0.04) for the rs3104793-C allele (16q12). Although a significant association was observed for an additional index SNP (rs3817198), it was in the opposite direction to prior GWAS studies. In conclusion, this study highlights the complexity of applying current GWAS findings across racial/ethnic groups, as none of GWAS-identified index SNPs could be replicated in women of African ancestry. Further fine-mapping studies in women of African ancestry will be needed to reveal additional and causal variants for breast cancer.

  10. Six Novel Susceptibility Loci for Early-Onset Androgenetic Alopecia and Their Unexpected Association with Common Diseases

    Science.gov (United States)

    Glass, Daniel; Medland, Sarah E.; Dimitriou, Maria; Waterworth, Dawn; Tung, Joyce Y.; Geller, Frank; Heilmann, Stefanie; Hillmer, Axel M.; Bataille, Veronique; Eigelshoven, Sibylle; Hanneken, Sandra; Moebus, Susanne; Herold, Christine; den Heijer, Martin; Montgomery, Grant W.; Deloukas, Panos; Eriksson, Nicholas; Heath, Andrew C.; Becker, Tim; Sulem, Patrick; Mangino, Massimo; Vollenweider, Peter; Spector, Tim D.; Dedoussis, George; Martin, Nicholas G.; Kiemeney, Lambertus A.; Mooser, Vincent; Stefansson, Kari; Hinds, David A.; Nöthen, Markus M.; Richards, J. Brent

    2012-01-01

    Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10−9–1.01×10−12). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06–1.55, p = 8.9×10−3). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10−88]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions. PMID:22693459

  11. Genome-wide association study identifies multiple susceptibility loci for glioma

    Science.gov (United States)

    Kinnersley, Ben; Labussière, Marianne; Holroyd, Amy; Di Stefano, Anna-Luisa; Broderick, Peter; Vijayakrishnan, Jayaram; Mokhtari, Karima; Delattre, Jean-Yves; Gousias, Konstantinos; Schramm, Johannes; Schoemaker, Minouk J.; Fleming, Sarah J.; Herms, Stefan; Heilmann, Stefanie; Schreiber, Stefan; Wichmann, Heinz-Erich; Nöthen, Markus M.; Swerdlow, Anthony; Lathrop, Mark; Simon, Matthias; Bondy, Melissa; Sanson, Marc; Houlston, Richard S.

    2015-01-01

    Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10−9) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10−8), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10−11), 12q21.2 (rs12230172, P=7.53 × 10−11) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10−9). Our findings provide further insights into the genetic basis of the different glioma subtypes. PMID:26424050

  12. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24

    DEFF Research Database (Denmark)

    Goode, Ellen L; Chenevix-Trench, Georgia; Song, Honglin

    2010-01-01

    Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow...... 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P ≤ 5 × 10⁻⁸ (8q24, P = 8.0 × 10⁻¹⁵ and 2q31, P = 3.8 × 10⁻¹⁴) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10⁻⁸ and 17q21, P = 1.4 × 10⁻⁷). The associations of these loci...... with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development....

  13. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24

    DEFF Research Database (Denmark)

    Goode, Ellen L; Chenevix-Trench, Georgia; Song, Honglin

    2010-01-01

    Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow...... 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P = 5 × 10¿8 (8q24, P = 8.0 × 10¿¹5 and 2q31, P = 3.8 × 10¿¹4) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10¿8 and 17q21, P = 1.4 × 10¿7). The associations of these loci...... with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development....

  14. Identification of six new susceptibility loci for invasive epithelial ovarian cancer

    NARCIS (Netherlands)

    K.B. Kuchenbaecker (Karoline); S.J. Ramus (Susan); J.P. Tyrer (Jonathan); A. Lee (Andrew); H.C. Shen (Howard C.); J. Beesley (Jonathan); K. Lawrenson (Kate); L. McGuffog (Lesley); S. Healey (Sue); J.M. Lee (Janet M.); T.J. Spindler (Tassja J.); Y.G. Lin (Yvonne G.); T. Pejovic (Tanja); Y. Bean (Yukie); Q. Li (Qiyuan); S. Coetzee (Simon); D. Hazelett (Dennis); A. Miron (Alexander); M.C. Southey (Melissa); M.B. Terry (Mary Beth); D. Goldgar (David); S.S. Buys (Saundra); R. Janavicius (Ramunas); C.M. Dorfling (Cecilia); E.J. van Rensburg (Elizabeth); S.L. Neuhausen (Susan); Y.C. Ding (Yuan); T.V.O. Hansen (Thomas); L. Jønson (Lars); A.-M. Gerdes (Anne-Marie); B. Ejlertsen (Bent); D. Barrowdale (Daniel); J. Dennis (Joe); J. Benítez (Javier); A. Osorio (Ana); M.J. Garcia (Maria Jose); I. Komenaka (Ian); J.N. Weitzel (Jeffrey); P. Ganschow (Pamela); P. Peterlongo (Paolo); L. Bernard (Loris); A. Viel (Alessandra); B. Bonnani (Bernardo); B. Peissel (Bernard); S. Manoukian (Siranoush); P. Radice (Paolo); L. Papi (Laura); L. Ottini (Laura); F. Fostira (Florentia); I. Konstantopoulou (I.); J. Garber (Judy); D. Frost (Debra); J. Perkins (Jo); R. Platte (Radka); S.D. Ellis (Steve); A.K. Godwin (Andrew K.); R.K. Schmutzler (Rita); A. Meindl (Alfons); C. Engel (Christoph); C. Sutter (Christian); O. Sinilnikova (Olga); F. Damiola (Francesca); S. Mazoyer (Sylvie); D. Stoppa-Lyonnet (Dominique); K.B.M. Claes (Kathleen B.M.); K. De Leeneer (Kim); J. Kirk (Judy); G. Rodriguez (Gustavo); M. Piedmonte (Marion); D.M. O'Malley (David M.); M. de La Hoya (Miguel); T. Caldes (Trinidad); K. Aittomäki (Kristiina); H. Nevanlinna (Heli); J.C. Margriet (J. Collée); M.A. Rookus (Matti); J.C. Oosterwijk (Jan); L. Tihomirova (Laima); N. Tung (Nadine); U. Hamann (Ute); C. Isaccs (Claudine); M. Tischkowitz (Marc); E.N. Imyanitov (Evgeny); M.A. Caligo (Maria); I. Campbell (Ian); F.B.L. Hogervorst (Frans); E. Olah; O. Díez (Orland); I. Blanco (Ignacio); J. Brunet (Joan); C. Lazaro (Conxi); M.A. Pujana (Miguel); A. Jakubowska (Anna); J. Gronwald (Jacek); J. Lubinski (Jan); G. Sukiennicki (Grzegorz); R.B. Barkardottir (Rosa); M. Plante (Marie); J. Simard (Jacques); P. Soucy (Penny); M. Montagna (Marco); S. Tognazzo (Silvia); P.J. Teixeira; V.S. Pankratz (Shane); X. Wang (Xianshu); N.M. Lindor (Noralane); C. Szabo (Csilla); N. Kauff (Noah); J. Vijai (Joseph); C.A. Aghajanian (Carol A.); G. Pfeiler (Georg); A. Berger (Andreas); C.F. Singer (Christian); M.-K. Tea; C. Phelan (Catherine); M.H. Greene (Mark H.); P.L. Mai (Phuong); G. Rennert (Gad); A.-M. Mulligan (Anna-Marie); S. Tchatchou (Sandrine); I.L. Andrulis (Irene); G. Glendon (Gord); A.E. Toland (Amanda); U.B. Jensen (Uffe Birk); T.A. Kruse (Torben); M. Thomassen (Mads); A. Bojesen (Anders); J. Zidan (Jamal); E. Friedman (Eitan); Y. Laitman (Yael); M. Soller (Maria); A. Liljegren (Annelie); B. Arver (Brita Wasteson); Z. Einbeigi (Zakaria); M. Stenmark-Askmalm (Marie); O.I. Olopade (Olufunmilayo I.); R.L. Nussbaum (Robert L.); T.R. Rebbeck (Timothy R.); K.L. Nathanson (Katherine); S.M. Domchek (Susan); K.H. Lu (Karen); B.Y. Karlan (Beth Y.); C. Walsh (Christine); K.J. Lester (Kathryn); R. Hein (Rebecca); A.B. Ekici (Arif); M.W. Beckmann (Matthias W.); P.A. Fasching (Peter); D. Lambrechts (Diether); E. Van Nieuwenhuysen (Els); I. Vergote (Ignace); S. Lambrechts (Sandrina); E. Dicks (Ed); J.A. Doherty (Jennifer A.); K.G. Wicklund (Kristine G.); M.A. Rossing (Mary Anne); A. Rudolph (Anja); J. Chang-Claude (Jenny); S. Wang-Gohrke (Shan); U. Eilber (Ursula); K.B. Moysich (Kirsten B.); K. Odunsi (Kunle); L. Sucheston (Lara); S. Lele (Shashi); L. Wilkens (Lynne); M.T. Goodman (Marc); P.J. Thompson (Pamela J.); Y.B. Shvetsov (Yurii B.); I.B. Runnebaum (Ingo); M. Dürst (Matthias); P. Hillemanns (Peter); T. Dörk (Thilo); N.N. Antonenkova (Natalia); N.V. Bogdanova (Natalia); A. Leminen (Arto); L.M. Pelttari (Liisa); R. Butzow (Ralf); F. Modugno (Francesmary); J.L. Kelley (Joseph L.); R. Edwards (Robert); R.B. Ness (Roberta); A. Du Bois (Andreas); P.U. Heitz; I. Schwaab (Ira); P. Harter (Philipp); K. Matsuo (Keitaro); N. Hosono (Naoya); S. Orsulic (Sandra); A. Jensen (Allan); M. Kjaer (Michael); E. Høgdall (Estrid); H.N. Hasmad (Hanis Nazihah); M.A. Noor Azmi (Mat Adenan); S.-H. Teo; Y.L. Woo (Yin Ling); B.L. Fridley (Brooke); E.L. Goode (Ellen); J.M. Cunningham (Julie); R.A. Vierkant (Robert); F. Bruinsma (Fiona); G.G. Giles (Graham G.); D. Liang (Dong); M.A.T. Hildebrandt (Michelle A.T.); X. Wu (Xifeng); D.A. Levine (Douglas); M. Bisogna (Maria); A. Berchuck (Andrew); E. Iversen (Erik); J.M. Schildkraut (Joellen); P. Concannon (Patrick); R.P. Weber (Rachel Palmieri); D.W. Cramer (Daniel); K.L. Terry (Kathryn); E.M. Poole (Elizabeth); S. Tworoger (Shelley); E.V. Bandera (Elisa); I. Orlow (Irene); S.H. Olson (Sara); C. Krakstad (Camilla); H.B. Salvesen (Helga); I.L. Tangen (Ingvild L.); L. Bjorge (Line); A.M. van Altena (Anne); K.K.H. Aben (Katja); L.A.L.M. Kiemeney (Bart); L.F. Massuger (Leon); M. Kellar (Melissa); A. Brooks-Wilson (Angela); L.E. Kelemen (Linda); L.S. Cook (Linda S.); N.D. Le (Nhu D.); C. Cybulski (Cezary); H. Yang (Hannah); J. Lissowska (Jolanta); L.A. Brinton (Louise); N. Wentzensen (N.); C.K. Høgdall (Claus); L. Lundvall (Lene); L. Nedergaard (Lotte); H. Baker (Helen); H. Song (Honglin); D. Eccles (Diana); I. McNeish (Ian); J. Paul (James); K. Carty (Karen); N. Siddiqui (Nadeem); R. Glasspool (Rosalind); A.S. Whittemore (Alice S.); J.H. Rothstein (Joseph H.); W.P. McGuire; W. Sieh (Weiva); B.-T. Ji (Bu-Tian); W. Zheng (Wei); X.-O. Shu (Xiao-Ou); Y. Gao; B. Rosen (Barry); H. Risch (Harvey); J. McLaughlin (John); S.A. Narod (Steven A.); A.N.A. Monteiro (Alvaro N.); A. Chen (Ann); H.-Y. Lin (Hui-Yi); J. Permuth-Wey (Jenny); T.F. Sellers; Y.-Y. Tsai (Ya-Yu); Z. Chen (Zhihua); A. Ziogas (Argyrios); H. Anton-Culver (Hoda); A. Gentry-Maharaj (Aleksandra); U. Menon (Usha); P. harrington (Patricia); A.W. Lee (Alice W.); A.H. Wu (Anna H.); C.L. Pearce (Celeste); G. Coetzee (Gerry); M.C. Pike (Malcolm C.); A. Dansonka-Mieszkowska (Agnieszka); A. Timorek (Agnieszka); I.K. Rzepecka (Iwona); J. Kupryjanczyk (Jolanta); M. Freedman (Matthew); H. Noushmehr (Houtan); D.F. Easton (Douglas F.); K. Offit (Kenneth); F.J. Couch (Fergus); S.A. Gayther (Simon); P.P.D.P. Pharoah (Paul P.D.P.); A.C. Antoniou (Antonis C.); G. Chenevix-Trench (Georgia)

    2015-01-01

    textabstractGenome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we

  15. Genome-wide association analysis identifies three new breast cancer susceptibility loci

    NARCIS (Netherlands)

    Ghoussaini, Maya; Fletcher, Olivia; Michailidou, Kyriaki; Turnbull, Clare; Schmidt, Marjanka K.; Dicks, Ed; Dennis, Joe; Wang, Qin; Humphreys, Manjeet K.; Luccarini, Craig; Baynes, Caroline; Conroy, Don; Maranian, Melanie; Ahmed, Shahana; Driver, Kristy; Johnson, Nichola; Orr, Nicholas; dos Santos Silva, Isabel; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Uitterlinden, Andre G.; Rivadeneira, Fernando; Hall, Per; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Nevanlinna, Heli; Aittomäki, Kristiina; Blomqvist, Carl; Meindl, Alfons; Schmutzler, Rita K.; Müller-Myhsok, Bertram; Lichtner, Peter; Chang-Claude, Jenny; Hein, Rebecca; Nickels, Stefan; Flesch-Janys, Dieter; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Hopper, John L.; Apicella, Carmel; Park, Daniel J.; Southey, Melissa; Hunter, David J.; Chanock, Stephen J.; Broeks, Annegien; Verhoef, Senno; Hogervorst, Frans B. L.; Fasching, Peter A.; Lux, Michael P.; Beckmann, Matthias W.; Ekici, Arif B.; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Guénel, Pascal; Truong, Thérèse; Cordina-Duverger, Emilie; Menegaux, Florence; Bojesen, Stig E.; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Milne, Roger L.; Alonso, M. Rosario; González-Neira, Anna; Benítez, Javier; Anton-Culver, Hoda; Ziogas, Argyrios; Bernstein, Leslie; Dur, Christina Clarke; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Justenhoven, Christina; Brauch, Hiltrud; Brüning, Thomas; Wang-Gohrke, Shan; Eilber, Ursula; Dörk, Thilo; Schürmann, Peter; Bremer, Michael; Hillemanns, Peter; Bogdanova, Natalia V.; Antonenkova, Natalia N.; Rogov, Yuri I.; Karstens, Johann H.; Bermisheva, Marina; Prokofieva, Darya; Khusnutdinova, Elza; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Lambrechts, Diether; Yesilyurt, Betul T.; Floris, Giuseppe; Leunen, Karin; Manoukian, Siranoush; Bonanni, Bernardo; Fortuzzi, Stefano; Peterlongo, Paolo; Couch, Fergus J.; Wang, Xianshu; Stevens, Kristen; Lee, Adam; Giles, Graham G.; Baglietto, Laura; Severi, Gianluca; McLean, Catriona; Alnaes, Grethe Grenaker; Kristensen, Vessela; Børrensen-Dale, Anne-Lise; John, Esther M.; Miron, Alexander; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L.; Glendon, Gord; Mulligan, Anna Marie; Devilee, Peter; van Asperen, Christie J.; Tollenaar, Rob A. E. M.; Seynaeve, Caroline; Figueroa, Jonine D.; Garcia-Closas, Montserrat; Brinton, Louise; Lissowska, Jolanta; Hooning, Maartje J.; Hollestelle, Antoinette; Oldenburg, Rogier A.; van den Ouweland, Ans M. W.; Cox, Angela; Reed, Malcolm W. R.; Shah, Mitul; Jakubowska, Ania; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Jones, Michael; Schoemaker, Minouk; Ashworth, Alan; Swerdlow, Anthony; Beesley, Jonathan; Chen, Xiaoqing; Muir, Kenneth R.; Lophatananon, Artitaya; Rattanamongkongul, Suthee; Chaiwerawattana, Arkom; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Shen, Chen-Yang; Yu, Jyh-Cherng; Wu, Pei-Ei; Hsiung, Chia-Ni; Perkins, Annie; Swann, Ruth; Velentzis, Louiza; Eccles, Diana M.; Tapper, Will J.; Gerty, Susan M.; Graham, Nikki J.; Ponder, Bruce A. J.; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Lathrop, Mark; Dunning, Alison M.; Rahman, Nazneen; Peto, Julian; Easton, Douglas F.

    2012-01-01

    Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for similar to 8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies

  16. Identification of six new susceptibility loci for invasive epithelial ovarian cancer

    NARCIS (Netherlands)

    Kuchenbaecker, Karoline B.; Ramus, Susan J.; Tyrer, Jonathan; Lee, Andrew; Shen, Howard C.; Beesley, Jonathan; Lawrenson, Kate; McGuffog, Lesley; Healey, Sue; Lee, Janet M.; Spindler, Tassja J.; Lin, Yvonne G.; Pejovic, Tanja; Bean, Yukie; Li, Qiyuan; Coetzee, Simon; Hazelett, Dennis; Miron, Alexander; Southey, Melissa; Terry, Mary Beth; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Neuhausen, Susan L.; Ding, Yuan Chun; Hansen, Thomas V. O.; Jonson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; Barrowdale, Daniel; Dennis, Joe; Benitez, Javier; Osorio, Ana; Garcia, Maria Jose; Komenaka, Ian; Weitzel, Jeffrey N.; Ganschow, Pamela; Peterlongo, Paolo; Bernard, Loris; Viel, Alessandra; Bonanni, Bernardo; Peissel, Bernard; Manoukian, Siranoush; Radice, Paolo; Papi, Laura; Ottini, Laura; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Frost, Debra; Perkins, Jo; Platte, Radka; Ellis, Steve; Godwin, Andrew K.; Schmutzler, Rita Katharina; Meindl, Alfons; Engel, Christoph; Sutter, Christian; Sinilnikova, Olga M.; Damiola, Francesca; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Claes, Kathleen; De Leeneer, Kim; Kirk, Judy; Rodriguez, Gustavo C.; Piedmonte, Marion; O'Malley, David M.; de la Hoya, Miguel; Caldes, Trinidad; Aittomaeki, Kristiina; Nevanlinna, Heli; Collee, J. Margriet; Rookus, Matti A.; Oosterwijk, Jan C.; Tihomirova, Laima; Tung, Nadine; Hamann, Ute; Isaccs, Claudine; Tischkowitz, Marc; Imyanitov, Evgeny N.; Caligo, Maria A.; Campbell, Ian G.; Hogervorst, Frans B. L.; Olah, Edith; Diez, Orland; Blanco, Ignacio; Brunet, Joan; Lazaroso, Conxi; Angel Pujana, Miguel; Jakubowska, Anna; Gronwald, Jacek; Lubinski, Jan; Sukiennicki, Grzegorz; Barkardottir, Rosa B.; Plante, Marie; Simard, Jacques; Soucy, Penny; Montagna, Marco; Tognazzo, Silvia; Teixeira, Manuel R.; Pankratz, Vernon S.; Wang, Xianshu; Lindor, Noralane; Szabo, Csilla I.; Kauff, Noah; Vijai, Joseph; Aghajanian, Carol A.; Pfeiler, Georg; Berger, Andreas; Singer, Christian F.; Tea, Muy-Kheng; Phelan, Catherine M.; Greene, Mark H.; Mai, Phuong L.; Rennert, Gad; Mulligan, Anna Marie; Tchatchou, Sandrine; Andrulis, Irene L.; Glendon, Gord; Toland, Amanda Ewart; Jensen, Uffe Birk; Kruse, Torben A.; Thomassen, Mads; Bojesen, Anders; Zidan, Jamal; Friedman, Eitan; Laitman, Yael; Soller, Maria; Liljegren, Annelie; Arver, Brita; Einbeigi, Zakaria; Stenmark-Askmalm, Marie; Olopade, Olufunmilayo I.; Nussbaum, Robert L.; Rebbeck, Timothy R.; Nathanson, Katherine L.; Domchek, Susan M.; Lu, Karen H.; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Hein, Alexander; Ekici, Arif B.; Beckmann, Matthias W.; Fasching, Peter A.; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Lambrechts, Sandrina; Dicks, Ed; Doherty, Jennifer A.; Wicklund, Kristine G.; Rossing, Mary Anne; Rudolph, Anja; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Moysich, Kirsten B.; Odunsi, Kunle; Sucheston, Lara; Lele, Shashi; Wilkens, Lynne R.; Goodman, Marc T.; Thompson, Pamela J.; Shvetsov, Yurii B.; Runnebaum, Ingo B.; Duerst, Matthias; Hillemanns, Peter; Doerk, Thilo; Antonenkova, Natalia; Bogdanova, Natalia; Leminen, Arto; Pelttari, Liisa M.; Butzow, Ralf; Modugno, Francesmary; Kelley, Joseph L.; Edwards, Robert P.; Ness, Roberta B.; du Bois, Andreas; Heitz, Florian; Schwaab, Ira; Harter, Philipp; Matsuo, Keitaro; Hosono, Satoyo; Orsulic, Sandra; Jensen, Allan; Kjaer, Susanne Kruger; Hogdall, Estrid; Hasmad, Hanis Nazihah; Azmi, Mat Adenan Noor; Teo, Soo-Hwang; Woo, Yin-Ling; Fridley, Brooke L.; Goode, Ellen L.; Cunningham, Julie M.; Vierkant, Robert A.; Bruinsma, Fiona; Giles, Graham G.; Liang, Dong; Hildebrandt, Michelle A. T.; Wu, Xifeng; Levine, Douglas A.; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S.; Schildkraut, Joellen M.; Concannon, Patrick; Weber, Rachel Palmieri; Cramer, Daniel W.; Terry, Kathryn L.; Poole, Elizabeth M.; Tworoger, Shelley S.; Bandera, Elisa V.; Orlow, Irene; Olson, Sara H.; Krakstad, Camilla; Salvesen, Helga B.; Tangen, Ingvild L.; Bjorge, Line; van Altena, Anne M.; Aben, Katja K. H.; Kiemeney, Lambertus A.; Massuger, Leon F. A. G.; Kellar, Melissa; Brooks-Wilson, Angela; Kelemen, Linda E.; Cook, Linda S.; Le, Nhu D.; Cybulski, Cezary; Yang, Hannah; Lissowska, Jolanta; Brinton, Louise A.; Wentzensen, Nicolas; Hogdall, Claus; Lundvall, Lene; Nedergaard, Lotte; Baker, Helen; Song, Honglin; Eccles, Diana; McNeish, Ian; Paul, James; Carty, Karen; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S.; Rothstein, Joseph H.; McGuire, Valerie; Sieh, Weiva; Ji, Bu-Tian; Zheng, Wei; Shu, Xiao-Ou; Gao, Yu-Tang; Rosen, Barry; Risch, Harvey A.; McLaughlin, John R.; Narod, Steven A.; Monteiro, Alvaro N.; Chen, Ann; Lin, Hui-Yi; Permuth-Wey, Jenny; Sellers, Thomas A.; Tsai, Ya-Yu; Chen, Zhihua; Ziogas, Argyrios; Anton-Culver, Hoda; Gentry-Maharaj, Aleksandra; Menon, Usha; Harrington, Patricia; Lee, Alice W.; Wu, Anna H.; Pearce, Celeste L.; Coetzee, Gerry; Pike, Malcolm C.; Dansonka-Mieszkowska, Agnieszka; Timorek, Agnieszka; Rzepecka, Iwona K.; Kupryjanczyk, Jolanta; Freedman, Matt; Noushmehr, Houtan; Easton, Douglas F.; Offit, Kenneth; Couch, Fergus J.; Gayther, Simon; Pharoah, Paul P.; Antoniou, Antonis C.; Chenevix-Trench, Georgia

    Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed

  17. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

    NARCIS (Netherlands)

    Tsoi, Lam C.; Spain, Sarah L.; Knight, Jo; Ellinghaus, Eva; Stuart, Philip E.; Capon, Francesca; Ding, Jun; Li, Yanming; Tejasvi, Trilokraj; Gudjonsson, Johann E.; Kang, Hyun M.; Allen, Michael H.; McManus, Ross; Novelli, Giuseppe; Samuelsson, Lena; Schalkwijk, Joost; Stahle, Mona; Burden, A. David; Smith, Catherine H.; Cork, Michael J.; Estivill, Xavier; Bowcock, Anne M.; Krueger, Gerald G.; Weger, Wolfgang; Worthington, Jane; Tazi-Ahnini, Rachid; Nestle, Frank O.; Hayday, Adrian; Hoffmann, Per; Winkelmann, Juliane; Wijmenga, Cisca; Langford, Cordelia; Edkins, Sarah; Andrews, Robert; Blackburn, Hannah; Strange, Amy; Band, Gavin; Pearson, Richard D.; Vukcevic, Damjan; Spencer, Chris C. A.; Deloukas, Panos; Mrowietz, Ulrich; Schreiber, Stefan; Weidinger, Stephan; Koks, Sulev; Kingo, Kuelli; Esko, Tonu; Metspalu, Andres; Lim, Henry W.; Voorhees, John J.; Weichenthal, Michael; Wichmann, H. Erich; Chandran, Vinod; Rosen, Cheryl F.; Rahman, Proton; Gladman, Dafna D.; Griffiths, Christopher E. M.; Reis, Andre; Kere, Juha; Nair, Rajan P.; Franke, Andre; Barker, Jonathan N. W. N.; Abecasis, Goncalo R.; Elder, James T.; Trembath, Richard C.; Duffin, Kristina Callis; Helms, Cindy; Goldgar, David; Li, Yun; Paschall, Justin; Malloy, Mary J.; Pullinger, Clive R.; Kane, John P.; Gardner, Jennifer; Perlmutter, Amy; Miner, Andrew; Feng, Bing Jian; Hiremagalore, Ravi; Ike, Robert W.; Christophers, Enno; Henseler, Tilo; Ruether, Andreas; Schrodi, Steven J.; Prahalad, Sampath; Guthery, Stephen L.; Fischer, Judith; Liao, Wilson; Kwok, Pui; Menter, Alan; Lathrop, G. Mark; Wise, C.; Begovich, Ann B.; Onoufriadis, Alexandros; Weale, Michael E.; Hofer, Angelika; Salmhofer, Wolfgang; Wolf, Peter; Kainu, Kati; Saarialho-Kere, Ulpu; Suomela, Sari; Badorf, Petra; Hueffmeier, Ulrike; Kurrat, Werner; Kuester, Wolfgang; Lascorz, Jesus; Moessner, Rotraut; Schuermeier-Horst, Funda; Staender, Markward; Traupe, Heiko; Bergboer, Judith G. M.; den Heijer, Martin; van de Kerkhof, Peter C.; Zeeuwen, Patrick L. J. M.; Barnes, Louise; Campbell, Linda E.; Cusack, Caitriona; Coleman, Ciara; Conroy, Judith; Ennis, Sean; Fitzgerald, Oliver; Gallagher, Phil; Irvine, Alan D.; Kirby, Brian; Markham, Trevor; McLean, W. H. Irwin; McPartlin, Joe; Rogers, Sarah F.; Ryan, Anthony W.; Zawirska, Agnieszka; Giardina, Emiliano; Lepre, Tiziana; Perricone, Carlo; Martin-Ezquerra, Gemma; Pujol, Ramon M.; Riveira-Munoz, Eva; Inerot, Annica; Naluai, Asa T.; Mallbris, Lotus; Wolk, Katarina; Leman, Joyce; Barton, Anne; Warren, Richard B.; Young, Helen S.; Ricaño Ponce, Isis; Trynka, Gosia; Pellett, Fawnda J.; Henschel, Andrew; Aurand, Marin; Bebo, Bruce; Gieger, Christian; Illig, Thomas; Moebus, Susanne; Joeckel, Karl-Heinz; Erbe, Raimund; Donnelly, Peter; Peltonen, Leena; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Craddock, Nicholas; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; McCarthy, Mark I.; Palmer, Colin N. A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Samani, Nilesh; Viswanathan, Ananth C.; Wood, Nicholas W.; Bellenguez, Celine; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Su, Zhan; Hunt, Sarah E.; Gwilliam, Rhian; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Perez, Marc L.; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew; Weston, Paul; Widaa, Sara; Whittaker, Pamela

    2012-01-01

    To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36

  18. Genome-wide association analyses identify 13 new susceptibility loci for generalized vitiligo

    NARCIS (Netherlands)

    Jin, Ying; Birlea, Stanca A.; Fain, Pamela R.; Ferrara, Tracey M.; Ben, Songtao; Riccardi, Sheri L.; Cole, Joanne B.; Gowan, Katherine; Holland, Paulene J.; Bennett, Dorothy C.; Luiten, Rosalie M.; Wolkerstorfer, Albert; van der Veen, J. P. Wietze; Hartmann, Anke; Eichner, Saskia; Schuler, Gerold; van Geel, Nanja; Lambert, Jo; Kemp, E. Helen; Gawkrodger, David J.; Weetman, Anthony P.; Taïeb, Alain; Jouary, Thomas; Ezzedine, Khaled; Wallace, Margaret R.; McCormack, Wayne T.; Picardo, Mauro; Leone, Giovanni; Overbeck, Andreas; Silverberg, Nanette B.; Spritz, Richard A.

    2012-01-01

    We previously reported a genome-wide association study (GWAS) identifying 14 susceptibility loci for generalized vitiligo. We report here a second GWAS (450 individuals with vitiligo (cases) and 3,182 controls), an independent replication study (1,440 cases and 1,316 controls) and a meta-analysis

  19. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

    NARCIS (Netherlands)

    Cerhan, James R.; Berndt, Sonja I.; Vijai, Joseph; Ghesquières, Hervé; McKay, James; Wang, Sophia S.; Wang, Zhaoming; Yeager, Meredith; Conde, Lucia; De Bakker, Paul I W; Nieters, Alexandra; Cox, David; Burdett, Laurie; Monnereau, Alain; Flowers, Christopher R.; De Roos, Anneclaire J.; Brooks-Wilson, Angela R.; Lan, Qing; Severi, Gianluca; Melbye, Mads; Gu, Jian; Jackson, Rebecca D.; Kane, Eleanor; Teras, Lauren R.; Purdue, Mark P.; Vajdic, Claire M.; Spinelli, John J.; Giles, Graham G.; Albanes, Demetrius; Kelly, Rachel S.; Zucca, Mariagrazia; Bertrand, Kimberly A.; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Hutchinson, Amy; Zhi, Degui; Habermann, Thomas M.; Link, Brian K.; Novak, Anne J.; Dogan, Ahmet; Asmann, Yan W.; Liebow, Mark; Thompson, Carrie A.; Ansell, Stephen M.; Witzig, Thomas E.; Weiner, George J.; Veron, Amelie S.; Zelenika, Diana; Tilly, Hervé; Haioun, Corinne; Molina, Thierry Jo; Hjalgrim, Henrik; Glimelius, Bengt; Adami, Hans Olov; Bracci, Paige M.; Riby, Jacques; Smith, Martyn T.; Holly, Elizabeth A.; Cozen, Wendy; Hartge, Patricia; Morton, Lindsay M.; Severson, Richard K.; Tinker, Lesley F.; North, Kari E.; Becker, Nikolaus; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; Staines, Anthony; Lightfoot, Tracy; Crouch, Simon; Smith, Alex; Roman, Eve; Diver, W. Ryan; Offit, Kenneth; Zelenetz, Andrew; Klein, Robert J.; Villano, Danylo J.; Zheng, Tongzhang; Zhang, Yawei; Holford, Theodore R.; Kricker, Anne; Turner, Jenny; Southey, Melissa C.; Clavel, Jacqueline; Virtamo, Jarmo; Weinstein, Stephanie; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Trichopoulos, Dimitrios; Vermeulen, Roel C H; Boeing, Heiner; Tjonneland, Anne; Angelucci, Emanuele; Di Lollo, Simonetta; Rais, Marco; Birmann, Brenda M.; Laden, Francine; Giovannucci, Edward; Kraft, Peter; Huang, Jinyan; Ma, Baoshan; Ye, Yuanqing; Chiu, Brian C H; Sampson, Joshua; Liang, Liming; Park, Ju Hyun; Chung, Charles C.; Weisenburger, Dennis D.; Chatterjee, Nilanjan; Fraumeni, Joseph F.; Slager, Susan L.; Wu, Xifeng; De Sanjose, Silvia; Smedby, Karin E.; Salles, Gilles; Skibola, Christine F.; Rothman, Nathaniel; Chanock, Stephen J.

    2014-01-01

    Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of

  20. Genome-wide association analysis identifies three new breast cancer susceptibility loci

    DEFF Research Database (Denmark)

    Ghoussaini, Maya; Fletcher, Olivia; Michailidou, Kyriaki

    2012-01-01

    Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS...

  1. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

    NARCIS (Netherlands)

    Phelan, Catherine M; Kuchenbaecker, Karoline B; Tyrer, Jonathan P; Kar, Siddhartha P; Lawrenson, Kate; Winham, Stacey J; Dennis, Joe; Pirie, Ailith; Riggan, Marjorie J; Chornokur, Ganna; Earp, Madalene A; Lyra, Paulo C; Lee, Janet M; Coetzee, Simon; Beesley, Jonathan; McGuffog, Lesley; Soucy, Penny; Dicks, Ed; Lee, Andrew; Barrowdale, Daniel; Lecarpentier, Julie; Leslie, Goska; Aalfs, Cora M; Aben, Katja K H; Adams, Marcia; Adlard, Julian; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia; Aravantinos, Gerasimos; Arnold, Norbert; Arun, Banu K; Arver, Brita; Azzollini, Jacopo; Balmaña, Judith; Banerjee, Susana N; Barjhoux, Laure; Barkardottir, Rosa B; Bean, Yukie; Beckmann, Matthias W; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Bernardini, Marcus Q; Birrer, Michael J; Bjorge, Line; Black, Amanda; Blankstein, Kenneth; Blok, Marinus J; Bodelon, Clara; Bogdanova, Natalia; Bojesen, Anders; Bonanni, Bernardo; Borg, Åke; Bradbury, Angela R; Brenton, James D; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Bruinsma, Fiona; Brunet, Joan; Buecher, Bruno; Butzow, Ralf; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Campbell, Ian; Cannioto, Rikki; Carney, Michael E; Cescon, Terence; Chan, Salina B; Chang-Claude, Jenny; Chanock, Stephen; Chen, Xiao Qing; Chiew, Yoke-Eng; Chiquette, Jocelyne; Chung, Wendy K; Claes, Kathleen B M; Conner, Thomas; Cook, Linda S; Cook, Jackie; Cramer, Daniel W; Cunningham, Julie M; D'Aloisio, Aimee A; Daly, Mary B; Damiola, Francesca; Damirovna, Sakaeva Dina; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Davidson, Rosemarie; DeFazio, Anna; Delnatte, Capucine; Doheny, Kimberly F; Diez, Orland; Ding, Yuan Chun; Doherty, Jennifer Anne; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; Dossus, Laure; Duran, Mercedes; Dürst, Matthias; Dworniczak, Bernd; Eccles, Diana; Edwards, Todd; Eeles, Ros; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B; Ellis, Steve; Elvira, Mingajeva; Eng, Kevin H; Engel, Christoph; Evans, D Gareth; Fasching, Peter A; Ferguson, Sarah; Ferrer, Sandra Fert; Flanagan, James M; Fogarty, Zachary C; Fortner, Renée T; Fostira, Florentia; Foulkes, William D; Fountzilas, George; Fridley, Brooke L; Friebel, Tara M; Friedman, Eitan; Frost, Debra; Ganz, Patricia A; Garber, Judy; García, María J; Garcia-Barberan, Vanesa; Gehrig, Andrea; Gentry-Maharaj, Aleksandra; Gerdes, Anne-Marie; Giles, Graham G; Glasspool, Rosalind; Glendon, Gord; Godwin, Andrew K; Goldgar, David E; Goranova, Teodora; Gore, Martin; Greene, Mark H; Gronwald, Jacek; Gruber, Stephen; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hamann, Ute; Hansen, Thomas V O; Harrington, Patricia A; Harris, Holly R; Hauke, Jan; Hein, Alexander; Henderson, Alex; Hildebrandt, Michelle A T; Hillemanns, Peter; Hodgson, Shirley; Høgdall, Claus K; Høgdall, Estrid; Hogervorst, Frans B L; Holland, Helene; Hooning, Maartje J; Hosking, Karen; Huang, Ruea-Yea; Hulick, Peter J; Hung, Jillian; Hunter, David J; Huntsman, David G; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Iversen, Edwin S; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jernetz, Mats; Jensen, Allan; Jensen, Uffe Birk; John, Esther M; Johnatty, Sharon; Jones, Michael E; Kannisto, Päivi; Karlan, Beth Y; Karnezis, Anthony; Kast, Karin; Kennedy, Catherine J; Khusnutdinova, Elza; Kiemeney, Lambertus A; Kiiski, Johanna I; Kim, Sung-Won; Kjaer, Susanne K; Köbel, Martin; Kopperud, Reidun K; Kruse, Torben A; Kupryjanczyk, Jolanta; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Larrañaga, Nerea; Larson, Melissa C; Lazaro, Conxi; Le, Nhu D; Le Marchand, Loic; Lee, Jong Won; Lele, Shashikant B; Leminen, Arto; Leroux, Dominique; Lester, Jenny; Lesueur, Fabienne; Levine, Douglas A; Liang, Dong; Liebrich, Clemens; Lilyquist, Jenna; Lipworth, Loren; Lissowska, Jolanta; Lu, Karen H; Lubinński, Jan; Luccarini, Craig; Lundvall, Lene; Mai, Phuong L; Mendoza-Fandiño, Gustavo; Manoukian, Siranoush; Massuger, Leon F A G; May, Taymaa; Mazoyer, Sylvie; McAlpine, Jessica N; McGuire, Valerie; McLaughlin, John R; McNeish, Iain; Meijers-Heijboer, Hanne; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R; Merritt, Melissa A; Milne, Roger L; Mitchell, Gillian; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moffitt, Melissa; Montagna, Marco; Moysich, Kirsten B; Mulligan, Anna Marie; Musinsky, Jacob; Nathanson, Katherine L; Nedergaard, Lotte; Ness, Roberta B; Neuhausen, Susan L; Nevanlinna, Heli; Niederacher, Dieter; Nussbaum, Robert L; Odunsi, Kunle; Olah, Edith; Olopade, Olufunmilayo I; Olsson, Håkan; Olswold, Curtis; O'Malley, David M; Ong, Kai-Ren; Onland-Moret, N Charlotte|info:eu-repo/dai/nl/26504362X; Orr, Nicholas; Orsulic, Sandra; Osorio, Ana; Palli, Domenico; Papi, Laura; Park-Simon, Tjoung-Won; Paul, James; Pearce, Celeste L; Pedersen, Inge Søkilde; Peeters, Petra H M|info:eu-repo/dai/nl/074099655; Peissel, Bernard; Peixoto, Ana; Pejovic, Tanja; Pelttari, Liisa M; Permuth, Jennifer B; Peterlongo, Paolo; Pezzani, Lidia; Pfeiler, Georg; Phillips, Kelly-Anne; Piedmonte, Marion; Pike, Malcolm C; Piskorz, Anna M; Poblete, Samantha R; Pocza, Timea; Poole, Elizabeth M; Poppe, Bruce; Porteous, Mary E; Prieur, Fabienne; Prokofyeva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pujol, Pascal; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rhiem, Kerstin; Rice, Patricia; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C; Rodríguez-Antona, Cristina; Romm, Jane; Rookus, Matti A; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Salvesen, Helga B; Sandler, Dale P; Schoemaker, Minouk J; Senter, Leigha; Setiawan, V Wendy; Severi, Gianluca; Sharma, Priyanka; Shelford, Tameka; Siddiqui, Nadeem; Side, Lucy E; Sieh, Weiva; Singer, Christian F; Sobol, Hagay; Song, Honglin; Southey, Melissa C; Spurdle, Amanda B; Stadler, Zsofia; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sucheston-Campbell, Lara E; Sukiennicki, Grzegorz; Sutphen, Rebecca; Sutter, Christian; Swerdlow, Anthony J; Szabo, Csilla I; Szafron, Lukasz; Tan, Yen Y; Taylor, Jack A; Tea, Muy-Kheng; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Thomsen, Liv Cecilie Vestrheim; Thull, Darcy L; Tihomirova, Laima; Tinker, Anna V; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tone, Alicia; Trabert, Britton; Travis, Ruth C; Trichopoulou, Antonia; Tung, Nadine; Tworoger, Shelley S; van Altena, Anne M; Van Den Berg, David; van der Hout, Annemarie H; van der Luijt, Rob B|info:eu-repo/dai/nl/153170824; Van Heetvelde, Mattias; Van Nieuwenhuysen, Els; van Rensburg, Elizabeth J; Vanderstichele, Adriaan; Varon-Mateeva, Raymonda; Vega, Ana; Edwards, Digna Velez; Vergote, Ignace; Vierkant, Robert A; Vijai, Joseph; Vratimos, Athanassios; Walker, Lisa; Walsh, Christine; Wand, Dorothea; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Webb, Penelope M; Weinberg, Clarice R; Weitzel, Jeffrey N; Wentzensen, Nicolas; Whittemore, Alice S; Wijnen, Juul T; Wilkens, Lynne R; Wolk, Alicja; Woo, Michelle; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Yannoukakos, Drakoulis; Ziogas, Argyrios; Zorn, Kristin K; Narod, Steven A; Easton, Douglas F; Amos, Christopher I; Schildkraut, Joellen M; Ramus, Susan J; Ottini, Laura; Goodman, Marc T; Park, Sue K; Kelemen, Linda E; Risch, Harvey A; Thomassen, Mads; Offit, Kenneth; Simard, Jacques; Schmutzler, Rita Katharina; Hazelett, Dennis; Monteiro, Alvaro N; Couch, Fergus J; Berchuck, Andrew; Chenevix-Trench, Georgia; Goode, Ellen L; Sellers, Thomas A; Gayther, Simon A; Antoniou, Antonis C; Pharoah, Paul D P

    2017-01-01

    To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC

  2. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

    NARCIS (Netherlands)

    Phelan, Catherine M.; Kuchenbaecker, Karoline B.; Tyrer, Jonathan P.; Kar, Siddhartha P.; Lawrenson, Kate; Winham, Stacey J.; Dennis, Joe; Pirie, Ailith; Riggan, Marjorie J.; Chornokur, Ganna; Earp, Madalene A.; Lyra, Paulo C.; Lee, Janet M.; Coetzee, Simon; Beesley, Jonathan; McGuffog, Lesley; Soucy, Penny; Dicks, Ed; Lee, Andrew; Barrowdale, Daniel; Lecarpentier, Julie; Leslie, Goska; Aalfs, Cora M.; Aben, Katja K. H.; Adams, Marcia; Adlard, Julian; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia; Aravantinos, Gerasimos; Arnold, Norbert; Arun, Banu K.; Arver, Brita; Azzollini, Jacopo; Balmana, Judith; Banerjee, Susana N.; Barjhoux, Laure; Barkardottir, Rosa B.; Bean, Yukie; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Bermisheva, Marina; Bernardini, Marcus Q.; Birrer, Michael J.; Bjorge, Line; Black, Amanda; Blankstein, Kenneth; Blok, Marinus J.; Bodelon, Clara; Bogdanova, Natalia; Bojesen, Anders; Bonanni, Bernardo; Borg, Ake; Bradbury, Angela R.; Brenton, James D.; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Bruinsma, Fiona; Brunet, Joan; Buecher, Bruno; Butzow, Ralf; Buys, Saundra S.; Caldes, Trinidad; Caligo, Maria A.; Campbell, Ian; Cannioto, Rikki; Carney, Michael E.; Cescon, Terence; Chan, Salina B.; Chang-Claude, Jenny; Chanock, Stephen; Chen, Xiao Qing; Chiew, Yoke-Eng; Chiquette, Jocelyne; Chung, Wendy K.; Claes, Kathleen B. M.; Conner, Thomas; Cook, Linda S.; Cook, Jackie; Cramer, Daniel W.; Cunningham, Julie M.; D'Aloisio, Aimee A.; Daly, Mary B.; Damiola, Francesca; Damirovna, Sakaeva Dina; Dansonka-Mieszkowska, Agnieszka; Dao, Fanny; Davidson, Rosemarie; DeFazio, Anna; Delnatte, Capucine; Doheny, Kimberly F.; Diez, Orland; Ding, Yuan Chun; Doherty, Jennifer Anne; Domchek, Susan M.; Dorfling, Cecilia M.; Dork, Thilo; Dossus, Laure; Duran, Mercedes; Durst, Matthias; Dworniczak, Bernd; Eccles, Diana; Edwards, Todd; Eeles, Ros; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B.; Ellis, Steve; Elvira, Mingajeva; Eng, Kevin H.; Engel, Christoph; Evans, D. Gareth; Fasching, Peter A.; Ferguson, Sarah; Ferrer, Sandra Fert; Flanagan, James M.; Fogarty, Zachary C.; Fortner, Renee T.; Fostira, Florentia; Foulkes, William D.; Fountzilas, George; Fridley, Brooke L.; Friebel, Tara M.; Friedman, Eitan; Frost, Debra; Ganz, Patricia A.; Garber, Judy; Garcia, Maria J.; Garcia-Barberan, Vanesa; Gehrig, Andrea; Gentry-Maharaj, Aleksandra; Gerdes, Anne-Marie; Giles, Graham G.; Glasspool, Rosalind; Glendon, Gord; Godwin, Andrew K.; Goldgar, David E.; Goranova, Teodora; Gore, Martin; Greene, Mark H.; Gronwald, Jacek; Gruber, Stephen; Hahnen, Eric; Haiman, Christopher A.; Hakansson, Niclas; Hamann, Ute; Hansen, Thomas V. O.; Harrington, Patricia A.; Harris, Holly R.; Hauke, Jan; Hein, Alexander; Henderson, Alex; Hildebrandt, Michelle A. T.; Hillemanns, Peter; Hodgson, Shirley; Hogdall, Claus K.; Hogdall, Estrid; Hogervorst, Frans B. L.; Holland, Helene; Hooning, Maartje J.; Hosking, Karen; Huang, Ruea-Yea; Hulick, Peter J.; Hung, Jillian; Hunter, David J.; Huntsman, David G.; Huzarski, Tomasz; Imyanitov, Evgeny N.; Isaacs, Claudine; Iversen, Edwin S.; Izatt, Louise; Izquierdo, Angel; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jernetz, Mats; Jensen, Allan; Jensen, Uffe Birk; John, Esther M.; Johnatty, Sharon; Jones, Michael E.; Kannisto, Paivi; Karlan, Beth Y.; Karnezis, Anthony; Kast, Karin; Kennedy, Catherine J.; Khusnutdinova, Elza; Kiemeney, Lambertus A.; Kiiski, Johanna I.; Kim, Sung-Won; Kjaer, Susanne K.; Kobel, Martin; Kopperud, Reidun K.; Kruse, Torben A.; Kupryjanczyk, Jolanta; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Larranaga, Nerea; Larson, Melissa C.; Lazaro, Conxi; Le, Nhu D.; Le Marchand, Loic; Lee, Jong Won; Lele, Shashikant B.; Leminen, Arto; Leroux, Dominique; Lester, Jenny; Lesueur, Fabienne; Levine, Douglas A.; Liang, Dong; Liebrich, Clemens; Lilyquist, Jenna; Lipworth, Loren; Lissowska, Jolanta; Lu, Karen H.; Lubinski, Jan; Luccarini, Craig; Lundvall, Lene; Mai, Phuong L.; Mendoza-Fandino, Gustavo; Manoukian, Siranoush; Massuger, Leon F. A. G.; May, Taymaa; Mazoyer, Sylvie; McAlpine, Jessica N.; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Meijers-Heijboer, Hanne; Meindl, Alfons; Menon, Usha; Mensenkamp, Arjen R.; Merritt, Melissa A.; Milne, Roger L.; Mitchell, Gillian; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moffitt, Melissa; Montagna, Marco; Moysich, Kirsten B.; Mulligan, Anna Marie; Musinsky, Jacob; Nathanson, Katherine L.; Nedergaard, Lotte; Ness, Roberta B.; Neuhausen, Susan L.; Nevanlinna, Heli; Niederacher, Dieter; Nussbaum, Robert L.; Odunsi, Kunle; Olah, Edith; Olopade, Olufunmilayo I.; Olsson, Hakan; Olswold, Curtis; O'Malley, David M.; Ong, Kai-ren; Onland-Moret, N. Charlotte; Orr, Nicholas; Orsulic, Sandra; Osorio, Ana; Palli, Domenico; Papi, Laura; Park-Simon, Tjoung-Won; Paul, James; Pearce, Celeste L.; Pedersen, Inge Sokilde; Peeters, Petra H. M.; Peissel, Bernard; Peixoto, Ana; Pejovic, Tanja; Pelttari, Liisa M.; Permuth, Jennifer B.; Peterlongo, Paolo; Pezzani, Lidia; Pfeiler, Georg; Phillips, Kelly-Anne; Piedmonte, Marion; Pike, Malcolm C.; Piskorz, Anna M.; Poblete, Samantha R.; Pocza, Timea; Poole, Elizabeth M.; Poppe, Bruce; Porteous, Mary E.; Prieur, Fabienne; Prokofyeva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pujol, Pascal; Radice, Paolo; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rhiem, Kerstin; Rice, Patricia; Richardson, Andrea; Robson, Mark; Rodriguez, Gustavo C.; Rodriguez-Antona, Cristina; Romm, Jane; Rookus, Matti A.; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Salvesen, Helga B.; Sandler, Dale P.; Schoemaker, Minouk J.; Senter, Leigha; Setiawan, V. Wendy; Severi, Gianluca; Sharma, Priyanka; Shelford, Tameka; Siddiqui, Nadeem; Side, Lucy E.; Sieh, Weiva; Singer, Christian F.; Sobol, Hagay; Song, Honglin; Southey, Melissa C.; Spurdle, Amanda B.; Stadler, Zsofia; Steinemann, Doris; Stoppa-Lyonnet, Dominique; Sucheston-Campbell, Lara E.; Sukiennicki, Grzegorz; Sutphen, Rebecca; Sutter, Christian; Swerdlow, Anthony J.; Szabo, Csilla I.; Szafron, Lukasz; Tan, Yen Y.; Taylor, Jack A.; Tea, Muy-Kheng; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J.; Thomsen, Liv Cecilie Vestrheim; Thull, Darcy L.; Tihomirova, Laima; Tinker, Anna V.; Tischkowitz, Marc; Tognazzo, Silvia; Toland, Amanda Ewart; Tone, Alicia; Trabert, Britton; Travis, Ruth C.; Trichopoulou, Antonia; Tung, Nadine; Tworoger, Shelley S.; Van Altena, Anne M.; Van den Berg, David; van der Hout, Annemarie H.; van der Luijt, Rob B.; Van Heetvelde, Mattias; Van Nieuwenhuysen, Els; Van Rensburg, Elizabeth J.; Vanderstichele, Adriaan; Varon-Mateeva, Raymonda; Vega, Ana; Edwards, Digna Velez; Vergote, Ignace; Vierkant, Robert A.; Vijai, Joseph; Vratimos, Athanassios; Walker, Lisa; Walsh, Christine; Wand, Dorothea; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Webb, Penelope M.; Weinberg, Clarice R.; Weitzel, Jeffrey N.; Wentzensen, Nicolas; Whittemore, Alice S.; Wijnen, Juul T.; Wilkens, Lynne R.; Wolk, Alicja; Woo, Michelle; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Yannoukakos, Drakoulis; Ziogas, Argyrios; Zorn, Kristin K.; Narod, Steven A.; Easton, Douglas F.; Amos, Christopher I.; Schildkraut, Joellen M.; Ramus, Susan J.; Ottini, Laura; Goodman, Marc T.; Park-, Sue K.; Kelemen, Linda E.; Risch, Harvey A.; Thomassen, Mads; Offit, Kenneth; Simard, Jacques; Schmutzler, Rita Katharina; Hazelett, Dennis; Monteiro, Alvaro N.; Couch, Fergus J.; Berchuck, Andrew; Chenevix-Trench, Georgia; Goode, Ellen L.; Sellers, Thomas A.; Gayther, Simon A.; Antoniou, Antonis C.; Pharoah, Paul D. P.

    To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC

  3. Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study

    DEFF Research Database (Denmark)

    Kote-Jarai, Zsofia; Olama, Ali Amin Al; Giles, Graham G

    2011-01-01

    Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of st...

  4. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Phelan, Catherine M.; Kuchenbaecker, Karoline B.; Tyrer, Jonathan P.

    2017-01-01

    To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous E...

  5. Genome-wide association analysis identifies three new breast cancer susceptibility loci

    NARCIS (Netherlands)

    Ghoussaini, M.; Fletcher, O.; Michailidou, K.; Turnbull, C.; Schmidt, M.K.; Dicks, E.; Dennis, J.; Wang, Q.; Humphreys, M.K.; Luccarini, C.; Baynes, C.; Conroy, D.; Maranian, M.; Ahmed, S.; Driver, K.; Johnson, N.; Orr, N.; dos Santos Silva, I.; Waisfisz, Q.; Meijers-Heijboer, H.; Uitterlinden, A.G.; Rivadeneira, F.; Hall, P.; Czene, K.; Irwanto, A.; Liu, J.; Nevanlinna, H.; Aittomaki, K.; Blomqvist, C.; Meindl, A.; Schmutzler, R.K.; Muller-Myhsok, B.; Lichtner, P.; Chang-Claude, J.; Hein, R.; Nickels, S.; Flesch-Janys, D.; Tsimiklis, H.; Makalic, E.; Schmidt, D.; Bui, M.; Hopper, J.L.; Apicella, C.; Park, D.J.; Southey, M.; Hunter, D.J.; Chanock, S.J.; Broeks, A.; Verhoef, S.; Hogervorst, F.B.; Fasching, P.A.; Lux, M.P.; Beckmann, M.W.; Ekici, A.B.; Sawyer, E.; Tomlinson, I.; Kerin, M.; Marme, F.; Schneeweiss, A.; Sohn, C.; Burwinkel, B.; Guenel, P.; Truong, T.; Cordina-Duverger, E.; Menegaux, F.; Bojesen, S.E.; Nordestgaard, B.G.; Nielsen, S.F.; Flyger, H.; Milne, R.L.; Alonso, M.R.; Gonzalez-Neira, A.; Benitez, J.; Anton-Culver, H.; Ziogas, A.; Bernstein, L.; Dur, C.C.; Brenner, H.; Muller, H.; Arndt, V.; Stegmaier, C.; Justenhoven, C.; Brauch, H.; Bruning, T.; Wang-Gohrke, S.; Eilber, U.; Dork, T.; Schurmann, P.; Bremer, M.; Hillemanns, P.; Bogdanova, N.V.; Antonenkova, N.N.; Rogov, Y.I.; Karstens, J.H.; Bermisheva, M.; Prokofieva, D.; Ligtenberg, M.J.

    2012-01-01

    Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for approximately 8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies

  6. Alzheimer Disease Susceptibility Loci: Evidence for a Protein Network under Natural Selection

    Science.gov (United States)

    Raj, Towfique; Shulman, Joshua M.; Keenan, Brendan T.; Chibnik, Lori B.; Evans, Denis A.; Bennett, David A.; Stranger, Barbara E.; De Jager, Philip L.

    2012-01-01

    Recent genome-wide association studies have identified a number of susceptibility loci for Alzheimer disease (AD). To understand the functional consequences and potential interactions of the associated loci, we explored large-scale data sets interrogating the human genome for evidence of positive natural selection. Our findings provide significant evidence for signatures of recent positive selection acting on several haplotypes carrying AD susceptibility alleles; interestingly, the genes found in these selected haplotypes can be assembled, independently, into a molecular complex via a protein-protein interaction (PPI) network approach. These results suggest a possible coevolution of genes encoding physically-interacting proteins that underlie AD susceptibility and are coexpressed in different tissues. In particular, PICALM, BIN1, CD2AP, and EPHA1 are interconnected through multiple interacting proteins and appear to have coordinated evidence of selection in the same human population, suggesting that they may be involved in the execution of a shared molecular function. This observation may be AD-specific, as the 12 loci associated with Parkinson disease do not demonstrate excess evidence of natural selection. The context for selection is probably unrelated to AD itself; it is likely that these genes interact in another context, such as in immune cells, where we observe cis-regulatory effects at several of the selected AD loci. PMID:22482808

  7. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers

    DEFF Research Database (Denmark)

    Onengut-Gumuscu, Suna; Chen, Wei-Min; Burren, Oliver

    2015-01-01

    Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array......, the Immunochip, was developed, from which we identified four new T1D-associated regions (P T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis...... and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer...

  8. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes

    DEFF Research Database (Denmark)

    Broeks, Annegien; Schmidt, Marjanka K; Sherman, Mark E

    2011-01-01

    Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes...... were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations......3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor...

  9. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes

    DEFF Research Database (Denmark)

    Broeks, Annegien; Schmidt, Marjanka K; Sherman, Mark E

    2011-01-01

    Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes...... were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations......3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P = 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor...

  10. Obesity susceptibility loci and uncontrolled eating, emotional eating and cognitive restraint behaviors in men and women.

    Science.gov (United States)

    Cornelis, Marilyn C; Rimm, Eric B; Curhan, Gary C; Kraft, Peter; Hunter, David J; Hu, Frank B; van Dam, Rob M

    2014-05-01

    Many confirmed genetic loci for obesity are expressed in regions of the brain that regulate energy intake and reward-seeking behavior. Whether these loci contribute to the development of specific eating behaviors has not been investigated. The relationship between a genetic susceptibility to obesity and cognitive restraint, uncontrolled and emotional eating was examined. Eating behavior and body mass index (BMI) were determined by questionnaires for 1471 men and 2381 women from two US cohorts. Genotypes were extracted from genome-wide scans and a genetic-risk score (GRS) derived from 32 obesity-loci was calculated. The GRS was positively associated with emotional and uncontrolled eating (Peating and those of TNNI3K and ZC3H4 were positively associated with uncontrolled eating. The BMI-increasing variant of FTO was positively and those of LRP1B and TFAP2B were inversely associated with cognitive restraint. These associations for single SNPs were independent of BMI but were not significant after multiple-testing correction. An overall genetic susceptibility to obesity may also extend to eating behaviors. The link between specific loci and obesity may be mediated by eating behavior but larger studies are warranted to confirm these results. © 2013 The Obesity Society.

  11. Comprehensive assessment of rheumatoid arthritis susceptibility loci in a large psoriatic arthritis cohort

    Science.gov (United States)

    Bowes, John; Ho, Pauline; Flynn, Edw; Ali, Faisal; Marzo-Ortega, Helena; Coates, Laura C; Warren, Rich B; McManus, Ross; Ryan, Anthony W; Kane, David; Korendowych, Eleanor; McHugh, Neil; FitzGerald, Oliver; Packham, Jonathon; Morgan, Ann W; Bruce, Ian N; Barton, Anne

    2012-01-01

    Objective A number of rheumatoid arthritis (RA) susceptibility genes have been identified in recent years. Given the overlap in phenotypic expression of synovial joint inflammation between RA and psoriatic arthritis (PsA), the authors explored whether RA susceptibility genes are also associated with PsA. Methods 56 single nucleotide polymorphisms (SNPs) mapping to 41 genes previously reported as RA susceptibility loci were selected for investigation. PsA was defined as an inflammatory arthritis associated with psoriasis and subjects were recruited from the UK and Ireland. Genotyping was performed using the Sequenom MassArray platform and frequencies compared with data derived from large UK control collections. Results Significant evidence for association with susceptibility to PsA was found toa SNP mapping to the REL (rs13017599, ptrend=5.2×104) gene, while nominal evidence for association (ptrendarthritis. PMID:22328738

  12. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11

    NARCIS (Netherlands)

    Siddiq, Afshan; Couch, Fergus J.; Chen, Gary K.; Lindström, Sara; Eccles, Diana; Millikan, Robert C.; Michailidou, Kyriaki; Stram, Daniel O.; Beckmann, Lars; Rhie, Suhn Kyong; Ambrosone, Christine B.; Aittomäki, Kristiina; Amiano, Pilar; Apicella, Carmel; Baglietto, Laura; Bandera, Elisa V.; Beckmann, Matthias W.; Berg, Christine D.; Bernstein, Leslie; Blomqvist, Carl; Brauch, Hiltrud; Brinton, Louise; Bui, Quang M.; Buring, Julie E.; Buys, Saundra S.; Campa, Daniele; Carpenter, Jane E.; Chasman, Daniel I.; Chang-Claude, Jenny; Chen, Constance; Clavel-Chapelon, Françoise; Cox, Angela; Cross, Simon S.; Czene, Kamila; Deming, Sandra L.; Diasio, Robert B.; Diver, W. Ryan; Dunning, Alison M.; Durcan, Lorraine; Ekici, Arif B.; Fasching, Peter A.; Feigelson, Heather Spencer; Fejerman, Laura; Figueroa, Jonine D.; Fletcher, Olivia; Flesch-Janys, Dieter; Gaudet, Mia M.; Gerty, Susan M.; Rodriguez-Gil, Jorge L.; Giles, Graham G.; van Gils, Carla H.; Godwin, Andrew K.; Graham, Nikki; Greco, Dario; Hall, Per; Hankinson, Susan E.; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Hoover, Robert N.; Hopper, John L.; Hu, Jennifer J.; Huntsman, Scott; Ingles, Sue A.; Irwanto, Astrid; Isaacs, Claudine; Jacobs, Kevin B.; John, Esther M.; Justenhoven, Christina; Kaaks, Rudolf; Kolonel, Laurence N.; Coetzee, Gerhard A.; Lathrop, Mark; Le Marchand, Loic; Lee, Adam M.; Lee, I.-Min; Lesnick, Timothy; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Martin, Nicholas G.; McLean, Catriona A.; Meijers-Heijboer, Hanne; Meindl, Alfons; Miron, Penelope; Monroe, Kristine R.; Montgomery, Grant W.; Müller-Myhsok, Bertram; Nickels, Stefan; Nyante, Sarah J.; Olswold, Curtis; Overvad, Kim; Palli, Domenico; Park, Daniel J.; Palmer, Julie R.; Pathak, Harsh; Peto, Julian; Pharoah, Paul; Rahman, Nazneen; Rivadeneira, Fernando; Schmidt, Daniel F.; Schmutzler, Rita K.; Slager, Susan; Southey, Melissa C.; Stevens, Kristen N.; Sinn, Hans-Peter; Press, Michael F.; Ross, Eric; Riboli, Elio; Ridker, Paul M.; Schumacher, Fredrick R.; Severi, Gianluca; dos Santos Silva, Isabel; Stone, Jennifer; Sund, Malin; Tapper, William J.; Thun, Michael J.; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Waisfisz, Quinten; Wang, Xianshu; Wang, Zhaoming; Weaver, Joellen; Schulz-Wendtland, Rüdiger; Wilkens, Lynne R.; van den Berg, David; Zheng, Wei; Ziegler, Regina G.; Ziv, Elad; Nevanlinna, Heli; Easton, Douglas F.; Hunter, David J.; Henderson, Brian E.; Chanock, Stephen J.; Garcia-Closas, Montserrat; Kraft, Peter; Haiman, Christopher A.; Vachon, Celine M.

    2012-01-01

    Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of

  13. High density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

    Science.gov (United States)

    Eyre, Steve; Bowes, John; Diogo, Dorothée; Lee, Annette; Barton, Anne; Martin, Paul; Zhernakova, Alexandra; Stahl, Eli; Viatte, Sebastien; McAllister, Kate; Amos, Christopher I.; Padyukov, Leonid; Toes, Rene E.M.; Huizinga, Tom W.J.; Wijmenga, Cisca; Trynka, Gosia; Franke, Lude; Westra, Harm-Jan; Alfredsson, Lars; Hu, Xinli; Sandor, Cynthia; de Bakker, Paul I.W.; Davila, Sonia; Khor, Chiea Chuen; Heng, Khai Koon; Andrews, Robert; Edkins, Sarah; Hunt, Sarah E; Langford, Cordelia; Symmons, Deborah; Concannon, Pat; Onengut-Gumuscu, Suna; Rich, Stephen S; Deloukas, Panos; Gonzalez-Gay, Miguel A.; Rodriguez-Rodriguez, Luis; Ärlsetig, Lisbeth; Martin, Javier; Rantapää-Dahlqvist, Solbritt; Plenge, Robert; Raychaudhuri, Soumya; Klareskog, Lars; Gregersen, Peter K; Worthington, Jane

    2012-01-01

    Summary Using the Immunochip custom single nucleotide polymorphism (SNP) array, designed for dense genotyping of 186 genome wide association study (GWAS) confirmed loci we analysed 11,475 rheumatoid arthritis cases of European ancestry and 15,870 controls for 129,464 markers. The data were combined in meta-analysis with GWAS data from additional independent cases (n=2,363) and controls (n=17,872). We identified fourteen novel loci; nine were associated with rheumatoid arthritis overall and 5 specifically in anti-citrillunated peptide antibody positive disease, bringing the number of confirmed European ancestry rheumatoid arthritis loci to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at six loci and association to low frequency variants (minor allele frequency <0.05) at 4 loci. Bioinformatic analysis of the data generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations. PMID:23143596

  14. Six novel susceptibility Loci for early-onset androgenetic alopecia and their unexpected association with common diseases.

    Directory of Open Access Journals (Sweden)

    Rui Li

    2012-05-01

    Full Text Available Androgenetic alopecia (AGA is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10⁻⁹-1.01×10⁻¹². Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06-1.55, p = 8.9×10⁻³. Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR = 5.78, p = 1.4×10⁻⁸⁸]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.

  15. Six Novel Susceptibility Loci for Early-Onset Androgenetic Alopecia and Their Unexpected Association with Common Diseases

    NARCIS (Netherlands)

    Li, R.; Brockschmidt, F.F.; Kiefer, A.K.; Stefansson, H.; Nyholt, DR; Song, K.; Vermeulen, S.H.; Kanoni, S.; Glass, D.; Medland, S.E.; Dimitriou, M.; Waterworth, D.; Tung, J.Y.; Geller, F.; Heilmann, S.; Hillmer, A.M.; Bataille, V.; Eigelshoven, S.; Hanneken, S.; Moebus, S.; Herold, C.; den Heijer, M.; Montgomery, G.W.; Deloukas, P.; Eriksson, N.; Heath, A.C.; Becker, T.; Sulem, P.; Mangino, M.; Vollenweider, P.; Spector, T.D.; Dedoussis, G.; Martin, N.G.; Kiemeney, L.A.; Mooser, V.; Stefansson, K.; Hinds, D.A.; Nothen, M. M.; Richards, J.B.

    2012-01-01

    Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven

  16. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

    NARCIS (Netherlands)

    Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara; Canisius, Sander; Dennis, Joe; Lush, Michael J.; Maranian, Mel J.; Bolla, Manjeet K.; Wang, Qin; Shah, Mitul; Perkins, Barbara J.; Czene, Kamila; Eriksson, Mikael; Darabi, Hatef; Brand, Judith S.; Bojesen, Stig E.; Nordestgaard, Borge G.; Flyger, Henrik; Nielsen, Sune F.; Rahman, Nazneen; Turnbull, Clare; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; dos-Santos-Silva, Isabel; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Eilber, Ursula; Behrens, Sabine; Nevanlinna, Heli; Muranen, Taru A.; Aittomaki, Kristiina; Blomqvist, Carl; Khan, Sofia; Aaltonen, Kirsimari; Ahsan, Habibul; Kibriya, Muhammad G.; Whittemore, Alice S.; John, Esther M.; Malone, Kathleen E.; Gammon, Marilie D.; Santella, Regina M.; Ursin, Giske; Makalic, Enes; Schmidt, Daniel F.; Casey, Graham; Hunter, David J.; Gapstur, Susan M.; Gaudet, Mia M.; Diver, W. Ryan; Haiman, Christopher A.; Schumacher, Fredrick; Henderson, Brian E.; Le Marchand, Loic; Berg, Christine D.; Chanock, Stephen J.; Figueroa, Jonine; Hoover, Robert N.; Lambrechts, Diether; Neven, Patrick; Wildiers, Hans; van Limbergen, Erik; Schmidt, Marjanka K.; Broeks, Annegien; Verhoef, Senno; Cornelissen, Sten; Couch, Fergus J.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel A.; van der Luijt, Rob B.|info:eu-repo/dai/nl/153170824; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Yoo, Keun-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Guenel, Pascal; Truong, Therese; Mulot, Claire; Sanchez, Marie; Burwinkel, Barbara; Marme, Frederik; Surowy, Harald; Sohn, Christof; Wu, Anna H.; Tseng, Chiu-chen; Van den Berg, David; Stram, Daniel O.; Gonzalez-Neira, Anna; Benitez, Javier; Zamora, M. Pilar; Arias Perez, Jose Ignacio; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S.; Reed, Malcolm W. R.; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Lindblom, Annika; Margolin, Sara; Teo, Soo Hwang; Yip, Cheng Har; Taib, Nur Aishah Mohd; Tan, Gie-Hooi; Hooning, Maartje J.; Hollestelle, Antoinette; Martens, John W. M.; Collee, J. Margriet; Blot, William; Signorello, Lisa B.; Cai, Qiuyin; Hopper, John L.; Southey, Melissa C.; Tsimiklis, Helen; Apicella, Carmel; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Hou, Ming-Feng; Kristensen, Vessela N.; Nord, Silje; Alnaes, Grethe I. Grenaker; Giles, Graham G.; Milne, Roger L.; McLean, Catriona; Canzian, Federico; Trichopoulos, Dimitrios; Peeters, Petra|info:eu-repo/dai/nl/074099655; Lund, Eiliv; Sund, Malin; Khaw, Kay-Tee; Gunter, Marc J.; Palli, Domenico; Mortensen, Lotte Maxild; Dossus, Laure; Huerta, Jose-Maria; Meindl, Alfons; Schmutzler, Rita K.; Sutter, Christian; Yang, Rongxi; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Hartman, Mikael; Miao, Hui; Chia, Kee Seng; Chan, Ching Wan; Fasching, Peter A.; Hein, Alexander; Beckmann, Matthias W.; Haeberle, Lothar; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J.; Swerdlow, Anthony J.; Brinton, Louise; Garcia-Closas, Montserrat; Zheng, Wei; Halverson, Sandra L.; Shrubsole, Martha; Long, Jirong; Goldberg, Mark S.; Labreche, France; Dumont, Martine; Winqvist, Robert; Pylkas, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Bruening, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Bogdanova, Natalia V.; Doerk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Devilee, Peter; Tollenaar, Robert A. E. M.; Seynaeve, Caroline; Van Asperen, Christi J.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Huzarski, Tomasz; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; Mckay, James; Slager, Susan; Toland, Amanda E.; Ambrosone, Christine B.; Yannoukakos, Drakoulis; Kabisch, Maria; Torres, Diana; Neuhausen, Susan L.; Anton-Culver, Hoda; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S.; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; Pita, Guillermo; Rosario Alonso, M.; Alvarez, Nuria; Herrero, Daniel; Simard, Jacques; Pharoah, Paul P. D. P.; Kraft, Peter; Dunning, Alison M.; Chenevix-Trench, Georgia; Hall, Per; Easton, Douglas F.

    Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining similar to 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising

  17. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

    NARCIS (Netherlands)

    K. Michailidou (Kyriaki); J. Beesley (Jonathan); S. Lindstrom (Stephen); S. Canisius (Sander); J. Dennis (Joe); M. Lush (Michael); M. Maranian (Melanie); M.K. Bolla (Manjeet); Q. Wang (Qing); M. Shah (Mitul); B. Perkins (Barbara); K. Czene (Kamila); M. Eriksson (Mikael); H. Darabi (Hatef); J.S. Brand (Judith S.); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); H. Flyger (Henrik); S.F. Nielsen (Sune); N. Rahman (Nazneen); C. Turnbull (Clare); O. Fletcher (Olivia); J. Peto (Julian); L.J. Gibson (Lorna); I. dos Santos Silva (Isabel); J. Chang-Claude (Jenny); D. Flesch-Janys (Dieter); A. Rudolph (Anja); U. Eilber (Ursula); T.W. Behrens (Timothy); H. Nevanlinna (Heli); T.A. Muranen (Taru); K. Aittomäki (Kristiina); C. Blomqvist (Carl); S. Khan (Sofia); K. Aaltonen (Kirsimari); H. Ahsan (Habibul); M.G. Kibriya (Muhammad); A.S. Whittemore (Alice S.); E.M. John (Esther M.); K.E. Malone (Kathleen E.); M.D. Gammon (Marilie); R.M. Santella (Regina M.); G. Ursin (Giske); E. Makalic (Enes); D.F. Schmidt (Daniel); G. Casey (Graham); D.J. Hunter (David J.); S.M. Gapstur (Susan M.); M.M. Gaudet (Mia); W.R. Diver (Ryan); C.A. Haiman (Christopher A.); F.R. Schumacher (Fredrick); B.E. Henderson (Brian); L. Le Marchand (Loic); C.D. Berg (Christine); S.J. Chanock (Stephen); J.D. Figueroa (Jonine); R.N. Hoover (Robert N.); D. Lambrechts (Diether); P. Neven (Patrick); H. Wildiers (Hans); E. van Limbergen (Erik); M.K. Schmidt (Marjanka); A. Broeks (Annegien); S. Verhoef; S. Cornelissen (Sten); F.J. Couch (Fergus); J.E. Olson (Janet); B. Hallberg (Boubou); C. Vachon (Celine); Q. Waisfisz (Quinten); E.J. Meijers-Heijboer (Hanne); M.A. Adank (Muriel); R.B. van der Luijt (Rob); J. Li (Jingmei); J. Liu (Jianjun); M.K. Humphreys (Manjeet); D. Kang (Daehee); J.-Y. Choi (Ji-Yeob); S.K. Park (Sue K.); K.Y. Yoo; K. Matsuo (Keitaro); H. Ito (Hidemi); H. Iwata (Hiroji); K. Tajima (Kazuo); P. Guénel (Pascal); T. Truong (Thérèse); C. Mulot (Claire); M. Sanchez (Marie); B. Burwinkel (Barbara); F. Marme (Federick); H. Surowy (Harald); C. Sohn (Christof); A.H. Wu (Anna H); C.-C. Tseng (Chiu-chen); D. Van Den Berg (David); D.O. Stram (Daniel O.); A. González-Neira (Anna); J. Benítez (Javier); M.P. Zamora (Pilar); J.I.A. Perez (Jose Ignacio Arias); X.-O. Shu (Xiao-Ou); W. Lu (Wei); Y. Gao; H. Cai (Hui); A. Cox (Angela); S.S. Cross (Simon); M.W.R. Reed (Malcolm); I.L. Andrulis (Irene); J.A. Knight (Julia); G. Glendon (Gord); A.-M. Mulligan (Anna-Marie); E.J. Sawyer (Elinor); I.P. Tomlinson (Ian); M. Kerin (Michael); N. Miller (Nicola); A. Lindblom (Annika); S. Margolin (Sara); S.H. Teo (Soo Hwang); C.H. Yip (Cheng Har); N.A.M. Taib (Nur Aishah Mohd); G.-H. Tan (Gie-Hooi); M.J. Hooning (Maartje); A. Hollestelle (Antoinette); J.W.M. Martens (John); J. Margriet Collée; W.J. Blot (William); L.B. Signorello (Lisa B.); Q. Cai (Qiuyin); J. Hopper (John); M.C. Southey (Melissa); H. Tsimiklis (Helen); C. Apicella (Carmel); C-Y. Shen (Chen-Yang); C.-N. Hsiung (Chia-Ni); P.-E. Wu (Pei-Ei); M.-F. Hou (Ming-Feng); V. Kristensen (Vessela); S. Nord (Silje); G.G. Alnæs (Grethe); G.G. Giles (Graham G.); R.L. Milne (Roger); C.A. McLean (Catriona Ann); F. Canzian (Federico); D. Trichopoulos (Dimitrios); P.H.M. Peeters; E. Lund (Eiliv); R. Sund (Reijo); K.T. Khaw; M.J. Gunter (Marc J.); D. Palli (Domenico); L.M. Mortensen (Lotte Maxild); L. Dossus (Laure); J.-M. Huerta (Jose-Maria); A. Meindl (Alfons); R.K. Schmutzler (Rita); C. Sutter (Christian); R. Yang (Rongxi); K. Muir (Kenneth); A. Lophatananon (Artitaya); S. Stewart-Brown (Sarah); P. Siriwanarangsan (Pornthep); J.M. Hartman (Joost); X. Miao; K.S. Chia (Kee Seng); C.W. Chan (Ching Wan); P.A. Fasching (Peter); R. Hein (Rebecca); M.W. Beckmann (Matthias W.); L. Haeberle (Lothar); H. Brenner (Hermann); A.K. Dieffenbach (Aida Karina); V. Arndt (Volker); C. Stegmaier (Christa); A. Ashworth (Alan); N. Orr (Nick); M. Schoemaker (Minouk); A.J. Swerdlow (Anthony ); L.A. Brinton (Louise); M. García-Closas (Montserrat); W. Zheng (Wei); S.L. Halverson (Sandra L.); M. Shrubsole (Martha); J. Long (Jirong); M.S. Goldberg (Mark); F. Labrèche (France); M. Dumont (Martine); R. Winqvist (Robert); K. Pykäs (Katri); A. Jukkola-Vuorinen (Arja); M. Grip (Mervi); H. Brauch (Hiltrud); U. Hamann (Ute); T. Brüning (Thomas); P. Radice (Paolo); P. Peterlongo (Paolo); S. Manoukian (Siranoush); L. Bernard (Loris); N.V. Bogdanova (Natalia); T. Dörk (Thilo); A. Mannermaa (Arto); V. Kataja (Vesa); V-M. Kosma (Veli-Matti); J.M. Hartikainen (J.); P. Devilee (Peter); R.A.E.M. Tollenaar (Rob); C.M. Seynaeve (Caroline); C.J. van Asperen (Christi); A. Jakubowska (Anna); J. Lubinski (Jan); K. Jaworska (Katarzyna); T. Huzarski (Tomasz); S. Sangrajrang (Suleeporn); V. Gaborieau (Valerie); P. Brennan (Paul); J.D. McKay (James); S. Slager (Susan); A.E. Toland (Amanda); C.B. Ambrosone (Christine); D. Yannoukakos (Drakoulis); M. Kabisch (Maria); D. Torres (Diana); S.L. Neuhausen (Susan); H. Anton-Culver (Hoda); C. Luccarini (Craig); C. Baynes (Caroline); S. Ahmed (Shahana); S. Healey (Sue); D.C. Tessier (Daniel C.); D. Vincent (Daniel); F. Bacot (Francois); G. Pita (G.); M.R. Alonso (Rosario); N. Álvarez (Nuria); D. Herrero (Daniel); J. Simard (Jacques); P.P.D.P. Pharoah (Paul P.D.P.); P. Kraft (Peter); A.M. Dunning (Alison); G. Chenevix-Trench (Georgia); P. Hall (Per); D.F. Easton (Douglas)

    2015-01-01

    textabstractGenome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS,

  18. Genome-wide association analysis identifies three new breast cancer susceptibility loci

    Science.gov (United States)

    Ghoussaini, Maya; Fletcher, Olivia; Michailidou, Kyriaki; Turnbull, Clare; Schmidt, Marjanka K; Dicks, Ed; Dennis, Joe; Wang, Qin; Humphreys, Manjeet K; Luccarini, Craig; Baynes, Caroline; Conroy, Don; Maranian, Melanie; Ahmed, Shahana; Driver, Kristy; Johnson, Nichola; Orr, Nicholas; Silva, Isabel dos Santos; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Uitterlinden, Andre G.; Rivadeneira, Fernando; Hall, Per; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Nevanlinna, Heli; Aittomäki, Kristiina; Blomqvist, Carl; Meindl, Alfons; Schmutzler, Rita K; Müller-Myhsok, Bertram; Lichtner, Peter; Chang-Claude, Jenny; Hein, Rebecca; Nickels, Stefan; Flesch-Janys, Dieter; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Hopper, John L; Apicella, Carmel; Park, Daniel J; Southey, Melissa; Hunter, David J; Chanock, Stephen J; Broeks, Annegien; Verhoef, Senno; Hogervorst, Frans BL; Fasching, Peter A.; Lux, Michael P.; Beckmann, Matthias W.; Ekici, Arif B.; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Guénel, Pascal; Truong, Thérèse; Cordina-Duverger, Emilie; Menegaux, Florence; Bojesen, Stig E; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Milne, Roger L.; Alonso, M. Rosario; González-Neira, Anna; Benítez, Javier; Anton-Culver, Hoda; Ziogas, Argyrios; Bernstein, Leslie; Dur, Christina Clarke; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Justenhoven, Christina; Brauch, Hiltrud; Brüning, Thomas; Wang-Gohrke, Shan; Eilber, Ursula; Dörk, Thilo; Schürmann, Peter; Bremer, Michael; Hillemanns, Peter; Bogdanova, Natalia V.; Antonenkova, Natalia N.; Rogov, Yuri I.; Karstens, Johann H.; Bermisheva, Marina; Prokofieva, Darya; Khusnutdinova, Elza; Lindblom, Annika; Margolin, Sara; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Lambrechts, Diether; Yesilyurt, Betul T.; Floris, Giuseppe; Leunen, Karin; Manoukian, Siranoush; Bonanni, Bernardo; Fortuzzi, Stefano; Peterlongo, Paolo; Couch, Fergus J; Wang, Xianshu; Stevens, Kristen; Lee, Adam; Giles, Graham G.; Baglietto, Laura; Severi, Gianluca; McLean, Catriona; Alnæs, Grethe Grenaker; Kristensen, Vessela; Børrensen-Dale, Anne-Lise; John, Esther M.; Miron, Alexander; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Andrulis, Irene L.; Glendon, Gord; Mulligan, Anna Marie; Devilee, Peter; van Asperen, Christie J.; Tollenaar, Rob A.E.M.; Seynaeve, Caroline; Figueroa, Jonine D; Garcia-Closas, Montserrat; Brinton, Louise; Lissowska, Jolanta; Hooning, Maartje J.; Hollestelle, Antoinette; Oldenburg, Rogier A.; van den Ouweland, Ans M.W.; Cox, Angela; Reed, Malcolm WR; Shah, Mitul; Jakubowska, Ania; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Jones, Michael; Schoemaker, Minouk; Ashworth, Alan; Swerdlow, Anthony; Beesley, Jonathan; Chen, Xiaoqing; Muir, Kenneth R; Lophatananon, Artitaya; Rattanamongkongul, Suthee; Chaiwerawattana, Arkom; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Shen, Chen-Yang; Yu, Jyh-Cherng; Wu, Pei-Ei; Hsiung, Chia-Ni; Perkins, Annie; Swann, Ruth; Velentzis, Louiza; Eccles, Diana M; Tapper, Will J; Gerty, Susan M; Graham, Nikki J; Ponder, Bruce A. J.; Chenevix-Trench, Georgia; Pharoah, Paul D.P.; Lathrop, Mark; Dunning, Alison M.; Rahman, Nazneen; Peto, Julian; Easton, Douglas F

    2013-01-01

    Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ~ 8% of the heritability of the disease. We followed up 72 promising associations from two independent Genome Wide Association Studies (GWAS) in ~70,000 cases and ~68,000 controls from 41 case-control studies and nine breast cancer GWAS. We identified three new breast cancer risk loci on 12p11 (rs10771399; P=2.7 × 10−35), 12q24 (rs1292011; P=4.3×10−19) and 21q21 (rs2823093; P=1.1×10−12). SNP rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) plays a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, while NRIP1 (21q21) encodes an ER co-factor and has a role in the regulation of breast cancer cell growth. PMID:22267197

  19. Evaluation of two putative susceptibility loci for oral clefts in the Danish population

    DEFF Research Database (Denmark)

    Mitchell, L E; Murray, J C; O'Brien, S

    2001-01-01

    Previous studies suggest that the risk of nonsyndromic cleft lip with or without cleft palate (CL+/-P) and isolated cleft palate (CP) is influenced by genetic variation at several loci and that the relation between specific genetic variants and disease risk may be modified by environmental factors....... The present study evaluated potential associations between CL+/-P and CP and two putative clefting susceptibility loci, MSX1 and TGFB3, using data from a nationwide case-control study conducted in Denmark from 1991 to 1994. The potential effects of interactions between these genes and two common environmental...... exposures, first trimester exposure to maternal cigarette smoke and alcohol intake, were also examined. Analyses of these data provide evidence of an association between the risk of CP and variation at the TGFB3 locus. However, there is no evidence that the risk of CL+/-P or CP is influenced by gene...

  20. The association between candidate migraine susceptibility loci and severe migraine phenotype in a clinical sample

    DEFF Research Database (Denmark)

    Esserlind, Ann-Louise; Christensen, Anne Francke; Steinberg, Stacy

    2016-01-01

    -structured migraine interviews, blood sampling and genotyping were performed on 1806 unrelated migraineurs recruited from the Danish Headache Center. Genotyping was also performed on a control group of 6415 people with no history of migraine. Association analyses were carried out using logistic regression and odds...... in both a case-control and case-only logistic regression model. RESULTS: We successfully replicated five out of the 12 previously reported loci and confirmed the same direction of effects for all the 12 single nucleotide polymorphisms. In line with the recently published genome-wide association meta...... polymorphisms showed nominal association with many lifetime attacks and prolonged migraine attacks. CONCLUSION: Our study supports previously reported findings on the association of several single nucleotide polymorphisms with migraine. It also suggests that the migraine susceptibility loci may be risk factors...

  1. Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers

    DEFF Research Database (Denmark)

    Plant, Darren; Flynn, Edward; Mbarek, Hamdi

    2010-01-01

    Genetic factors have a substantial role in determining development of rheumatoid arthritis (RA), and are likely to account for 50-60% of disease susceptibility. Genome-wide association studies have identified non-human leucocyte antigen RA susceptibility loci which associate with RA with low...

  2. Association study confirms two susceptibility loci for breast cancer in Chinese Han women.

    Science.gov (United States)

    Xu, Minggui; Xu, Yihui; Chen, Mengyun; Li, Yang; Li, Wei; Zhu, Jun; Zhang, Mingjun; Chen, Zhendong; Zhang, Xuejun; Liu, Jianjun; Zhang, Bo

    2016-10-01

    To date, many loci associated with breast cancer have been identified through genome-wide association studies; most of these studies were conducted using populations of European descent. Thus, it is not clear whether these susceptibility loci are also risk factors for Chinese populations. We selected and genotyped 32 single nucleotide polymorphisms (SNPs) using the Sequenom iPLEX platform in a female Chinese cohort of 3036 breast cancer cases and 3036 healthy controls. A total of 23 SNPs passed the quality control test. The associations of these SNPs with disease susceptibility were assessed using logistic regression, adjusting for age. The Bonferroni correction was used to conservatively account for multiple testing, and the threshold for statistical significance was P associated variants within three reported breast cancer susceptibility loci in a Chinese Han population: 5q11.2 (rs16886181, P = 5.29 × 10(-6), OR = 1.19; rs1017226, P = 5.24 × 10(-4), OR = 1.22; rs16886034, P = 2.00 × 10(-3), OR = 1.21; rs16886113, P = 1.24 × 10(-3), OR = 1.20; rs16886364, P = 9.20 × 10(-4), OR = 1.21; rs16886397, P = 1.17 × 10(-3), OR = 1.20; rs16886448, P = 1.62 × 10(-3,)OR = 1.20; and rs2229882, P = 5.14 × 10(-4), OR = 1.31), 5q14.3 (rs421379, P = 2.83 × 10(-13), OR = 1.83), and 10q26.1 (rs35054928, P = 7.73 × 10(-6), OR = 1.18). The 10q26.1 locus was found to be a susceptibility locus for breast cancer in Chinese Han women in our previous studies. 5q11.2 and 5q14.3 are confirmed here for the first time as susceptibility loci for breast cancer in Chinese Han women. This study reports three breast cancer susceptibility loci that were previously identified in European populations and are also risk factors for Chinese populations. This study may extend the genetic basis of breast cancer in Chinese Han women and highlight the contribution of multiple variants of modest effect.

  3. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

    Science.gov (United States)

    Voight, Benjamin F; Scott, Laura J; Steinthorsdottir, Valgerdur; Morris, Andrew P; Dina, Christian; Welch, Ryan P; Zeggini, Eleftheria; Huth, Cornelia; Aulchenko, Yurii S; Thorleifsson, Gudmar; McCulloch, Laura J; Ferreira, Teresa; Grallert, Harald; Amin, Najaf; Wu, Guanming; Willer, Cristen J; Raychaudhuri, Soumya; McCarroll, Steve A; Langenberg, Claudia; Hofmann, Oliver M; Dupuis, Josée; Qi, Lu; Segrè, Ayellet V; van Hoek, Mandy; Navarro, Pau; Ardlie, Kristin; Balkau, Beverley; Benediktsson, Rafn; Bennett, Amanda J; Blagieva, Roza; Boerwinkle, Eric; Bonnycastle, Lori L; Boström, Kristina Bengtsson; Bravenboer, Bert; Bumpstead, Suzannah; Burtt, Noisël P; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn; Couper, David J; Crawford, Gabe; Doney, Alex S F; Elliott, Katherine S; Elliott, Amanda L; Erdos, Michael R; Fox, Caroline S; Franklin, Christopher S; Ganser, Martha; Gieger, Christian; Grarup, Niels; Green, Todd; Griffin, Simon; Groves, Christopher J; Guiducci, Candace; Hadjadj, Samy; Hassanali, Neelam; Herder, Christian; Isomaa, Bo; Jackson, Anne U; Johnson, Paul R V; Jørgensen, Torben; Kao, Wen H L; Klopp, Norman; Kong, Augustine; Kraft, Peter; Kuusisto, Johanna; Lauritzen, Torsten; Li, Man; Lieverse, Aloysius; Lindgren, Cecilia M; Lyssenko, Valeriya; Marre, Michel; Meitinger, Thomas; Midthjell, Kristian; Morken, Mario A; Narisu, Narisu; Nilsson, Peter; Owen, Katharine R; Payne, Felicity; Perry, John R B; Petersen, Ann-Kristin; Platou, Carl; Proença, Christine; Prokopenko, Inga; Rathmann, Wolfgang; Rayner, N William; Robertson, Neil R; Rocheleau, Ghislain; Roden, Michael; Sampson, Michael J; Saxena, Richa; Shields, Beverley M; Shrader, Peter; Sigurdsson, Gunnar; Sparsø, Thomas; Strassburger, Klaus; Stringham, Heather M; Sun, Qi; Swift, Amy J; Thorand, Barbara; Tichet, Jean; Tuomi, Tiinamaija; van Dam, Rob M; van Haeften, Timon W; van Herpt, Thijs; van Vliet-Ostaptchouk, Jana V; Walters, G Bragi; Weedon, Michael N; Wijmenga, Cisca; Witteman, Jacqueline; Bergman, Richard N; Cauchi, Stephane; Collins, Francis S; Gloyn, Anna L; Gyllensten, Ulf; Hansen, Torben; Hide, Winston A; Hitman, Graham A; Hofman, Albert; Hunter, David J; Hveem, Kristian; Laakso, Markku; Mohlke, Karen L; Morris, Andrew D; Palmer, Colin N A; Pramstaller, Peter P; Rudan, Igor; Sijbrands, Eric; Stein, Lincoln D; Tuomilehto, Jaakko; Uitterlinden, Andre; Walker, Mark; Wareham, Nicholas J; Watanabe, Richard M; Abecasis, Gonçalo R; Boehm, Bernhard O; Campbell, Harry; Daly, Mark J; Hattersley, Andrew T; Hu, Frank B; Meigs, James B; Pankow, James S; Pedersen, Oluf; Wichmann, H-Erich; Barroso, Inês; Florez, Jose C; Frayling, Timothy M; Groop, Leif; Sladek, Rob; Thorsteinsdottir, Unnur; Wilson, James F; Illig, Thomas; Froguel, Philippe; van Duijn, Cornelia M; Stefansson, Kari; Altshuler, David; Boehnke, Michael; McCarthy, Mark I

    2011-01-01

    By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combinedP < 5 × 10−8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits. PMID:20581827

  4. SUSCEPTIBILITY LOCI FOR UMBILICAL HERNIA IN SWINE DETECTED BY GENOME-WIDE ASSOCIATION.

    Science.gov (United States)

    Liao, X J; Lia, L; Zhang, Z Y; Long, Y; Yang, B; Ruan, G R; Su, Y; Ai, H S; Zhang, W C; Deng, W Y; Xiao, S J; Ren, J; Ding, N S; Huang, L S

    2015-10-01

    Umbilical hernia (UH) is a complex disorder caused by both genetic and environmental factors. UH brings animal welfare problems and severe economic loss to the pig industry. Until now, the genetic basis of UH is poorly understood. The high-density 60K porcine SNP array enables the rapid application of genome-wide association study (GWAS) to identify genetic loci for phenotypic traits at genome wide scale in pigs. The objective of this research was to identify susceptibility loci for swine umbilical hernia using the GWAS approach. We genotyped 478 piglets from 142 families representing three Western commercial breeds with the Illumina PorcineSNP60 BeadChip. Then significant SNPs were detected by GWAS using ROADTRIPS (Robust Association-Detection Test for Related Individuals with Population Substructure) software base on a Bonferroni corrected threshold (P = 1.67E-06) or suggestive threshold (P = 3.34E-05) and false discovery rate (FDR = 0.05). After quality control, 29,924 qualified SNPs and 472 piglets were used for GWAS. Two suggestive loci predisposing to pig UH were identified at 44.25MB on SSC2 (rs81358018, P = 3.34E-06, FDR = 0.049933) and at 45.90MB on SSC17 (rs81479278, P = 3.30E-06, FDR = 0.049933) in Duroc population, respectively. And no SNP was detected to be associated with pig UH at significant level in neither Landrace nor Large White population. Furthermore, we carried out a meta-analysis in the combined pure-breed population containing all the 472 piglets. rs81479278 (P = 1.16E-06, FDR = 0.022475) was identified to associate with pig UH at genome-wide significant level. SRC was characterized as plausible candidate gene for susceptibility to pig UH according to its genomic position and biological functions. To our knowledge, this study gives the first description of GWAS identifying susceptibility loci for umbilical hernia in pigs. Our findings provide deeper insights to the genetic architecture of umbilical hernia in pigs.

  5. Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

    Science.gov (United States)

    Kuchenbaecker, Karoline B; Ramus, Susan J; Tyrer, Jonathan; Lee, Andrew; Shen, Howard C; Beesley, Jonathan; Lawrenson, Kate; McGuffog, Lesley; Healey, Sue; Lee, Janet M; Spindler, Tassja J; Lin, Yvonne G; Pejovic, Tanja; Bean, Yukie; Li, Qiyuan; Coetzee, Simon; Hazelett, Dennis; Miron, Alexander; Southey, Melissa; Terry, Mary Beth; Goldgar, David E; Buys, Saundra S; Janavicius, Ramunas; Dorfling, Cecilia M; van Rensburg, Elizabeth J; Neuhausen, Susan L; Ding, Yuan Chun; Hansen, Thomas V O; Jønson, Lars; Gerdes, Anne-Marie; Ejlertsen, Bent; Barrowdale, Daniel; Dennis, Joe; Benitez, Javier; Osorio, Ana; Garcia, Maria Jose; Komenaka, Ian; Weitzel, Jeffrey N; Ganschow, Pamela; Peterlongo, Paolo; Bernard, Loris; Viel, Alessandra; Bonanni, Bernardo; Peissel, Bernard; Manoukian, Siranoush; Radice, Paolo; Papi, Laura; Ottini, Laura; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Frost, Debra; Perkins, Jo; Platte, Radka; Ellis, Steve; Godwin, Andrew K; Schmutzler, Rita Katharina; Meindl, Alfons; Engel, Christoph; Sutter, Christian; Sinilnikova, Olga M; Damiola, Francesca; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Claes, Kathleen; De Leeneer, Kim; Kirk, Judy; Rodriguez, Gustavo C; Piedmonte, Marion; O'Malley, David M; de la Hoya, Miguel; Caldes, Trinidad; Aittomäki, Kristiina; Nevanlinna, Heli; Collée, J Margriet; Rookus, Matti A; Oosterwijk, Jan C; Tihomirova, Laima; Tung, Nadine; Hamann, Ute; Isaccs, Claudine; Tischkowitz, Marc; Imyanitov, Evgeny N; Caligo, Maria A; Campbell, Ian G; Hogervorst, Frans B L; Olah, Edith; Diez, Orland; Blanco, Ignacio; Brunet, Joan; Lazaro, Conxi; Pujana, Miquel Angel; Jakubowska, Anna; Gronwald, Jacek; Lubinski, Jan; Sukiennicki, Grzegorz; Barkardottir, Rosa B; Plante, Marie; Simard, Jacques; Soucy, Penny; Montagna, Marco; Tognazzo, Silvia; Teixeira, Manuel R; Pankratz, Vernon S; Wang, Xianshu; Lindor, Noralane; Szabo, Csilla I; Kauff, Noah; Vijai, Joseph; Aghajanian, Carol A; Pfeiler, Georg; Berger, Andreas; Singer, Christian F; Tea, Muy-Kheng; Phelan, Catherine M; Greene, Mark H; Mai, Phuong L; Rennert, Gad; Mulligan, Anna Marie; Tchatchou, Sandrine; Andrulis, Irene L; Glendon, Gord; Toland, Amanda Ewart; Jensen, Uffe Birk; Kruse, Torben A; Thomassen, Mads; Bojesen, Anders; Zidan, Jamal; Friedman, Eitan; Laitman, Yael; Soller, Maria; Liljegren, Annelie; Arver, Brita; Einbeigi, Zakaria; Stenmark-Askmalm, Marie; Olopade, Olufunmilayo I; Nussbaum, Robert L; Rebbeck, Timothy R; Nathanson, Katherine L; Domchek, Susan M; Lu, Karen H; Karlan, Beth Y; Walsh, Christine; Lester, Jenny; Hein, Alexander; Ekici, Arif B; Beckmann, Matthias W; Fasching, Peter A; Lambrechts, Diether; Van Nieuwenhuysen, Els; Vergote, Ignace; Lambrechts, Sandrina; Dicks, Ed; Doherty, Jennifer A; Wicklund, Kristine G; Rossing, Mary Anne; Rudolph, Anja; Chang-Claude, Jenny; Wang-Gohrke, Shan; Eilber, Ursula; Moysich, Kirsten B; Odunsi, Kunle; Sucheston, Lara; Lele, Shashi; Wilkens, Lynne R; Goodman, Marc T; Thompson, Pamela J; Shvetsov, Yurii B; Runnebaum, Ingo B; Dürst, Matthias; Hillemanns, Peter; Dörk, Thilo; Antonenkova, Natalia; Bogdanova, Natalia; Leminen, Arto; Pelttari, Liisa M; Butzow, Ralf; Modugno, Francesmary; Kelley, Joseph L; Edwards, Robert P; Ness, Roberta B; du Bois, Andreas; Heitz, Florian; Schwaab, Ira; Harter, Philipp; Matsuo, Keitaro; Hosono, Satoyo; Orsulic, Sandra; Jensen, Allan; Kjaer, Susanne Kruger; Hogdall, Estrid; Hasmad, Hanis Nazihah; Azmi, Mat Adenan Noor; Teo, Soo-Hwang; Woo, Yin-Ling; Fridley, Brooke L; Goode, Ellen L; Cunningham, Julie M; Vierkant, Robert A; Bruinsma, Fiona; Giles, Graham G; Liang, Dong; Hildebrandt, Michelle A T; Wu, Xifeng; Levine, Douglas A; Bisogna, Maria; Berchuck, Andrew; Iversen, Edwin S; Schildkraut, Joellen M; Concannon, Patrick; Weber, Rachel Palmieri; Cramer, Daniel W; Terry, Kathryn L; Poole, Elizabeth M; Tworoger, Shelley S; Bandera, Elisa V; Orlow, Irene; Olson, Sara H; Krakstad, Camilla; Salvesen, Helga B; Tangen, Ingvild L; Bjorge, Line; van Altena, Anne M; Aben, Katja K H; Kiemeney, Lambertus A; Massuger, Leon F A G; Kellar, Melissa; Brooks-Wilson, Angela; Kelemen, Linda E; Cook, Linda S; Le, Nhu D; Cybulski, Cezary; Yang, Hannah; Lissowska, Jolanta; Brinton, Louise A; Wentzensen, Nicolas; Hogdall, Claus; Lundvall, Lene; Nedergaard, Lotte; Baker, Helen; Song, Honglin; Eccles, Diana; McNeish, Ian; Paul, James; Carty, Karen; Siddiqui, Nadeem; Glasspool, Rosalind; Whittemore, Alice S; Rothstein, Joseph H; McGuire, Valerie; Sieh, Weiva; Ji, Bu-Tian; Zheng, Wei; Shu, Xiao-Ou; Gao, Yu-Tang; Rosen, Barry; Risch, Harvey A; McLaughlin, John R; Narod, Steven A; Monteiro, Alvaro N; Chen, Ann; Lin, Hui-Yi; Permuth-Wey, Jenny; Sellers, Thomas A; Tsai, Ya-Yu; Chen, Zhihua; Ziogas, Argyrios; Anton-Culver, Hoda; Gentry-Maharaj, Aleksandra; Menon, Usha; Harrington, Patricia; Lee, Alice W; Wu, Anna H; Pearce, Celeste L; Coetzee, Gerry; Pike, Malcolm C; Dansonka-Mieszkowska, Agnieszka; Timorek, Agnieszka; Rzepecka, Iwona K; Kupryjanczyk, Jolanta; Freedman, Matt; Noushmehr, Houtan; Easton, Douglas F; Offit, Kenneth; Couch, Fergus J; Gayther, Simon; Pharoah, Paul P; Antoniou, Antonis C; Chenevix-Trench, Georgia

    2015-02-01

    Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

  6. A genome-wide association analysis identifies NMNAT2 and HCP5 as susceptibility loci for Kawasaki disease.

    Science.gov (United States)

    Kim, Jae-Jung; Yun, Sin Weon; Yu, Jeong Jin; Yoon, Kyung Lim; Lee, Kyung-Yil; Kil, Hong-Ryang; Kim, Gi Beom; Han, Myung-Ki; Song, Min Seob; Lee, Hyoung Doo; Ha, Kee Soo; Sohn, Sejung; Johnson, Todd A; Takahashi, Atsushi; Kubo, Michiaki; Tsunoda, Tatsuhiko; Ito, Kaoru; Onouchi, Yoshihiro; Hong, Young Mi; Jang, Gi Young; Lee, Jong-Keuk

    2017-08-31

    Kawasaki disease (KD), a systemic vasculitis of infants and children, manifests as fever and mucocutaneous inflammation. Although its etiology is largely unknown, the epidemiological data suggest that genetic factors are important in KD susceptibility. To identify genetic variants influencing KD susceptibility, we performed a genome-wide association study (GWAS) and replication study using a total of 915 children with KD and 4553 controls in the Korean population. Six single-nucleotide polymorphisms (SNPs) in three loci were associated significantly with KD susceptibility (P<1.0 × 10(-5)), including the previously reported BLK locus (rs6993775, odds ratio (OR)=1.52, P=2.52 × 10(-11)). The other two loci were newly identified: NMNAT2 on chromosome 1q25.3 (rs2078087, OR=1.33, P=1.15 × 10(-6)) and the human leukocyte antigen (HLA) region on chromosome 6p21.3 (HLA-C, HLA-B, MICA and HCP5) (rs9380242, rs9378199, rs9266669 and rs6938467; OR=1.33-1.51, P=8.93 × 10(-6) to 5.24 × 10(-8)). Additionally, SNP rs17280682 in NLRP14 was associated significantly with KD with a family history (18 cases vs 4553 controls, OR=6.76, P=5.46 × 10(-6)). These results provide new insights into the pathogenesis and pathophysiology of KD.Journal of Human Genetics advance online publication, 31 August 2017; doi:10.1038/jhg.2017.87.

  7. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

    Science.gov (United States)

    Felix, Janine F; Bradfield, Jonathan P; Monnereau, Claire; van der Valk, Ralf J P; Stergiakouli, Evie; Chesi, Alessandra; Gaillard, Romy; Feenstra, Bjarke; Thiering, Elisabeth; Kreiner-Møller, Eskil; Mahajan, Anubha; Pitkänen, Niina; Joro, Raimo; Cavadino, Alana; Huikari, Ville; Franks, Steve; Groen-Blokhuis, Maria M; Cousminer, Diana L; Marsh, Julie A; Lehtimäki, Terho; Curtin, John A; Vioque, Jesus; Ahluwalia, Tarunveer S; Myhre, Ronny; Price, Thomas S; Vilor-Tejedor, Natalia; Yengo, Loïc; Grarup, Niels; Ntalla, Ioanna; Ang, Wei; Atalay, Mustafa; Bisgaard, Hans; Blakemore, Alexandra I; Bonnefond, Amelie; Carstensen, Lisbeth; Eriksson, Johan; Flexeder, Claudia; Franke, Lude; Geller, Frank; Geserick, Mandy; Hartikainen, Anna-Liisa; Haworth, Claire M A; Hirschhorn, Joel N; Hofman, Albert; Holm, Jens-Christian; Horikoshi, Momoko; Hottenga, Jouke Jan; Huang, Jinyan; Kadarmideen, Haja N; Kähönen, Mika; Kiess, Wieland; Lakka, Hanna-Maaria; Lakka, Timo A; Lewin, Alexandra M; Liang, Liming; Lyytikäinen, Leo-Pekka; Ma, Baoshan; Magnus, Per; McCormack, Shana E; McMahon, George; Mentch, Frank D; Middeldorp, Christel M; Murray, Clare S; Pahkala, Katja; Pers, Tune H; Pfäffle, Roland; Postma, Dirkje S; Power, Christine; Simpson, Angela; Sengpiel, Verena; Tiesler, Carla M T; Torrent, Maties; Uitterlinden, André G; van Meurs, Joyce B; Vinding, Rebecca; Waage, Johannes; Wardle, Jane; Zeggini, Eleftheria; Zemel, Babette S; Dedoussis, George V; Pedersen, Oluf; Froguel, Philippe; Sunyer, Jordi; Plomin, Robert; Jacobsson, Bo; Hansen, Torben; Gonzalez, Juan R; Custovic, Adnan; Raitakari, Olli T; Pennell, Craig E; Widén, Elisabeth; Boomsma, Dorret I; Koppelman, Gerard H; Sebert, Sylvain; Järvelin, Marjo-Riitta; Hyppönen, Elina; McCarthy, Mark I; Lindi, Virpi; Harri, Niinikoski; Körner, Antje; Bønnelykke, Klaus; Heinrich, Joachim; Melbye, Mads; Rivadeneira, Fernando; Hakonarson, Hakon; Ring, Susan M; Smith, George Davey; Sørensen, Thorkild I A; Timpson, Nicholas J; Grant, Struan F A; Jaddoe, Vincent W V

    2016-01-15

    A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11

    OpenAIRE

    Siddiq, A.; Couch, F.J. (Fergus J.); Chen, G. K.; Lindstrom, S.; Eccles, D.; Millikan, R. C.; Michailidou, K. (Kyriaki); Stram, D O; Beckmann, L; Rhie, S. K.; Ambrosone, C. B. (Christine B.); Aittomaki, K.; Amiano, P.; Apicella, C.; Baglietto, L

    2012-01-01

    Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls o...

  9. Evaluation of shared genetic susceptibility loci between autoimmune diseases and schizophrenia based on genome-wide association studies

    DEFF Research Database (Denmark)

    Hoeffding, Louise K E; Rosengren, Anders; Thygesen, Johan H

    2017-01-01

    Background: Epidemiological studies have documented higher than expected comorbidity (or, in some cases, inverse comorbidity) between schizophrenia and several autoimmune disorders. It remains unknown whether this comorbidity reflects shared genetic susceptibility loci.  Aims: The present study...... associated with schizophrenia (1.7 × 10−8≥ p ≥ 4.0 × 10−21). While these observations confirm the existence of shared genetic susceptibility loci between schizophrenia and autoimmune diseases, the findings did not show a significant enrichment.  Conclusion: The findings do not support a genetic overlap...

  10. Identification of six new susceptibility loci for invasive epithelial ovarian cancer

    DEFF Research Database (Denmark)

    Kuchenbaecker, Karoline B; Ramus, Susan J; Tyrer, Jonathan

    2015-01-01

    associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded...... subtype, all with P improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.......Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed...

  11. Novel Association Between Immune-Mediated Susceptibility Loci and Persistent Autoantibody Positivity in Type 1 Diabetes

    DEFF Research Database (Denmark)

    Brorsson, Caroline A; Onengut, Suna; Chen, Wei-Min

    2015-01-01

    Islet autoantibodies detected at disease onset in patients with type 1 diabetes are signs of an autoimmune destruction of the insulin-producing β-cells. To further investigate the genetic determinants of autoantibody positivity, we performed dense immune-focused genotyping on the Immunochip array...... and tested for association with seven disease-specific autoantibodies in a large cross-sectional cohort of 6,160 type 1 diabetes-affected siblings. The genetic association with positivity for GAD autoantibodies (GADAs), IA2 antigen (IA-2A), zinc transporter 8, thyroid peroxidase, gastric parietal cells (PCAs...... and constitute candidates for early screening. Major susceptibility loci for islet autoantibodies are separate from type 1 diabetes risk, which may have consequences for intervention strategies to reduce autoimmunity....

  12. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

    Science.gov (United States)

    Beecham, Ashley H; Patsopoulos, Nikolaos A; Xifara, Dionysia K; Davis, Mary F; Kemppinen, Anu; Cotsapas, Chris; Shahi, Tejas S; Spencer, Chris; Booth, David; Goris, An; Oturai, Annette; Saarela, Janna; Fontaine, Bertrand; Hemmer, Bernhard; Martin, Claes; Zipp, Frauke; D’alfonso, Sandra; Martinelli-Boneschi, Filippo; Taylor, Bruce; Harbo, Hanne F; Kockum, Ingrid; Hillert, Jan; Olsson, Tomas; Ban, Maria; Oksenberg, Jorge R; Hintzen, Rogier; Barcellos, Lisa F; Agliardi, Cristina; Alfredsson, Lars; Alizadeh, Mehdi; Anderson, Carl; Andrews, Robert; Søndergaard, Helle Bach; Baker, Amie; Band, Gavin; Baranzini, Sergio E; Barizzone, Nadia; Barrett, Jeffrey; Bellenguez, Céline; Bergamaschi, Laura; Bernardinelli, Luisa; Berthele, Achim; Biberacher, Viola; Binder, Thomas M C; Blackburn, Hannah; Bomfim, Izaura L; Brambilla, Paola; Broadley, Simon; Brochet, Bruno; Brundin, Lou; Buck, Dorothea; Butzkueven, Helmut; Caillier, Stacy J; Camu, William; Carpentier, Wassila; Cavalla, Paola; Celius, Elisabeth G; Coman, Irène; Comi, Giancarlo; Corrado, Lucia; Cosemans, Leentje; Cournu-Rebeix, Isabelle; Cree, Bruce A C; Cusi, Daniele; Damotte, Vincent; Defer, Gilles; Delgado, Silvia R; Deloukas, Panos; di Sapio, Alessia; Dilthey, Alexander T; Donnelly, Peter; Dubois, Bénédicte; Duddy, Martin; Edkins, Sarah; Elovaara, Irina; Esposito, Federica; Evangelou, Nikos; Fiddes, Barnaby; Field, Judith; Franke, Andre; Freeman, Colin; Frohlich, Irene Y; Galimberti, Daniela; Gieger, Christian; Gourraud, Pierre-Antoine; Graetz, Christiane; Graham, Andrew; Grummel, Verena; Guaschino, Clara; Hadjixenofontos, Athena; Hakonarson, Hakon; Halfpenny, Christopher; Hall, Gillian; Hall, Per; Hamsten, Anders; Harley, James; Harrower, Timothy; Hawkins, Clive; Hellenthal, Garrett; Hillier, Charles; Hobart, Jeremy; Hoshi, Muni; Hunt, Sarah E; Jagodic, Maja; Jelčić, Ilijas; Jochim, Angela; Kendall, Brian; Kermode, Allan; Kilpatrick, Trevor; Koivisto, Keijo; Konidari, Ioanna; Korn, Thomas; Kronsbein, Helena; Langford, Cordelia; Larsson, Malin; Lathrop, Mark; Lebrun-Frenay, Christine; Lechner-Scott, Jeannette; Lee, Michelle H; Leone, Maurizio A; Leppä, Virpi; Liberatore, Giuseppe; Lie, Benedicte A; Lill, Christina M; Lindén, Magdalena; Link, Jenny; Luessi, Felix; Lycke, Jan; Macciardi, Fabio; Männistö, Satu; Manrique, Clara P; Martin, Roland; Martinelli, Vittorio; Mason, Deborah; Mazibrada, Gordon; McCabe, Cristin; Mero, Inger-Lise; Mescheriakova, Julia; Moutsianas, Loukas; Myhr, Kjell-Morten; Nagels, Guy; Nicholas, Richard; Nilsson, Petra; Piehl, Fredrik; Pirinen, Matti; Price, Siân E; Quach, Hong; Reunanen, Mauri; Robberecht, Wim; Robertson, Neil P; Rodegher, Mariaemma; Rog, David; Salvetti, Marco; Schnetz-Boutaud, Nathalie C; Sellebjerg, Finn; Selter, Rebecca C; Schaefer, Catherine; Shaunak, Sandip; Shen, Ling; Shields, Simon; Siffrin, Volker; Slee, Mark; Sorensen, Per Soelberg; Sorosina, Melissa; Sospedra, Mireia; Spurkland, Anne; Strange, Amy; Sundqvist, Emilie; Thijs, Vincent; Thorpe, John; Ticca, Anna; Tienari, Pentti; van Duijn, Cornelia; Visser, Elizabeth M; Vucic, Steve; Westerlind, Helga; Wiley, James S; Wilkins, Alastair; Wilson, James F; Winkelmann, Juliane; Zajicek, John; Zindler, Eva; Haines, Jonathan L; Pericak-Vance, Margaret A; Ivinson, Adrian J; Stewart, Graeme; Hafler, David; Hauser, Stephen L; Compston, Alastair; McVean, Gil; De Jager, Philip; Sawcer, Stephen; McCauley, Jacob L

    2013-01-01

    Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value sclerosis subjects and 26,703 healthy controls. In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value sclerosis risk variants in 103 discrete loci outside of the Major Histocompatibility Complex. With high resolution Bayesian fine-mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals. PMID:24076602

  13. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease

    Science.gov (United States)

    Lambert, Jean-Charles; Ibrahim-Verbaas, Carla A; Harold, Denise; Naj, Adam C; Sims, Rebecca; Bellenguez, Céline; Jun, Gyungah; DeStefano, Anita L; Bis, Joshua C; Beecham, Gary W; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A; Jones, Nicola; Smith, Albert V; Chouraki, Vincent; Thomas, Charlene; Ikram, M Arfan; Zelenika, Diana; Vardarajan, Badri N; Kamatani, Yoichiro; Lin, Chiao-Feng; Gerrish, Amy; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Choi, Seung-Hoan; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Ramirez, Alfredo; Hanon, Olivier; Fitzpatrick, Annette L; Buxbaum, Joseph D; Campion, Dominique; Crane, Paul K; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L; De Jager, Philip L; Deramecourt, Vincent; Johnston, Janet A; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Morón, Francisco J; Rubinsztein, David C; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M; Fiévet, Nathalie; Huentelman, Matthew J; Gill, Michael; Brown, Kristelle; Kamboh, M Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B; Green, Robert; Myers, Amanda J; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; St George-Hyslop, Peter; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petroula; Collinge, John; Sorbi, Sandro; Sanchez-Garcia, Florentino; Fox, Nick C; Hardy, John; Deniz Naranjo, Maria Candida; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Matthews, Fiona; Moebus, Susanne; Mecocci, Patrizia; Zompo, Maria Del; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G; Coto, Eliecer; Hamilton-Nelson, Kara L; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J; Faber, Kelley M; Jonsson, Palmi V; Combarros, Onofre; O’Donovan, Michael C; Cantwell, Laura B; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H; Bennett, David A; Harris, Tamara B; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee F A G; Passmore, Peter; Montine, Thomas J; Bettens, Karolien; Rotter, Jerome I; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M; Kukull, Walter A; Hannequin, Didier; Powell, John F; Nalls, Michael A; Ritchie, Karen; Lunetta, Kathryn L; Kauwe, John S K; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R; Schmidt, Reinhold; Rujescu, Dan; Wang, Li-san; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M; Graff, Caroline; Psaty, Bruce M; Jones, Lesley; Haines, Jonathan L; Holmans, Peter A; Lathrop, Mark; Pericak-Vance, Margaret A; Launer, Lenore J; Farrer, Lindsay A; van Duijn, Cornelia M; Van Broeckhoven, Christine; Moskvina, Valentina; Seshadri, Sudha; Williams, Julie; Schellenberg, Gerard D; Amouyel, Philippe

    2013-01-01

    Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease. PMID:24162737

  14. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

    DEFF Research Database (Denmark)

    Felix, Janine F; Bradfield, Jonathan P; Monnereau, Claire

    2016-01-01

    A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We...... increased 0.04 Standard Deviation Score (SDS) (Standard Error (SE) 0.007), 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503, and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0....... These loci likely represent age-related differences in strength of the associations with body mass index....

  15. A genome-wide "pleiotropy scan" does not identify new susceptibility loci for estrogen receptor negative breast cancer.

    Directory of Open Access Journals (Sweden)

    Daniele Campa

    Full Text Available Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-. Compared with ER-positive (ER+ disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS. We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P<5 × 10(-8 to perform a secondary analysis of an ER-negative GWAS from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3, including 1998 cases and 2305 controls from prospective studies. We then tested the top ten associations (i.e. with the lowest P-values using three additional populations with a total sample size of 3509 ER+ cases, 2543 ER- cases and 7031 healthy controls. None of the 3079 selected variants in the BPC3 ER-GWAS were significant at the adjusted threshold. 186 variants were associated with ER- breast cancer risk at a conventional threshold of P<0.05, with P-values ranging from 0.049 to 2.3 × 10(-4. None of the variants reached statistical significance in the replication phase. In conclusion, this study did not identify any novel susceptibility loci for ER-breast cancer using a "pleiotropic approach".

  16. Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci

    NARCIS (Netherlands)

    Betz, Regina C; Petukhova, Lynn; Ripke, Stephan; Huang, Hailiang; Menelaou, Androniki; Redler, Silke; Becker, Tim; Heilmann, Stefanie; Yamany, Tarek; Duvic, Madeliene; Hordinsky, Maria; Norris, David; Price, Vera H; Mackay-Wiggan, Julian; de Jong, Annemieke; DeStefano, Gina M; Moebus, Susanne; Böhm, Markus; Blume-Peytavi, Ulrike; Wolff, Hans; Lutz, Gerhard; Kruse, Roland; Bian, Li; Amos, Christopher I; Lee, Annette; Gregersen, Peter K; Blaumeiser, Bettina; Altshuler, David; Clynes, Raphael; de Bakker, Paul I W; Nöthen, Markus M; Daly, Mark J; Christiano, Angela M

    2015-01-01

    Alopecia areata (AA) is a prevalent autoimmune disease with 10 known susceptibility loci. Here we perform the first meta-analysis of research on AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and

  17. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

    DEFF Research Database (Denmark)

    Amin Al Olama, Ali; Dadaev, Tokhir; Hazelett, Dennis J

    2015-01-01

    Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancest...

  18. Genome-wide Meta-analyses of Breast, Ovarian and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by At Least Two Cancer Types

    Science.gov (United States)

    Kar, Siddhartha P.; Beesley, Jonathan; Al Olama, Ali Amin; Michailidou, Kyriaki; Tyrer, Jonathan; Kote-Jarai, ZSofia; Lawrenson, Kate; Lindstrom, Sara; Ramus, Susan J.; Thompson, Deborah J.; Kibel, Adam S.; Dansonka-Mieszkowska, Agnieszka; Michael, Agnieszka; Dieffenbach, Aida K.; Gentry-Maharaj, Aleksandra; Whittemore, Alice S.; Wolk, Alicja; Monteiro, Alvaro; Peixoto, Ana; Kierzek, Andrzej; Cox, Angela; Rudolph, Anja; Gonzalez-Neira, Anna; Wu, Anna H.; Lindblom, Annika; Swerdlow, Anthony; Ziogas, Argyrios; Ekici, Arif B.; Burwinkel, Barbara; Karlan, Beth Y.; Nordestgaard, Børge G.; Blomqvist, Carl; Phelan, Catherine; McLean, Catriona; Pearce, Celeste Leigh; Vachon, Celine; Cybulski, Cezary; Slavov, Chavdar; Stegmaier, Christa; Maier, Christiane; Ambrosone, Christine B.; Høgdall, Claus K.; Teerlink, Craig C.; Kang, Daehee; Tessier, Daniel C.; Schaid, Daniel J.; Stram, Daniel O.; Cramer, Daniel W.; Neal, David E.; Eccles, Diana; Flesch-Janys, Dieter; Velez Edwards, Digna R.; Wokozorczyk, Dominika; Levine, Douglas A.; Yannoukakos, Drakoulis; Sawyer, Elinor J.; Bandera, Elisa V.; Poole, Elizabeth M.; Goode, Ellen L.; Khusnutdinova, Elza; Høgdall, Estrid; Song, Fengju; Bruinsma, Fiona; Heitz, Florian; Modugno, Francesmary; Hamdy, Freddie C.; Wiklund, Fredrik; Giles, Graham G.; Olsson, Håkan; Wildiers, Hans; Ulmer, Hans-Ulrich; Pandha, Hardev; Risch, Harvey A.; Darabi, Hatef; Salvesen, Helga B.; Nevanlinna, Heli; Gronberg, Henrik; Brenner, Hermann; Brauch, Hiltrud; Anton-Culver, Hoda; Song, Honglin; Lim, Hui-Yi; McNeish, Iain; Campbell, Ian; Vergote, Ignace; Gronwald, Jacek; Lubiński, Jan; Stanford, Janet L.; Benítez, Javier; Doherty, Jennifer A.; Permuth, Jennifer B.; Chang-Claude, Jenny; Donovan, Jenny L.; Dennis, Joe; Schildkraut, Joellen M.; Schleutker, Johanna; Hopper, John L.; Kupryjanczyk, Jolanta; Park, Jong Y.; Figueroa, Jonine; Clements, Judith A.; Knight, Julia A.; Peto, Julian; Cunningham, Julie M.; Pow-Sang, Julio; Batra, Jyotsna; Czene, Kamila; Lu, Karen H.; Herkommer, Kathleen; Khaw, Kay-Tee; Matsuo, Keitaro; Muir, Kenneth; Offitt, Kenneth; Chen, Kexin; Moysich, Kirsten B.; Aittomäki, Kristiina; Odunsi, Kunle; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; Fitzgerald, Liesel M.; Cook, Linda S.; Cannon-Albright, Lisa; Hooning, Maartje J.; Pike, Malcolm C.; Bolla, Manjeet K.; Luedeke, Manuel; Teixeira, Manuel R.; Goodman, Marc T.; Schmidt, Marjanka K.; Riggan, Marjorie; Aly, Markus; Rossing, Mary Anne; Beckmann, Matthias W.; Moisse, Matthieu; Sanderson, Maureen; Southey, Melissa C.; Jones, Michael; Lush, Michael; Hildebrandt, Michelle A. T.; Hou, Ming-Feng; Schoemaker, Minouk J.; Garcia-Closas, Montserrat; Bogdanova, Natalia; Rahman, Nazneen; Le, Nhu D.; Orr, Nick; Wentzensen, Nicolas; Pashayan, Nora; Peterlongo, Paolo; Guénel, Pascal; Brennan, Paul; Paulo, Paula; Webb, Penelope M.; Broberg, Per; Fasching, Peter A.; Devilee, Peter; Wang, Qin; Cai, Qiuyin; Li, Qiyuan; Kaneva, Radka; Butzow, Ralf; Kopperud, Reidun Kristin; Schmutzler, Rita K.; Stephenson, Robert A.; MacInnis, Robert J.; Hoover, Robert N.; Winqvist, Robert; Ness, Roberta; Milne, Roger L.; Travis, Ruth C.; Benlloch, Sara; Olson, Sara H.; McDonnell, Shannon K.; Tworoger, Shelley S.; Maia, Sofia; Berndt, Sonja; Lee, Soo Chin; Teo, Soo-Hwang; Thibodeau, Stephen N.; Bojesen, Stig E.; Gapstur, Susan M.; Kjær, Susanne Krüger; Pejovic, Tanja; Tammela, Teuvo L.J.; Dörk, Thilo; Brüning, Thomas; Wahlfors, Tiina; Key, Tim J.; Edwards, Todd L.; Menon, Usha; Hamann, Ute; Mitev, Vanio; Kosma, Veli-Matti; Setiawan, Veronica Wendy; Kristensen, Vessela; Arndt, Volker; Vogel, Walther; Zheng, Wei; Sieh, Weiva; Blot, William J.; Kluzniak, Wojciech; Shu, Xiao-Ou; Gao, Yu-Tang; Schumacher, Fredrick; Freedman, Matthew L.; Berchuck, Andrew; Dunning, Alison M.; Simard, Jacques; Haiman, Christopher A.; Spurdle, Amanda; Sellers, Thomas A.; Hunter, David J.; Henderson, Brian E.; Kraft, Peter; Chanock, Stephen J.; Couch, Fergus J.; Hall, Per; Gayther, Simon A.; Easton, Douglas F.; Chenevix-Trench, Georgia; Eeles, Rosalind; Pharoah, Paul D.P.; Lambrechts, Diether

    2016-01-01

    Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. PMID:27432226

  19. Fine mapping of breast cancer genome-wide association studies loci in women of African ancestry identifies novel susceptibility markers.

    Science.gov (United States)

    Zheng, Yonglan; Ogundiran, Temidayo O; Falusi, Adeyinka G; Nathanson, Katherine L; John, Esther M; Hennis, Anselm J M; Ambs, Stefan; Domchek, Susan M; Rebbeck, Timothy R; Simon, Michael S; Nemesure, Barbara; Wu, Suh-Yuh; Leske, Maria Cristina; Odetunde, Abayomi; Niu, Qun; Zhang, Jing; Afolabi, Chibuzor; Gamazon, Eric R; Cox, Nancy J; Olopade, Christopher O; Olopade, Olufunmilayo I; Huo, Dezheng

    2013-07-01

    Numerous single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility have been identified by genome-wide association studies (GWAS). However, these SNPs were primarily discovered and validated in women of European and Asian ancestry. Because linkage disequilibrium is ancestry-dependent and heterogeneous among racial/ethnic populations, we evaluated common genetic variants at 22 GWAS-identified breast cancer susceptibility loci in a pooled sample of 1502 breast cancer cases and 1378 controls of African ancestry. None of the 22 GWAS index SNPs could be validated, challenging the direct generalizability of breast cancer risk variants identified in Caucasians or Asians to other populations. Novel breast cancer risk variants for women of African ancestry were identified in regions including 5p12 (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.11-1.76; P = 0.004), 5q11.2 (OR = 1.22, 95% CI = 1.09-1.36; P = 0.00053) and 10p15.1 (OR = 1.22, 95% CI = 1.08-1.38; P = 0.0015). We also found positive association signals in three regions (6q25.1, 10q26.13 and 16q12.1-q12.2) previously confirmed by fine mapping in women of African ancestry. In addition, polygenic model indicated that eight best markers in this study, compared with 22 GWAS-identified SNPs, could better predict breast cancer risk in women of African ancestry (per-allele OR = 1.21, 95% CI = 1.16-1.27; P = 9.7 × 10(-16)). Our results demonstrate that fine mapping is a powerful approach to better characterize the breast cancer risk alleles in diverse populations. Future studies and new GWAS in women of African ancestry hold promise to discover additional variants for breast cancer susceptibility with clinical implications throughout the African diaspora.

  20. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.

    Science.gov (United States)

    Kar, Siddhartha P; Beesley, Jonathan; Amin Al Olama, Ali; Michailidou, Kyriaki; Tyrer, Jonathan; Kote-Jarai, ZSofia; Lawrenson, Kate; Lindstrom, Sara; Ramus, Susan J; Thompson, Deborah J; Kibel, Adam S; Dansonka-Mieszkowska, Agnieszka; Michael, Agnieszka; Dieffenbach, Aida K; Gentry-Maharaj, Aleksandra; Whittemore, Alice S; Wolk, Alicja; Monteiro, Alvaro; Peixoto, Ana; Kierzek, Andrzej; Cox, Angela; Rudolph, Anja; Gonzalez-Neira, Anna; Wu, Anna H; Lindblom, Annika; Swerdlow, Anthony; Ziogas, Argyrios; Ekici, Arif B; Burwinkel, Barbara; Karlan, Beth Y; Nordestgaard, Børge G; Blomqvist, Carl; Phelan, Catherine; McLean, Catriona; Pearce, Celeste Leigh; Vachon, Celine; Cybulski, Cezary; Slavov, Chavdar; Stegmaier, Christa; Maier, Christiane; Ambrosone, Christine B; Høgdall, Claus K; Teerlink, Craig C; Kang, Daehee; Tessier, Daniel C; Schaid, Daniel J; Stram, Daniel O; Cramer, Daniel W; Neal, David E; Eccles, Diana; Flesch-Janys, Dieter; Edwards, Digna R Velez; Wokozorczyk, Dominika; Levine, Douglas A; Yannoukakos, Drakoulis; Sawyer, Elinor J; Bandera, Elisa V; Poole, Elizabeth M; Goode, Ellen L; Khusnutdinova, Elza; Høgdall, Estrid; Song, Fengju; Bruinsma, Fiona; Heitz, Florian; Modugno, Francesmary; Hamdy, Freddie C; Wiklund, Fredrik; Giles, Graham G; Olsson, Håkan; Wildiers, Hans; Ulmer, Hans-Ulrich; Pandha, Hardev; Risch, Harvey A; Darabi, Hatef; Salvesen, Helga B; Nevanlinna, Heli; Gronberg, Henrik; Brenner, Hermann; Brauch, Hiltrud; Anton-Culver, Hoda; Song, Honglin; Lim, Hui-Yi; McNeish, Iain; Campbell, Ian; Vergote, Ignace; Gronwald, Jacek; Lubiński, Jan; Stanford, Janet L; Benítez, Javier; Doherty, Jennifer A; Permuth, Jennifer B; Chang-Claude, Jenny; Donovan, Jenny L; Dennis, Joe; Schildkraut, Joellen M; Schleutker, Johanna; Hopper, John L; Kupryjanczyk, Jolanta; Park, Jong Y; Figueroa, Jonine; Clements, Judith A; Knight, Julia A; Peto, Julian; Cunningham, Julie M; Pow-Sang, Julio; Batra, Jyotsna; Czene, Kamila; Lu, Karen H; Herkommer, Kathleen; Khaw, Kay-Tee; Matsuo, Keitaro; Muir, Kenneth; Offitt, Kenneth; Chen, Kexin; Moysich, Kirsten B; Aittomäki, Kristiina; Odunsi, Kunle; Kiemeney, Lambertus A; Massuger, Leon F A G; Fitzgerald, Liesel M; Cook, Linda S; Cannon-Albright, Lisa; Hooning, Maartje J; Pike, Malcolm C; Bolla, Manjeet K; Luedeke, Manuel; Teixeira, Manuel R; Goodman, Marc T; Schmidt, Marjanka K; Riggan, Marjorie; Aly, Markus; Rossing, Mary Anne; Beckmann, Matthias W; Moisse, Matthieu; Sanderson, Maureen; Southey, Melissa C; Jones, Michael; Lush, Michael; Hildebrandt, Michelle A T; Hou, Ming-Feng; Schoemaker, Minouk J; Garcia-Closas, Montserrat; Bogdanova, Natalia; Rahman, Nazneen; Le, Nhu D; Orr, Nick; Wentzensen, Nicolas; Pashayan, Nora; Peterlongo, Paolo; Guénel, Pascal; Brennan, Paul; Paulo, Paula; Webb, Penelope M; Broberg, Per; Fasching, Peter A; Devilee, Peter; Wang, Qin; Cai, Qiuyin; Li, Qiyuan; Kaneva, Radka; Butzow, Ralf; Kopperud, Reidun Kristin; Schmutzler, Rita K; Stephenson, Robert A; MacInnis, Robert J; Hoover, Robert N; Winqvist, Robert; Ness, Roberta; Milne, Roger L; Travis, Ruth C; Benlloch, Sara; Olson, Sara H; McDonnell, Shannon K; Tworoger, Shelley S; Maia, Sofia; Berndt, Sonja; Lee, Soo Chin; Teo, Soo-Hwang; Thibodeau, Stephen N; Bojesen, Stig E; Gapstur, Susan M; Kjær, Susanne Krüger; Pejovic, Tanja; Tammela, Teuvo L J; Dörk, Thilo; Brüning, Thomas; Wahlfors, Tiina; Key, Tim J; Edwards, Todd L; Menon, Usha; Hamann, Ute; Mitev, Vanio; Kosma, Veli-Matti; Setiawan, Veronica Wendy; Kristensen, Vessela; Arndt, Volker; Vogel, Walther; Zheng, Wei; Sieh, Weiva; Blot, William J; Kluzniak, Wojciech; Shu, Xiao-Ou; Gao, Yu-Tang; Schumacher, Fredrick; Freedman, Matthew L; Berchuck, Andrew; Dunning, Alison M; Simard, Jacques; Haiman, Christopher A; Spurdle, Amanda; Sellers, Thomas A; Hunter, David J; Henderson, Brian E; Kraft, Peter; Chanock, Stephen J; Couch, Fergus J; Hall, Per; Gayther, Simon A; Easton, Douglas F; Chenevix-Trench, Georgia; Eeles, Rosalind; Pharoah, Paul D P; Lambrechts, Diether

    2016-09-01

    Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P cancer meta-analysis. We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932. ©2016 American Association for Cancer Research.

  1. Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration

    Science.gov (United States)

    Chen, Wei; Stambolian, Dwight; Edwards, Albert O.; Branham, Kari E.; Othman, Mohammad; Jakobsdottir, Johanna; Tosakulwong, Nirubol; Pericak-Vance, Margaret A.; Campochiaro, Peter A.; Klein, Michael L.; Tan, Perciliz L.; Conley, Yvette P.; Kanda, Atsuhiro; Kopplin, Laura; Li, Yanming; Augustaitis, Katherine J.; Karoukis, Athanasios J.; Scott, William K.; Agarwal, Anita; Kovach, Jaclyn L.; Schwartz, Stephen G.; Postel, Eric A.; Brooks, Matthew; Baratz, Keith H.; Brown, William L.; Brucker, Alexander J.; Orlin, Anton; Brown, Gary; Ho, Allen; Regillo, Carl; Donoso, Larry; Tian, Lifeng; Kaderli, Brian; Hadley, Dexter; Hagstrom, Stephanie A.; Peachey, Neal S.; Klein, Ronald; Klein, Barbara E. K.; Gotoh, Norimoto; Yamashiro, Kenji; Ferris, Frederick; Fagerness, Jesen A.; Reynolds, Robyn; Farrer, Lindsay A.; Kim, Ivana K.; Miller, Joan W.; Cortón, Marta; Carracedo, Angel; Sanchez-Salorio, Manuel; Pugh, Elizabeth W.; Doheny, Kimberly F.; Brion, Maria; DeAngelis, Margaret M.; Weeks, Daniel E.; Zack, Donald J.; Chew, Emily Y.; Heckenlively, John R.; Yoshimura, Nagahisa; Iyengar, Sudha K.; Francis, Peter J.; Katsanis, Nicholas; Seddon, Johanna M.; Haines, Jonathan L.; Gorin, Michael B.; Abecasis, Gonçalo R.; Swaroop, Anand; Johnson, Robert N.; Ai, Everett; McDonald, H. Richard; Stolarczuk, Margaret; Pavan, Peter Reed; Billiris, Karina K.; Iyer, Mohan; Menosky, Matthew M.; Pautler, Scott E.; Millard, Sharon M.; Hubbard, Baker; Aaberg, Thomas; DuBois, Lindy; Lyon, Alice; Anderson-Nelson, Susan; Jampol, Lee M.; Weinberg, David V.; Muñana, Annie; Rozenbajgier, Zuzanna; Orth, David; Cohen, Jack; MacCumber, Matthew; MacCumber, Matthew; Figliulo, Celeste; Porcz, Liz; Folk, James; Boldt, H. Culver; Russell, Stephen R.; Ivins, Rachel; Hinz, Connie J.; Barr, Charles C.; Bloom, Steve; Jaegers, Ken; Kritchman, Brian; Whittington, Greg; Heier, Jeffrey; Frederick, Albert R.; Morley, Michael G.; Topping, Trexler; Davis, Heather L.; Bressler, Susan B.; Bressler, Neil M.; Doll, Warren; Trese, Michael; Capone, Antonio; Garretson, Bruce R.; Hassan, Tarek S.; Ruby, Alan J.; Osentoski, Tammy; McCannel, Colin A.; Ruszczyk, Margaret J.; Grand, Gilbert; Blinder, Kevin; Holekamp, Nancy M.; Joseph, Daniel P.; Shah, Gaurav; Nobel, Ginny S.; Antoszyk, Andrew N.; Browning, David J.; Stallings, Alison H; Singerman, Lawrence J.; Miller, David; Novak, Michael; Pendergast, Scott; Zegarra, Hernando; Schura, Stephanie A.; Smith-Brewer, Sheila; Davidorf, Frederick H.; Chambers, Robert; Chorich, Louis; Salerno, Jill; Dreyer, Richard F.; Ma, Colin; Kopfer, Marcia R.; Klein, Michael L.; Wilson, David J.; Nolte, Susan K.; Grunwald, Juan E.; Brucker, Alexander J.; Dunaief, Josh; Fine, Stuart L.; Maguire, Albert M.; Stoltz, Robert A.; McRay, Monique N.; Fish, Gary Edd; Anand, Rajiv; Spencer, Rand; Arnwine, Jean; Chandra, Suresh R.; Altaweel, Michael; Blodi, Barbara; Gottlieb, Justin; Ip, Michael; Nork, T. Michael; Perry-Raymond, Jennie; Fine, Stuart L.; Maguire, Maureen G.; Brightwell-Arnold, Mary; Harkins, Sandra; Peskin, Ellen; Ying, Gui-Shuang; Kurinij, Natalie

    2010-01-01

    We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10−75), ARMS2 (P < 10−59), C2/CFB (P < 10−20), C3 (P < 10−9), and CFI (P < 10−6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10−11), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 × 10−7; CETP, P = 7.4 × 10−7) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL (P = 3.0 × 10−3) and ABCA1 (P = 5.6 × 10−4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies. PMID:20385819

  2. Sex-specific effects of NLRP6/AVR and ADM loci on susceptibility to essential hypertension in a Sardinian population.

    Directory of Open Access Journals (Sweden)

    Nicola Glorioso

    Full Text Available Coronary artery disease, heart failure, fatal arrhythmias, stroke, and renal disease are the most common causes of mortality for humans, and essential hypertension remains a major risk factor. Elucidation of susceptibility loci for essential hypertension has been difficult because of its complex, multifactorial nature involving genetic, environmental, and sex- and age-dependent nature. We investigated whether the 11p15.5 region syntenic to rat chromosome 1 region containing multiple blood pressure quantitative trait loci (QTL detected in Dahl rat intercrosses harbors polymorphisms that contribute to susceptibility/resistance to essential hypertension in a Sardinian population. Initial testing performed using microsatellite markers spanning 18 Mb of 11p15.5 detected a strong association between D11S1318 (at 2.1 Mb, P = 0.004 and D11S1346 (at 10.6 Mb, P = 0.00000004, suggesting that loci in close proximity to these markers may contribute to susceptibility in our Sardinian cohort. NLR family, pyrin domain containing 6/angiotensin-vasopressin receptor (NLRP6/AVR, and adrenomedullin (ADM are in close proximity to D11S1318 and D11S1346, respectively; thus we tested single nucleotide polymorphisms (SNPs within NLRP6/AVR and ADM for their association with hypertension in our Sardinian cohort. Upon sex stratification, we detected one NLRP6/AVR SNP associated with decreased susceptibility to hypertension in males (rs7948797G, P = 0.029; OR = 0.73 [0.57-0.94]. For ADM, sex-specific analysis showed a significant association between rs4444073C, with increased susceptibility to essential hypertension only in the male population (P = 0.006; OR = 1.44 [1.13-1.84]. Our results revealed an association between NLRP6/AVR and ADM loci with male essential hypertension, suggesting the existence of sex-specific NLRP6/AVR and ADM variants affecting male susceptibility to essential hypertension.

  3. Genomewide scan for affective disorder susceptibility Loci in families of a northern Swedish isolated population.

    Science.gov (United States)

    Venken, Tine; Claes, Stephan; Sluijs, Samuel; Paterson, Andrew D; van Duijn, Cornelia; Adolfsson, Rolf; Del-Favero, Jurgen; Van Broeckhoven, Christine

    2005-02-01

    We analyzed nine multigenerational families with ascertained affective spectrum disorders in northern Sweden's geographically isolated population of Vasterbotten. This northern Swedish population, which originated from a limited number of early settlers approximately 8,000 years ago, is genetically more homogeneous than outbred populations. In a genomewide linkage analysis, we identified three chromosomal loci with multipoint LOD scores (MPLOD) >/=2 at 9q31.1-q34.1 (MPLOD 3.24), 6q22.2-q24.2 (MPLOD 2.48), and 2q33-q36 (MPLOD 2.26) under a recessive affected-only model. Follow-up genotyping with application of a 2-cM density simple-tandem-repeat (STR) map confirmed linkage at 9q31.1-q34.1 (MPLOD 3.22), 6q23-q24 (MPLOD 3.25), and 2q33-q36 (MPLOD 2.2). In an initial analysis aimed at identification of the underlying susceptibility genes, we focused our attention on the 9q locus. We fine mapped this region at a 200-kb STR density, with the result of an MPLOD of 3.70. Genealogical studies showed that three families linked to chromosome 9q descended from common founder couples approximately 10 generations ago. In this approximately 10-generation pedigree, a common ancestral haplotype was inherited by the patients, which reduced the 9q candidate region to 1.6 Mb. Further, the shared haplotype was observed in 4.2% of patients with bipolar disorder with alternating episodes of depression and mania, but it was not observed in control individuals in a patient-control sample from the Vasterbotten isolate. These results suggest a susceptibility locus on 9q31-q33 for affective disorder in this common ancestral region.

  4. Mapping of quantitative trait loci affecting resistance/susceptibility to Sarcocystis miescheriana in swine.

    Science.gov (United States)

    Reiner, Gerald; Kliemt, Damaris; Willems, Hermann; Berge, Thomas; Fischer, Reiner; Köhler, Florian; Hepp, Sabine; Hertrampf, Barbara; Daugschies, Arwid; Geldermann, Hermann; Mackenstedt, Ute; Zahner, Horst

    2007-05-01

    The outcome of infectious diseases in vertebrates is under genetic control at least to some extent. In swine, e.g., marked differences in resistance/susceptibility to Sarcocystis miescheriana have been shown between Chinese Meishan and European Pietrain pigs, and these differences are associated with high heritabilities. A first step toward the identification of genes and polymorphisms causal for these differences may be the mapping of quantitative trait loci (QTLs). Considering clinical, immunological, and parasitological traits in the above model system, this survey represents the first QTL study on parasite resistance in pigs. QTL mapping was performed in 139 F(2) pigs of a Meishan/Pietrain family infected with S. miescheriana. Fourteen genome-wide significant QTLs were mapped to several chromosomal areas. Among others, major QTLs were identified for bradyzoite numbers in skeletal muscles (F = 17.4; p < 0.001) and for S. miescheriana-specific plasma IgG(2) levels determined 42 days p.i. (F = 20.9; p < 0.001). The QTLs were mapped to different regions of chromosome 7, i.e., to the region of the major histocompatibility complex (bradyzoites) and to an immunoglobulin heavy chain cluster, respectively. These results provide evidence for a direct and causal role for gene variants within these gene clusters (cis-acting) in differences in resistance to S. miescheriana.

  5. A genome-wide association study identifies four novel susceptibility loci underlying inguinal hernia

    Science.gov (United States)

    Jorgenson, Eric; Makki, Nadja; Shen, Ling; Chen, David C.; Tian, Chao; Eckalbar, Walter L.; Hinds, David; Ahituv, Nadav; Avins, Andrew

    2015-01-01

    Inguinal hernia repair is one of the most commonly performed operations in the world, yet little is known about the genetic mechanisms that predispose individuals to develop inguinal hernias. We perform a genome-wide association analysis of surgically confirmed inguinal hernias in 72,805 subjects (5,295 cases and 67,510 controls) and confirm top associations in an independent cohort of 92,444 subjects with self-reported hernia repair surgeries (9,701 cases and 82,743 controls). We identify four novel inguinal hernia susceptibility loci in the regions of EFEMP1, WT1, EBF2 and ADAMTS6. Moreover, we observe expression of all four genes in mouse connective tissue and network analyses show an important role for two of these genes (EFEMP1 and WT1) in connective tissue maintenance/homoeostasis. Our findings provide insight into the aetiology of hernia development and highlight genetic pathways for studies of hernia development and its treatment. PMID:26686553

  6. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.

    Science.gov (United States)

    Beecham, Ashley H; Patsopoulos, Nikolaos A; Xifara, Dionysia K; Davis, Mary F; Kemppinen, Anu; Cotsapas, Chris; Shah, Tejas S; Spencer, Chris; Booth, David; Goris, An; Oturai, Annette; Saarela, Janna; Fontaine, Bertrand; Hemmer, Bernhard; Martin, Claes; Zipp, Frauke; D'Alfonso, Sandra; Martinelli-Boneschi, Filippo; Taylor, Bruce; Harbo, Hanne F; Kockum, Ingrid; Hillert, Jan; Olsson, Tomas; Ban, Maria; Oksenberg, Jorge R; Hintzen, Rogier; Barcellos, Lisa F; Agliardi, Cristina; Alfredsson, Lars; Alizadeh, Mehdi; Anderson, Carl; Andrews, Robert; Søndergaard, Helle Bach; Baker, Amie; Band, Gavin; Baranzini, Sergio E; Barizzone, Nadia; Barrett, Jeffrey; Bellenguez, Céline; Bergamaschi, Laura; Bernardinelli, Luisa; Berthele, Achim; Biberacher, Viola; Binder, Thomas M C; Blackburn, Hannah; Bomfim, Izaura L; Brambilla, Paola; Broadley, Simon; Brochet, Bruno; Brundin, Lou; Buck, Dorothea; Butzkueven, Helmut; Caillier, Stacy J; Camu, William; Carpentier, Wassila; Cavalla, Paola; Celius, Elisabeth G; Coman, Irène; Comi, Giancarlo; Corrado, Lucia; Cosemans, Leentje; Cournu-Rebeix, Isabelle; Cree, Bruce A C; Cusi, Daniele; Damotte, Vincent; Defer, Gilles; Delgado, Silvia R; Deloukas, Panos; di Sapio, Alessia; Dilthey, Alexander T; Donnelly, Peter; Dubois, Bénédicte; Duddy, Martin; Edkins, Sarah; Elovaara, Irina; Esposito, Federica; Evangelou, Nikos; Fiddes, Barnaby; Field, Judith; Franke, Andre; Freeman, Colin; Frohlich, Irene Y; Galimberti, Daniela; Gieger, Christian; Gourraud, Pierre-Antoine; Graetz, Christiane; Graham, Andrew; Grummel, Verena; Guaschino, Clara; Hadjixenofontos, Athena; Hakonarson, Hakon; Halfpenny, Christopher; Hall, Gillian; Hall, Per; Hamsten, Anders; Harley, James; Harrower, Timothy; Hawkins, Clive; Hellenthal, Garrett; Hillier, Charles; Hobart, Jeremy; Hoshi, Muni; Hunt, Sarah E; Jagodic, Maja; Jelčić, Ilijas; Jochim, Angela; Kendall, Brian; Kermode, Allan; Kilpatrick, Trevor; Koivisto, Keijo; Konidari, Ioanna; Korn, Thomas; Kronsbein, Helena; Langford, Cordelia; Larsson, Malin; Lathrop, Mark; Lebrun-Frenay, Christine; Lechner-Scott, Jeannette; Lee, Michelle H; Leone, Maurizio A; Leppä, Virpi; Liberatore, Giuseppe; Lie, Benedicte A; Lill, Christina M; Lindén, Magdalena; Link, Jenny; Luessi, Felix; Lycke, Jan; Macciardi, Fabio; Männistö, Satu; Manrique, Clara P; Martin, Roland; Martinelli, Vittorio; Mason, Deborah; Mazibrada, Gordon; McCabe, Cristin; Mero, Inger-Lise; Mescheriakova, Julia; Moutsianas, Loukas; Myhr, Kjell-Morten; Nagels, Guy; Nicholas, Richard; Nilsson, Petra; Piehl, Fredrik; Pirinen, Matti; Price, Siân E; Quach, Hong; Reunanen, Mauri; Robberecht, Wim; Robertson, Neil P; Rodegher, Mariaemma; Rog, David; Salvetti, Marco; Schnetz-Boutaud, Nathalie C; Sellebjerg, Finn; Selter, Rebecca C; Schaefer, Catherine; Shaunak, Sandip; Shen, Ling; Shields, Simon; Siffrin, Volker; Slee, Mark; Sorensen, Per Soelberg; Sorosina, Melissa; Sospedra, Mireia; Spurkland, Anne; Strange, Amy; Sundqvist, Emilie; Thijs, Vincent; Thorpe, John; Ticca, Anna; Tienari, Pentti; van Duijn, Cornelia; Visser, Elizabeth M; Vucic, Steve; Westerlind, Helga; Wiley, James S; Wilkins, Alastair; Wilson, James F; Winkelmann, Juliane; Zajicek, John; Zindler, Eva; Haines, Jonathan L; Pericak-Vance, Margaret A; Ivinson, Adrian J; Stewart, Graeme; Hafler, David; Hauser, Stephen L; Compston, Alastair; McVean, Gil; De Jager, Philip; Sawcer, Stephen J; McCauley, Jacob L

    2013-11-01

    Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

  7. Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor.

    Science.gov (United States)

    Litchfield, Kevin; Levy, Max; Orlando, Giulia; Loveday, Chey; Law, Philip J; Migliorini, Gabriele; Holroyd, Amy; Broderick, Peter; Karlsson, Robert; Haugen, Trine B; Kristiansen, Wenche; Nsengimana, Jérémie; Fenwick, Kerry; Assiotis, Ioannis; Kote-Jarai, ZSofia; Dunning, Alison M; Muir, Kenneth; Peto, Julian; Eeles, Rosalind; Easton, Douglas F; Dudakia, Darshna; Orr, Nick; Pashayan, Nora; Bishop, D Timothy; Reid, Alison; Huddart, Robert A; Shipley, Janet; Grotmol, Tom; Wiklund, Fredrik; Houlston, Richard S; Turnbull, Clare

    2017-07-01

    Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.

  8. Test of linkage between candidate loci and a prostate cancer susceptibility locus in a set of high risk kindreds

    Energy Technology Data Exchange (ETDEWEB)

    Cannon-Albright, L.A.; Neuhausen, S.; Goldgar, D.E. [Univ. of Utah, Salt Lake City, UT (United States)] [and others

    1994-09-01

    Although no prostate cancer susceptibility locus has yet been mapped, candidate loci have been suggested by a series of allele loss studies in prostate tumors. We have used linkage analysis to investigate each locus previously shown to be lost in at least 30 percent of tumors. Seven high risk cases were screened with 31 markers representing loci on 11 chromosome arms to test for cosegregation of the markers and prostate cancer. Age of cancer onset for prostate cancer cases was not considered for ascertainment. A variety of models were utilized in linkage analysis, as well as model-free methods. A subset of Lod scored at {theta}=.01 are shown for a low penetrance affected-only model which assumed a rare dominant susceptibility and allowed sporadic cases. Multiple markers were run for each locus considered. Positive Lod scores >1.0 in specific kindreds are being investigated further and an exclusion map will be presented.

  9. Genetic association studies in complex disease : Disentangling additional predisposing loci from associated neutral loci using a constrained - permutation approach

    NARCIS (Netherlands)

    Spijker, G T; Nolte, I.M.; Jansen, R.C.; te Meerman, G.J.

    2005-01-01

    In the process of genetically mapping a complex disease, the question may arise whether a certain polymorphism is the only causal variant in a region. A number of methods can answer this question, but unfortunately these methods are optimal for bi-allelic loci only. We wanted to develop a method

  10. Impact of diabetes susceptibility loci on progression from pre-diabetes to diabetes in at-risk individuals of the diabetes prevention trial-type 1 (DPT-1).

    Science.gov (United States)

    Butty, Vincent; Campbell, Christopher; Mathis, Diane; Benoist, Christophe

    2008-09-01

    The unfolding of type 1 diabetes involves a number of steps: defective immunological tolerance, priming of anti-islet autoimmunity, and destruction of insulin-producing beta-cells. A number of genetic loci contribute to susceptibility to type 1 diabetes, but it is unclear which stages of the disease are influenced by the different loci. Here, we analyzed the frequency of type 1 diabetes-risk alleles among individuals from the Diabetes Prevention Trial-Type 1 (DPT-1) clinical trial, which tested a preventive effect of insulin in at-risk relatives of diabetic individuals, all of which presented with autoimmune manifestations but only one-third of which eventually progressed to diabetes. In this study, 708 individuals randomized into DPT-1 were genotyped for 37 single nucleotide polymorphisms in diabetes susceptibility loci. Susceptibility alleles at loci expected to influence immunoregulation (PTPN22, CTLA4, and IL2RA) did not differ between progressors and nonprogressors but were elevated in both groups relative to general population frequencies, as was the INS promoter variant. In contrast, HLA DQB1*0302 and DQB1*0301 differed significantly in progressors versus nonprogressors (DQB*0302, 42.6 vs. 34.7%, P = 0.0047; DQB*0301, 8.6 vs. 14.3%, P = 0.0026). Multivariate analysis of the factors contributing to progression demonstrated that initial titers of anti-insulin autoantibodies (IAAs) could account for some (P = 0.0016) but not all of this effect on progression (P = 0.00038 for the independent effect of the number of DQB*0302 alleles). The INS-23 genotype was most strongly associated with anti-IAAs (median IAA levels in TT individuals, 60 nU/ml; AT, 121; and AA, 192; P = 0.000037) and only suggestively to the outcome of oral insulin administration. With the exception of HLA, most susceptibility loci tested condition the risk of autoimmunity rather than the risk of failed immunoregulation that results in islet destruction. Future clinical trials might consider

  11. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

    DEFF Research Database (Denmark)

    Anderson, Carl A; Boucher, Gabrielle; Lees, Charlie W

    2011-01-01

    Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association s...

  12. Detection of quantitative trait loci for resistance/susceptibility to pseudorabies virus in swine.

    Science.gov (United States)

    Reiner, Gerald; Melchinger, Elke; Kramarova, Marcela; Pfaff, Eberhardt; Büttner, Matthias; Saalmüller, Armin; Geldermann, Hermann

    2002-01-01

    This study describes genetic differences in resistance/susceptibility to pseudorabies virus (PrV) between European Large White and Chinese Meishan pigs, with a mapping of quantitative trait loci (QTL) obtained from a genome-wide scan in F(2) animals. Eighty-nine F(2) pigs were challenged intranasally at 12 weeks with 10(5) p.f.u. of the wild-type PrV strain NIA-3. For QTL analysis, 85 microsatellite markers, evenly spaced on the 18 porcine autosomes and on the pseudoautosomal region of the X chromosome, were genotyped. All pigs developed clinical signs, i.e. fever, from 3 to 7 days p.i. The pure-bred Large White pigs, the F(1) and three-quarters of the F(2) animals, but none of the Meishan pigs, developed neurological symptoms and died or were euthanized. QTLs for appearance/non-appearance of neurological symptoms were found on chromosomes 9, 5, 6 and 13. They explained 10.6-17.9% of F(2) phenotypic variance. QTL effects for rectal temperature after PrV challenge were found on chromosomes 2, 4, 8, 10, 11 and 16. Effects on chromosomes 9, 10 and 11 were significant on a genome-wide level. The results present chromosomal regions that are associated with presence/absence of neurological symptoms as well as temperature course after intranasal challenge with NIA-3. The QTLs are in proximity to important candidate genes that are assumed to play crucial roles in host defence against PrV.

  13. Large scale association analysis identifies three susceptibility loci for coronary artery disease.

    Directory of Open Access Journals (Sweden)

    Stephanie Saade

    Full Text Available Genome wide association studies (GWAS and their replications that have associated DNA variants with myocardial infarction (MI and/or coronary artery disease (CAD are predominantly based on populations of European or Eastern Asian descent. Replication of the most significantly associated polymorphisms in multiple populations with distinctive genetic backgrounds and lifestyles is crucial to the understanding of the pathophysiology of a multifactorial disease like CAD. We have used our Lebanese cohort to perform a replication study of nine previously identified CAD/MI susceptibility loci (LTA, CDKN2A-CDKN2B, CELSR2-PSRC1-SORT1, CXCL12, MTHFD1L, WDR12, PCSK9, SH2B3, and SLC22A3, and 88 genes in related phenotypes. The study was conducted on 2,002 patients with detailed demographic, clinical characteristics, and cardiac catheterization results. One marker, rs6922269, in MTHFD1L was significantly protective against MI (OR=0.68, p=0.0035, while the variant rs4977574 in CDKN2A-CDKN2B was significantly associated with MI (OR=1.33, p=0.0086. Associations were detected after adjustment for family history of CAD, gender, hypertension, hyperlipidemia, diabetes, and smoking. The parallel study of 88 previously published genes in related phenotypes encompassed 20,225 markers, three quarters of which with imputed genotypes The study was based on our genome-wide genotype data set, with imputation across the whole genome to HapMap II release 22 using HapMap CEU population as a reference. Analysis was conducted on both the genotyped and imputed variants in the 88 regions covering selected genes. This approach replicated HNRNPA3P1-CXCL12 association with CAD and identified new significant associations of CDKAL1, ST6GAL1, and PTPRD with CAD. Our study provides evidence for the importance of the multifactorial aspect of CAD/MI and describes genes predisposing to their etiology.

  14. Genome-wide association study in people of South Asian ancestry identifies six novel susceptibility loci for type 2 diabetes

    Science.gov (United States)

    Kooner, Jaspal S; Saleheen, Danish; Sim, Xueling; Sehmi, Joban; Zhang, Weihua; Frossard, Philippe; Been, Latonya F; Chia, Kee-Seng; Dimas, Antigone S; Hassanali, Neelam; Jafar, Tazeen; Jowett, Jeremy BM; Li, Xinzhing; Radha, Venkatesan; Rees, Simon D; Takeuchi, Fumihiko; Young, Robin; Aung, Tin; Basit, Abdul; Chidambaram, Manickam; Das, Debashish; Grunberg, Elin; Hedman, Åsa K; Hydrie, Zafar I; Islam, Muhammed; Khor, Chiea-Chuen; Kowlessur, Sudhir; Kristensen, Malene M; Liju, Samuel; Lim, Wei-Yen; Matthews, David R; Liu, Jianjun; Morris, Andrew P; Nica, Alexandra C; Pinidiyapathirage, Janani M; Prokopenko, Inga; Rasheed, Asif; Samuel, Maria; Shah, Nabi; Shera, A Samad; Small, Kerrin S; Suo, Chen; Wickremasinghe, Ananda R; Wong, Tien Yin; Yang, Mingyu; Zhang, Fan; Abecasis, Goncalo R; Barnett, Anthony H; Caulfield, Mark; Deloukas, Panos; Frayling, Tim; Froguel, Philippe; Kato, Norihiro; Katulanda, Prasad; Kelly, M Ann; Liang, Junbin; Mohan, Viswanathan; Sanghera, Dharambir K; Scott, James; Seielstad, Mark; Zimmet, Paul Z; Elliott, Paul; Teo, Yik Ying; McCarthy, Mark I; Danesh, John; Tai, E Shyong; Chambers, John C

    2013-01-01

    We carried out a genome wide association study of type-2 diabetes (T2D) amongst 20,119 people of South Asian ancestry (5,561 with T2D); we identified 20 independent SNPs associated with T2D at P<10−4 for testing amongst a further 38,568 South Asians (13,170 with T2D). In combined analysis, common genetic variants at six novel loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) were associated with T2D (P=4.1×10−8 to P=1.9×10−11); SNPs at GRB14 were also associated with insulin sensitivity, and at ST6GAL1 and HNF4A with pancreatic beta-cell function respectively. Our findings provide additional insight into mechanisms underlying T2D, and demonstrate the potential for new discovery from genetic association studies in South Asians who have increased susceptibility to T2D. PMID:21874001

  15. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

    DEFF Research Database (Denmark)

    Gaulton, Kyle J; Ferreira, Teresa; Lee, Yeji

    2015-01-01

    We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct...

  16. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

    NARCIS (Netherlands)

    F.J. Couch (Fergus); K.B. Kuchenbaecker (Karoline); K. Michailidou (Kyriaki); G.A. Mendoza-Fandino (Gustavo A.); S. Nord (Silje); J. Lilyquist (Janna); C. Olswold (Curtis); B. Hallberg (Boubou); S. Agata (Simona); H. Ahsan (Habibul); K. Aittomäki (Kristiina); C.B. Ambrosone (Christine); I.L. Andrulis (Irene); H. Anton-Culver (Hoda); V. Arndt (Volker); B.K. Arun (Banu); B. Arver (Brita Wasteson); M. Barile (Monica); R.B. Barkardottir (Rosa); D. Barrowdale (Daniel); L. Beckmann (Lars); M.W. Beckmann (Matthias); J. Benítez (Javier); S.V. Blank (Stephanie); C. Blomqvist (Carl); N.V. Bogdanova (Natalia); S.E. Bojesen (Stig); M.K. Bolla (Manjeet); B. Bonnani (Bernardo); H. Brauch (Hiltrud); H. Brenner (Hermann); B. Burwinkel (Barbara); S.S. Buys (Saundra S.); T. Caldes (Trinidad); M.A. Caligo (Maria); F. Canzian (Federico); T.A. Carpenter (Adrian); J. Chang-Claude (Jenny); S.J. Chanock (Stephen J.); W.K. Chung (Wendy K.); K.B.M. Claes (Kathleen B.M.); A. Cox (Angela); S.S. Cross (Simon); J.M. Cunningham (Julie); K. Czene (Kamila); M.B. Daly (Mary B.); F. Damiola (Francesca); H. Darabi (Hatef); M. de La Hoya (Miguel); P. Devilee (Peter); O. Díez (Orland); Y.C. Ding (Yuan); R. Dolcetti (Riccardo); S.M. Domchek (Susan); C.M. Dorfling (Cecilia); I. dos Santos Silva (Isabel); M. Dumont (Martine); A.M. Dunning (Alison); D. Eccles (Diana); H. Ehrencrona (Hans); A.B. Ekici (Arif); H. Eliassen (Heather); S.D. Ellis (Steve); P.A. Fasching (Peter); J.D. Figueroa (Jonine); D. Flesch-Janys (Dieter); A. Försti (Asta); F. Fostira (Florentia); W.D. Foulkes (William); M.O.W. Friebel (Mark ); E. Friedman (Eitan); D. Frost (Debra); M. Gabrielson (Marike); M. Gammon (Marilie); P.A. Ganz (Patricia A.); S.M. Gapstur (Susan M.); J. Garber (Judy); M.M. Gaudet (Mia); S.A. Gayther (Simon); A-M. Gerdes (Anne-Marie); M. Ghoussaini (Maya); G.G. Giles (Graham); G. Glendon (Gord); A.K. Godwin (Andrew K.); M.S. Goldberg (Mark); D. Goldgar (David); A. González-Neira (Anna); M.H. Greene (Mark H.); J. Gronwald (Jacek); P. Guénel (Pascal); M.J. Gunter (Marc J.); L. Haeberle (Lothar); C.A. Haiman (Christopher A.); U. Hamann (Ute); T.V.O. Hansen (Thomas); S. Hart (Stewart); S. Healey (Sue); T. Heikkinen (Tuomas); B.E. Henderson (Brian); J. Herzog (Josef); F.B.L. Hogervorst (Frans); A. Hollestelle (Antoinette); M.J. Hooning (Maartje); R.N. Hoover (Robert); J.L. Hopper (John); K. Humphreys (Keith); D. Hunter (David); T. Huzarski (Tomasz); E.N. Imyanitov (Evgeny N.); C. Isaacs (Claudine); A. Jakubowska (Anna); M. James (Margaret); R. Janavicius (Ramunas); U.B. Jensen; E.M. John (Esther); M. Jones (Michael); M. Kabisch (Maria); S. Kar (Siddhartha); B.Y. Karlan (Beth Y.); S. Khan (Sofia); K.T. Khaw; M.G. Kibriya (Muhammad); J.A. Knight (Julia); Y.-D. Ko (Yon-Dschun); I. Konstantopoulou (I.); V-M. Kosma (Veli-Matti); V. Kristensen (Vessela); A. Kwong (Ava); Y. Laitman (Yael); D. Lambrechts (Diether); C. Lazaro (Conxi); E. Lee (Eunjung); L. Le Marchand (Loic); K.J. Lester (Kathryn); A. Lindblom (Annika); N.M. Lindor (Noralane); S. Lindstrom (Stephen); J. Liu (Jianjun); J. Long (Jirong); J. Lubinski (Jan); P.L. Mai (Phuong); E. Makalic (Enes); K.E. Malone (Kathleen E.); A. Mannermaa (Arto); S. Manoukian (Siranoush); S. Margolin (Sara); F. Marme (Federick); J.W.M. Martens (John); L. McGuffog (Lesley); A. Meindl (Alfons); A. Miller (Austin); R.L. Milne (Roger); P. Miron (Penelope); M. Montagna (Marco); S. Mazoyer (Sylvie); A.-M. Mulligan (Anna-Marie); T.A. Muranen (Taru); K.L. Nathanson (Katherine); S.L. Neuhausen (Susan); H. Nevanlinna (Heli); B.G. Nordestgaard (Børge); R. Nussbaum (Robert); K. Offit (Kenneth); E. Olah; O.I. Olopade (Olufunmilayo I.); J.E. Olson (Janet); A. Osorio (Ana); S.K. Park (Sue K.); P.H.M. Peeters; B. Peissel (Bernard); P. Peterlongo (Paolo); J. Peto (Julian); C. Phelan (Catherine); R. Pilarski (Robert); B. Poppe (Bruce); K. Pykäs (Katri); P. Radice (Paolo); N. Rahman (Nazneen); J. Rantala (Johanna); C. Rappaport (Christine); G. Rennert (Gad); A.L. Richardson (Andrea); M. Robson (Mark); I. Romieu (Isabelle); A. Rudolph (Anja); E.J.T. Rutgers (Emiel); M.-J. Sanchez (Maria-Jose); R. Santella (Regina); E.J. Sawyer (Elinor); D.F. Schmidt (Daniel); M.K. Schmidt (Marjanka); R.K. Schmutzler (Rita); F.R. Schumacher (Fredrick); R.J. Scott (Rodney); L. Senter (Leigha); P. Sharma (Priyanka); J. Simard (Jacques); C.F. Singer (Christian); O. Sinilnikova (Olga); P. Soucy (Penny); M.C. Southey (Melissa); D. Steinemann (Doris); M. Stenmark-Askmalm (Marie); D. Stoppa-Lyonnet (Dominique); A.J. Swerdlow (Anthony ); C. Szabo (Csilla); R. Tamimi (Rulla); W. Tapper (William); P.J. Teixeira; S.-H. Teo; M.B. Terry (Mary Beth); M. Thomassen (Mads); D. Thompson (Deborah); L. Tihomirova (Laima); A.E. Toland (Amanda); R.A.E.M. Tollenaar (Rob); I.P. Tomlinson (Ian); T. Truong (Thérèse); H. Tsimiklis (Helen); A. Teulé (A.); R. Tumino (Rosario); N. Tung (Nadine); C. Turnbull (Clare); G. Ursin (Giski); C.H.M. van Deurzen (Carolien); E.J. van Rensburg (Elizabeth); R. Varon-Mateeva (Raymonda); Z. Wang (Zhaoming); S. Wang-Gohrke (Shan); E. Weiderpass (Elisabete); J.N. Weitzel (Jeffrey); A.S. Whittemore (Alice S.); H. Wildiers (Hans); R. Winqvist (Robert); X.R. Yang (Xiaohong R.); D. Yannoukakos (Drakoulis); S. Yao (Song); M.P. Zamora (Pilar); W. Zheng (Wei); P. Hall (Per); P. Kraft (Peter); C. Vachon (Celine); S. Slager (Susan); G. Chenevix-Trench (Georgia); P.D.P. Pharoah (Paul); A.A.N. Monteiro (Alvaro A. N.); M. García-Closas (Montserrat); D.F. Easton (Douglas F.); A.C. Antoniou (Antonis C.)

    2016-01-01

    textabstractCommon variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10-8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative

  17. Three Ulcerative Colitis Susceptibility Loci Are Associated with Primary Sclerosing Cholangitis and Indicate a Role for IL2, REL, and CARD9

    NARCIS (Netherlands)

    Janse, Marcel; Lamberts, Laetitia E.; Franke, Lude; Raychaudhuri, Soumya; Ellinghaus, Eva; Boberg, Kirsten Muri; Melum, Espen; Folseraas, Trine; Schrumpf, Erik; Bergquist, Annika; Bjornsson, Einar; Fu, Jingyuan; Westra, Harm Jan; Groen, Harry J. M.; Fehrmann, Rudolf S. N.; Smolonska, Joanna; van den Berg, Leonard H.; Ophoff, Roel A.; Porte, Robert J.; Weismueller, Tobias J.; Wedemeyer, Jochen; Schramm, Christoph; Sterneck, Martina; Guenther, Rainer; Braun, Felix; Vermeire, Severine; Henckaerts, Liesbet; Wijmenga, Cisca; Ponsioen, Cyriel Y.; Schreiber, Stefan; Karlsen, Tom H.; Franke, Andre; Weersma, Rinse K.

    Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently

  18. Interaction of smoking and obesity susceptibility loci on adolescent BMI: The National Longitudinal Study of Adolescent to Adult Health.

    Science.gov (United States)

    Young, Kristin L; Graff, Misa; North, Kari E; Richardson, Andrea S; Mohlke, Karen L; Lange, Leslie A; Lange, Ethan M; Harris, Kathleen M; Gordon-Larsen, Penny

    2015-11-04

    Adolescence is a sensitive period for weight gain and risky health behaviors, such as smoking. Genome-wide association studies (GWAS) have identified loci contributing to adult body mass index (BMI). Evidence suggests that many of these loci have a larger influence on adolescent BMI. However, few studies have examined interactions between smoking and obesity susceptibility loci on BMI. This study investigates the interaction of current smoking and established BMI SNPs on adolescent BMI. Using data from the National Longitudinal Study of Adolescent to Adult Health, a nationally-representative, prospective cohort of the US school-based population in grades 7 to 12 (12-20 years of age) in 1994-95 who have been followed into adulthood (Wave II 1996; ages 12-21, Wave III; ages 18-27), we assessed (in 2014) interactions of 40 BMI-related SNPs and smoking status with percent of the CDC/NCHS 2000 median BMI (%MBMI) in European Americans (n = 5075), African Americans (n = 1744) and Hispanic Americans (n = 1294). Two SNPs showed nominal significance for interaction (p obesity risk by smoking status in adolescents, with those who may be most likely to initiate smoking (i.e., adolescent females), being at greatest risk for exacerbating genetic obesity susceptibility.

  19. Evaluation of shared genetic susceptibility loci between autoimmune diseases and schizophrenia based on genome-wide association studies.

    Science.gov (United States)

    Hoeffding, Louise K; Rosengren, Anders; Thygesen, Johan H; Schmock, Henriette; Werge, Thomas; Hansen, Thomas

    2017-01-01

    Epidemiological studies have documented higher than expected comorbidity (or, in some cases, inverse comorbidity) between schizophrenia and several autoimmune disorders. It remains unknown whether this comorbidity reflects shared genetic susceptibility loci. The present study aimed to investigate whether verified genome wide significant variants of autoimmune disorders confer risk of schizophrenia, which could suggest a common genetic basis. Seven hundred and fourteen genome wide significant risk variants of 25 autoimmune disorders were extracted from the NHGRI GWAS catalogue and examined for association to schizophrenia in the Psychiatric Genomics Consortium schizophrenia GWAS samples (36,989 cases and 113,075 controls). Two independent loci at 4q24 and 6p21.32-33 originally identified from GWAS of autoimmune diseases were found genome wide associated with schizophrenia (1.7 × 10(-8 )≥( )p ≥ 4.0 × 10(-21)). While these observations confirm the existence of shared genetic susceptibility loci between schizophrenia and autoimmune diseases, the findings did not show a significant enrichment. The findings do not support a genetic overlap in common SNPs between autoimmune diseases and schizophrenia that in part could explain the observed comorbidity from epidemiological studies.

  20. Design considerations in a sib-pair study of linkage for susceptibility loci in cancer

    Directory of Open Access Journals (Sweden)

    Finkelstein Dianne M

    2008-07-01

    Full Text Available Abstract Background Modern approaches to identifying new genes associated with disease allow very fine analysis of associaton and can be performed in population based case-control studies. However, the sibpair design is still valuable because it requires few assumptions other than acceptably high penetrance to identify genetic loci. Methods We conducted simulation studies to assess the impact of design factors on relative efficiency for a linkage study of colorectal cancer. We considered two test statistics, one comparing the mean IBD probability in affected pairs to its null value of 0.5, and one comparing the mean IBD probabilities between affected and discordant pairs. We varied numbers of parents available, numbers of affected and unaffected siblings, reconstructing the genotype of an unavailable affected sibling by a spouse and offspring, and elimination of sibships where the proband carries a mutation at another locus. Results Power and efficiency were most affected by the number of affected sibs, the number of sib pairs genotyped, and the risk attributable to linked and unlinked loci. Genotyping unaffected siblings added little power for low penetrance models, but improved validity of tests when there was genetic heterogeneity and for multipoint testing. The efficiency of the concordant-only test was nearly always better than the concordant-discordant test. Replacement of an unavailable affected sibling by a spouse and offspring recovered some linkage information, particularly if several offspring were available. In multipoint analysis, the concordant-only test was showed a small anticonservative bias at 5 cM, while the multipoint concordant-discordant test was generally the most powerful test, and was not biased away from the null at 5 cM. Conclusion Genotyping parents and unaffected siblings is useful for detecting genotyping errors and if allele frequencies are uncertain. If adequate allele frequency data are available, we suggest a

  1. Susceptibility loci of CNOT6 in the general mRNA degradation pathway and lung cancer risk-A re-analysis of eight GWASs.

    Science.gov (United States)

    Zhou, Fei; Wang, Yanru; Liu, Hongliang; Ready, Neal; Han, Younghun; Hung, Rayjean J; Brhane, Yonathan; McLaughlin, John; Brennan, Paul; Bickeböller, Heike; Rosenberger, Albert; Houlston, Richard S; Caporaso, Neil; Landi, Maria Teresa; Brüske, Irene; Risch, Angela; Ye, Yuanqing; Wu, Xifeng; Christiani, David C; Goodman, Gary; Chen, Chu; Amos, Christopher I; Wei, Qingyi

    2017-04-01

    mRNA degradation is an important regulatory step for controlling gene expression and cell functions. Genetic abnormalities involved in mRNA degradation genes were found to be associated with cancer risks. Therefore, we systematically investigated the roles of genetic variants in the general mRNA degradation pathway in lung cancer risk. Meta-analyses were conducted using summary data from six lung cancer genome-wide association studies (GWASs) from the Transdisciplinary Research in Cancer of the Lung and additional two GWASs from Harvard University and deCODE in the International Lung Cancer Consortium. Expression quantitative trait loci analysis (eQTL) was used for in silico functional validation of the identified significant susceptibility loci. This pathway-based analysis included 6816 single nucleotide polymorphisms (SNP) in 68 genes in 14 463 lung cancer cases and 44 188 controls. In the single-locus analysis, we found that 20 SNPs were associated with lung cancer risk with a false discovery rate threshold of lung cancer risk (odds ratio = 1.11, 95% confidence interval = 1.04-1.18) in the eight GWASs. In the eQTL analysis, we found that levels of CNOT6 mRNA expression were significantly correlated with the rs2453176 T allele, which provided additional biological basis for the observed positive association. The CNOT6 rs2453176 SNP may be a new functional susceptible locus for lung cancer risk. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  2. IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci

    DEFF Research Database (Denmark)

    Sørensen, Per Soelberg

    2010-01-01

    the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele...... and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value=3.55 x 10(-9)), IL12A (P=3.08 x 10(-8)) and MPHOSPH9/CDK2AP1 (P=3.96 x 10(-8)). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele...

  3. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

    DEFF Research Database (Denmark)

    Mitchell, Jonathan S; Li, Ni; Weinhold, Niels

    2016-01-01

    a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10(-8)), 6q21 (rs9372120, P=9.09 × 10(-15)), 7q36.1 (rs7781265, P=9.71 × 10(-9)), 8q24.21 (rs1948915, P=4.20 × 10...

  4. Multiple susceptibility loci for radiation-induced mammary tumorigenesis in F2[Dahl S x R]-intercross rats.

    Directory of Open Access Journals (Sweden)

    Victoria L Herrera

    Full Text Available Although two major breast cancer susceptibility genes, BRCA1 and BRCA2, have been identified accounting for 20% of breast cancer genetic risk, identification of other susceptibility genes accounting for 80% risk remains a challenge due to the complex, multi-factorial nature of breast cancer. Complexity derives from multiple genetic determinants, permutations of gene-environment interactions, along with presumptive low-penetrance of breast cancer predisposing genes, and genetic heterogeneity of human populations. As with other complex diseases, dissection of genetic determinants in animal models provides key insight since genetic heterogeneity and environmental factors can be experimentally controlled, thus facilitating the detection of quantitative trait loci (QTL. We therefore, performed the first genome-wide scan for loci contributing to radiation-induced mammary tumorigenesis in female F2-(Dahl S x R-intercross rats. Tumorigenesis was measured as tumor burden index (TBI after induction of rat mammary tumors at forty days of age via ¹²⁷Cs-radiation. We observed a spectrum of tumor latency, size-progression, and pathology from poorly differentiated ductal adenocarcinoma to fibroadenoma, indicating major effects of gene-environment interactions. We identified two mammary tumorigenesis susceptibility quantitative trait loci (Mts-QTLs with significant linkage: Mts-1 on chromosome-9 (LOD-2.98 and Mts-2 on chromosome-1 (LOD-2.61, as well as two Mts-QTLs with suggestive linkage: Mts-3 on chromosome-5 (LOD-1.93 and Mts-4 on chromosome-18 (LOD-1.54. Interestingly, Chr9-Mts-1, Chr5-Mts-3 and Chr18-Mts-4 QTLs are unique to irradiation-induced mammary tumorigenesis, while Chr1-Mts-2 QTL overlaps with a mammary cancer susceptibility QTL (Mcs 3 reported for 7,12-dimethylbenz-[α]antracene (DMBA-induced mammary tumorigenesis in F2[COP x Wistar-Furth]-intercross rats. Altogether, our results suggest at least three distinct susceptibility QTLs for

  5. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics

    NARCIS (Netherlands)

    M. García-Closas (Montserrat); P. Hall (Per); H. Nevanlinna (Heli); K.A. Pooley (Karen); J. Morrison (Jonathan); D.A. Richesson (Douglas); S.E. Bojesen (Stig); B.G. Nordestgaard (Børge); C.K. Axelsson (Christen); J.I. Arias Pérez (José Ignacio); R.L. Milne (Roger); G. Ribas (Gloria); A. González-Neira (Anna); J. Benítez (Javier); P. Zamora (Pilar); H. Brauch (Hiltrud); C. Justenhoven (Christina); U. Hamann (Ute); Y-D. Ko (Yon-Dschun); T. Bruening (Thomas); S. Haas (Susanne); T. Dörk (Thilo); P. Schürmann (Peter); P. Hillemanns (Peter); N.V. Bogdanova (Natalia); M. Bremer (Michael); J.H. Karstens (Johann); R. Fagerholm (Rainer); K. Aaltonen (Kirsimari); K. Aittomäki (Kristiina); K. von Smitten (Karl); C. Blomqvist (Carl); A. Mannermaa (Arto); M. Uusitupa (Matti); M. Eskelinen (Matti); M. Tengström (Maria); V-M. Kosma (Veli-Matti); V. Kataja (Vesa); G. Chenevix-Trench (Georgia); A.B. Spurdle (Amanda); J. Beesley (Jonathan); X. Chen (Xiaoqing); P. Devilee (Peter); C.J. van Asperen (Christi); C.E. Jacobi (Catharina); R.A.E.M. Tollenaar (Rob); P. Huijts (Petra); J.G.M. Klijn (Jan); J. Chang-Claude (Jenny); S. Kropp (Silke); T. Slanger (Tracy); D. Flesch-Janys (Dieter); E. Mutschelknauss (Elke); R. Salazar (Ramona); S. Wang-Gohrke (Shan); F.J. Couch (Fergus); E.L. Goode (Ellen); J.E. Olson (Janet); C. Vachon (Celine); Z. Fredericksen (Zachary); G.G. Giles (Graham); L. Baglietto (Laura); G. Severi (Gianluca); J.L. Hopper (John); D.R. English (Dallas); M.C. Southey (Melissa); C.A. Haiman (Christopher); B.E. Henderson (Brian); L.N. Kolonel (Laurence); L. Le Marchand (Loic); D.O. Stram (Daniel); D. Hunter (David); S.E. Hankinson (Susan); A. Cox (Angela); R. Tamimi (Rulla); P. Kraft (Peter); M.E. Sherman (Mark); S.J. Chanock (Stephen); J. Lissowska (Jolanta); L.A. Brinton (Louise); B. Peplonska (Beata); M.J. Hooning (Maartje); E.J. Meijers-Heijboer (Hanne); J.M. Collee (Margriet); A.M.W. van den Ouweland (Ans); A.G. Uitterlinden (André); J. Liu (Jianjun); Y.L. Low; L. Yuqing (Li); M.K. Humphreys (Manjeet); K. Czene (Kamila); S. Balasubramanian (Sabapathy); S.S. Cross (Simon); M.W.R. Reed (Malcolm); F. Blows (Fiona); K. Driver (Kristy); A.M. Dunning (Alison); J.P. Tyrer (Jonathan); B.A.J. Ponder (Bruce); S. Sangrajrang (Suleeporn); P. Brennan (Paul); J.D. McKay (James); F. Odefrey (Fabrice); V. Gabrieau (Valerie); A.J. Sigurdson (Alice); M. Doody (Michele); J.P. Struewing (Jeffrey); B.H. Alexander (Bruce); D.F. Easton (Douglas); P.D.P. Pharoah (Paul)

    2008-01-01

    textabstractA three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1

  6. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

    NARCIS (Netherlands)

    J.F. Felix (Janine); J.P. Bradfield (Jonathan); C. Monnereau; R.J.P. van der Valk (Ralf); E. Stergiakouli (Evie); A. Chesi (Alessandra); R. Gaillard (Romy); B. Feenstra (Bjarke); E. Thiering (Elisabeth); E. Kreiner-Møller (Eskil); A. Mahajan (Anubha); Niina Pitkänen; R. Joro (Raimo); A. Cavadino (Alana); V. Huikari (Ville); S. Franks (Steve); M. Groen-Blokhuis (Maria); D.L. Cousminer (Diana); J.A. Marsh (Julie); T. Lehtimäki (Terho); J.A. Curtin (John); J. Vioque (Jesus); T.S. Ahluwalia (Tarunveer Singh); R. Myhre (Ronny); T.S. Price (Thomas); Natalia Vilor-Tejedor; L. Yengo (Loic); N. Grarup (Niels); I. Ntalla (Ioanna); W.Q. Ang (Wei); M. Atalay (Mustafa); H. Bisgaard (Hans); A.I.F. Blakemore (Alexandra); A. Bonnefond (Amélie); L. Carstensen (Lisbeth); J.G. Eriksson (Johan G.); C. Flexeder (Claudia); L. Franke (Lude); F. Geller (Frank); M. Geserick (Mandy); A.L. Hartikainen; C.M.A. Haworth (Claire M.); J.N. Hirschhorn (Joel N.); A. Hofman (Albert); J.-C. Holm (Jens-Christian); M. Horikoshi (Momoko); J.J. Hottenga (Jouke Jan); J. Huang (Jian); H.N. Kadarmideen (Haja N.); M. Kähönen (Mika); W. Kiess (Wieland); T.A. Lakka (Timo); T.A. Lakka (Timo); A. Lewin (Alex); L. Liang (Liming); L.-P. Lyytikäinen (Leo-Pekka); B. Ma (Baoshan); P. Magnus (Per); S.E. McCormack (Shana E.); G. Mcmahon (George); F.D. Mentch (Frank); C.M. Middeldorp (Christel); C.S. Murray (Clare S.); K. Pahkala (Katja); T.H. Pers (Tune); R. Pfäffle (Roland); D.S. Postma (Dirkje); C. Power (Christine); A. Simpson (Angela); V. Sengpiel (Verena); C. Tiesler (Carla); M. Torrent (Maties); A.G. Uitterlinden (André); J.B.J. van Meurs (Joyce); R. Vinding (Rebecca); J. Waage (Johannes); J. Wardle (Jane); E. Zeggini (Eleftheria); B.S. Zemel (Babette S.); G.V. Dedoussis (George); O. Pedersen (Oluf); P. Froguel (Philippe); J. Sunyer (Jordi); R. Plomin (Robert); B. Jacobsson (Bo); T. Hansen (Torben); J.R. Gonzalez (Juan R.); A. Custovic; O.T. Raitakari (Olli T.); C.E. Pennell (Craig); Elisabeth Widén; D.I. Boomsma (Dorret); G.H. Koppelman (Gerard); S. Sebert (Sylvain); M.-R. Jarvelin (Marjo-Riitta); E. Hypponen (Elina); M.I. McCarthy (Mark); V. Lindi (Virpi); N. Harri (Niinikoski); A. Körner (Antje); K. Bønnelykke (Klaus); J. Heinrich (Joachim); M. Melbye (Mads); F. Rivadeneira Ramirez (Fernando); H. Hakonarson (Hakon); S.M. Ring (Susan); G.D. Smith; T.I.A. Sørensen (Thorkild I.A.); N.J. Timpson (Nicholas); S.F.A. Grant (Struan); V.W.V. Jaddoe (Vincent); H.J. Kalkwarf (Heidi J.); J.M. Lappe (Joan M.); V. Gilsanz (Vicente); S.E. Oberfield (Sharon E.); J.A. Shepherd (John A.); A. Kelly (Andrea)

    2016-01-01

    textabstractA large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown.We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation

  7. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

    NARCIS (Netherlands)

    Felix, Janine F.; Bradfield, Jonathan P.; Monnereau, Claire; van der Valk, Ralf J. P.; Stergiakouli, Evie; Chesi, Alessandra; Gaillard, Romy; Feenstra, Bjarke; Thiering, Elisabeth; Kreiner-Moller, Eskil; Mahajan, Anubha; Pitkanen, Niina; Joro, Raimo; Cavadino, Alana; Huikari, Ville; Franks, Steve; Groen-Blokhuis, Maria M.; Cousminer, Diana L.; Marsh, Julie A.; Lehtimaki, Terho; Curtin, John A.; Vioque, Jesus; Ahluwalia, Tarunveer S.; Myhre, Ronny; Price, Thomas S.; Vilor-Tejedor, Natalia; Yengo, Loic; Grarup, Niels; Ntalla, Ioanna; Ang, Wei; Atalay, Mustafa; Bisgaard, Hans; Blakemore, Alexandra I.; Bonnefond, Amelie; Carstensen, Lisbeth; Eriksson, Johan; Flexeder, Claudia; Franke, Lude; Geller, Frank; Geserick, Mandy; Hartikainen, Anna-Liisa; Haworth, Claire M. A.; Hirschhorn, Joel N.; Hofman, Albert; Holm, Jens-Christian; Horikoshi, Momoko; Hottenga, Jouke Jan; Huang, Jinyan; Kadarmideen, Haja N.; Kahonen, Mika; Kiess, Wieland; Lakka, Hanna-Maaria; Lakka, Timo A.; Lewin, Alexandra M.; Liang, Liming; Lyytikainen, Leo-Pekka; Ma, Baoshan; Magnus, Per; McCormack, Shana E.; McMahon, George; Mentch, Frank D.; Middeldorp, Christel M.; Murray, Clare S.; Pahkala, Katja; Pers, Tune H.; Pfaefle, Roland; Postma, Dirkje S.; Power, Christine; Simpson, Angela; Sengpiel, Verena; Tiesler, Carla M. T.; Torrent, Maties; Uitterlinden, Andre G.; van Meurs, Joyce B.; Vinding, Rebecca; Waage, Johannes; Wardle, Jane; Zeggini, Eleftheria; Zemel, Babette S.; Dedoussis, George V.; Pedersen, Oluf; Froguel, Philippe; Sunyer, Jordi; Plomin, Robert; Jacobsson, Bo; Hansen, Torben; Gonzalez, Juan R.; Custovic, Adnan; Raitakari, Olli T.; Pennell, Craig E.; Widen, Elisabeth; Boomsma, Dorret I.; Koppelman, Gerard H.; Sebert, Sylvain; Jarvelin, Marjo-Riitta; Hypponen, Elina; McCarthy, Mark I.; Lindi, Virpi; Harri, Niinikoski; Koerner, Antje; Bonnelykke, Klaus; Heinrich, Joachim; Melbye, Mads; Rivadeneira, Fernando; Hakonarson, Hakon; Ring, Susan M.; Smith, George Davey; Sorensen, Thorkild I. A.; Timpson, Nicholas J.; Grant, Struan F. A.; Jaddoe, Vincent W. V.

    2016-01-01

    A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex-and age-adjusted standard deviation scores. We

  8. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

    NARCIS (Netherlands)

    Nakayama, A.; Nakaoka, H.; Yamamoto, K.; Sakiyama, M.; Shaukat, A.; Toyoda, Y.; Okada, Y.; Kamatani, Y.; Nakamura, T.; Takada, T.; Inoue, K.; Yasujima, T.; Yuasa, H.; Shirahama, Y.; Nakashima, H.; Shimizu, S.; Higashino, T.; Kawamura, Y.; Ogata, H.; Kawaguchi, M.; Ohkawa, Y.; Danjoh, I.; Tokumasu, A.; Ooyama, K.; Ito, T.; Kondo, T.; Wakai, K.; Stiburkova, B.; Pavelka, K.; Stamp, L.K.; Dalbeth, N.; Sakurai, Y.; Suzuki, H; Hosoyamada, M.; Fujimori, S.; Yokoo, T.; Hosoya, T.; Inoue, I.; Takahashi, A.; Kubo, M.; Ooyama, H.; Shimizu, T.; Ichida, K.; Shinomiya, N.; Merriman, T.R.; Matsuo, H.; Andres, M; Joosten, L.A.; Janssen, M.C.H.; Jansen, T.L.; Liote, F.; Radstake, T.R.; Riches, P.L.; So, A.; Tauches, A.K.

    2017-01-01

    OBJECTIVE: A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. METHODS: Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were

  9. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

    Science.gov (United States)

    Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara; Canisius, Sander; Dennis, Joe; Lush, Michael; Maranian, Mel J; Bolla, Manjeet K; Wang, Qin; Shah, Mitul; Perkins, Barbara J; Czene, Kamila; Eriksson, Mikael; Darabi, Hatef; Brand, Judith S; Bojesen, Stig E; Nordestgaard, Børge G; Flyger, Henrik; Nielsen, Sune F; Rahman, Nazneen; Turnbull, Clare; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; dos-Santos-Silva, Isabel; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Eilber, Ursula; Behrens, Sabine; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Aaltonen, Kirsimari; Ahsan, Habibul; Kibriya, Muhammad G; Whittemore, Alice S; John, Esther M; Malone, Kathleen E; Gammon, Marilie D; Santella, Regina M; Ursin, Giske; Makalic, Enes; Schmidt, Daniel F; Casey, Graham; Hunter, David J; Gapstur, Susan M; Gaudet, Mia M; Diver, W Ryan; Haiman, Christopher A; Schumacher, Fredrick; Henderson, Brian E; Le Marchand, Loic; Berg, Christine D; Chanock, Stephen; Figueroa, Jonine; Hoover, Robert N; Lambrechts, Diether; Neven, Patrick; Wildiers, Hans; van Limbergen, Erik; Schmidt, Marjanka K; Broeks, Annegien; Verhoef, Senno; Cornelissen, Sten; Couch, Fergus J; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel A; van der Luijt, Rob B; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Yoo, Keun-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Guénel, Pascal; Truong, Thérèse; Mulot, Claire; Sanchez, Marie; Burwinkel, Barbara; Marme, Frederik; Surowy, Harald; Sohn, Christof; Wu, Anna H; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O; González-Neira, Anna; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S; Reed, Malcolm WR; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Lindblom, Annika; Margolin, Sara; Teo, Soo Hwang; Yip, Cheng Har; Taib, Nur Aishah Mohd; TAN, Gie-Hooi; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John WM; Collée, J Margriet; Blot, William; Signorello, Lisa B; Cai, Qiuyin; Hopper, John L; Southey, Melissa C; Tsimiklis, Helen; Apicella, Carmel; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Hou, Ming-Feng; Kristensen, Vessela N; Nord, Silje; Alnaes, Grethe I Grenaker; Giles, Graham G; Milne, Roger L; McLean, Catriona; Canzian, Federico; Trichopoulos, Dmitrios; Peeters, Petra; Lund, Eiliv; Sund, Malin; Khaw, Kay-Tee; Gunter, Marc J; Palli, Domenico; Mortensen, Lotte Maxild; Dossus, Laure; Huerta, Jose-Maria; Meindl, Alfons; Schmutzler, Rita K; Sutter, Christian; Yang, Rongxi; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Hartman, Mikael; Miao, Hui; Chia, Kee Seng; Chan, Ching Wan; Fasching, Peter A; Hein, Alexander; Beckmann, Matthias W; Haeberle, Lothar; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J; Swerdlow, Anthony J; Brinton, Louise; Garcia-Closas, Montserrat; Zheng, Wei; Halverson, Sandra L; Shrubsole, Martha; Long, Jirong; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Brüning, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Bogdanova, Natalia V; Dörk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Devilee, Peter; Tollenaar, Robert AEM; Seynaeve, Caroline; Van Asperen, Christi J; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Huzarski, Tomasz; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Kabisch, Maria; Torres, Diana; Neuhausen, Susan L; Anton-Culver, Hoda; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Simard, Jacques; Pharoah, Paul PDP; Kraft, Peter; Dunning, Alison M; Chenevix-Trench, Georgia; Hall, Per; Easton, Douglas F

    2015-01-01

    Genome wide association studies (GWAS) and large scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ~14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS comprising of 15,748 breast cancer cases and 18,084 controls, and 46,785 cases and 42,892 controls from 41 studies genotyped on a 200K custom array (iCOGS). Analyses were restricted to women of European ancestry. Genotypes for more than 11M SNPs were generated by imputation using the 1000 Genomes Project reference panel. We identified 15 novel loci associated with breast cancer at P<5×10−8. Combining association analysis with ChIP-Seq data in mammary cell lines and ChIA-PET chromatin interaction data in ENCODE, we identified likely target genes in two regions: SETBP1 on 18q12.3 and RNF115 and PDZK1 on 1q21.1. One association appears to be driven by an amino-acid substitution in EXO1. PMID:25751625

  10. Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci

    Science.gov (United States)

    Huang, Hailiang; Menelaou, Androniki; Redler, Silke; Becker, Tim; Heilmann, Stefanie; Yamany, Tarek; Duvic, Madeliene; Hordinsky, Maria; Norris, David; Price, Vera H.; Mackay-Wiggan, Julian; de Jong, Annemieke; DeStefano, Gina M.; Moebus, Susanne; Böhm, Markus; Blume-Peytavi, Ulrike; Wolff, Hans; Lutz, Gerhard; Kruse, Roland; Bian, Li; Amos, Christopher I.; Lee, Annette; Gregersen, Peter K.; Blaumeiser, Bettina; Altshuler, David; Clynes, Raphael; de Bakker, Paul I. W.; Nöthen, Markus M.; Daly, Mark J.; Christiano, Angela M.

    2015-01-01

    Alopecia areata (AA) is a prevalent autoimmune disease with ten known susceptibility loci. Here we perform the first meta-analysis in AA by combining data from two genome-wide association studies (GWAS), and replication with supplemented ImmunoChip data for a total of 3,253 cases and 7,543 controls. The strongest region of association is the MHC, where we fine-map 4 independent effects, all implicating HLA-DR as a key etiologic driver. Outside the MHC, we identify two novel loci that exceed statistical significance, containing ACOXL/BCL2L11(BIM) (2q13); GARP (LRRC32) (11q13.5), as well as a third nominally significant region SH2B3(LNK)/ATXN2 (12q24.12). Candidate susceptibility gene expression analysis in these regions demonstrates expression in relevant immune cells and the hair follicle. We integrate our results with data from seven other autoimmune diseases and provide insight into the alignment of AA within these disorders. Our findings uncover new molecular pathways disrupted in AA, including autophagy/apoptosis, TGFß/Tregs and JAK kinase signaling, and support the causal role of aberrant immune processes in AA. PMID:25608926

  11. Comprehensive assessment of rheumatoid arthritis susceptibility loci in a large psoriatic arthritis cohort.

    LENUS (Irish Health Repository)

    Bowes, John

    2012-08-01

    A number of rheumatoid arthritis (RA) susceptibility genes have been identified in recent years. Given the overlap in phenotypic expression of synovial joint inflammation between RA and psoriatic arthritis (PsA), the authors explored whether RA susceptibility genes are also associated with PsA.

  12. Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies.

    Science.gov (United States)

    Kao, Chung-Feng; Chen, Hui-Wen; Chen, Hsi-Chung; Yang, Jenn-Hwai; Huang, Ming-Chyi; Chiu, Yi-Hang; Lin, Shih-Ku; Lee, Ya-Chin; Liu, Chih-Min; Chuang, Li-Chung; Chen, Chien-Hsiun; Wu, Jer-Yuarn; Lu, Ru-Band; Kuo, Po-Hsiu

    2016-12-01

    This study aimed to identify susceptible loci and enriched pathways for bipolar disorder subtype II. We conducted a genome-wide association scan in discovery samples with 189 bipolar disorder subtype II patients and 1773 controls, and replication samples with 283 bipolar disorder subtype II patients and 500 controls in a Taiwanese Han population using Affymetrix Axiom Genome-Wide CHB1 Array. We performed single-marker and gene-based association analyses, as well as calculated polygeneic risk scores for bipolar disorder subtype II. Pathway enrichment analyses were employed to reveal significant biological pathways. Seven markers were found to be associated with bipolar disorder subtype II in meta-analysis combining both discovery and replication samples (Pbipolar disorder subtype II (Pbipolar disorder subtype II patients from healthy controls in both discovery (P=3.9×10(-4)~1.0×10(-3)) and replication samples (2.8×10(-4)~1.7×10(-3)). Genetic variance explained by chip markers for bipolar disorder subtype II was substantial in the discovery (55.1%) and replication (60.5%) samples. Moreover, pathways related to neurodevelopmental function, signal transduction, neuronal system, and cell adhesion molecules were significantly associated with bipolar disorder subtype II. We reported novel susceptible loci for pure bipolar subtype II disorder that is less addressed in the literature. Future studies are needed to confirm the roles of these loci for bipolar disorder subtype II. © The Author 2016. Published by Oxford University Press on behalf of CINP.

  13. Additional mechanisms conferring genetic susceptibility to Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Miguel eCalero

    2015-04-01

    Full Text Available Familial Alzheimer's disease (AD, mostly associated with early onset, is caused by mutations in three genes (APP, PSEN1 and PSEN2 involved in the production of the amyloid  peptide. In contrast, the molecular mechanisms that trigger the most common late onset sporadic AD remain largely unknown. With the implementation of an increasing number of case-control studies and the upcoming of large-scale genome-wide association studies (GWAS there is a mounting list of genetic risk factors associated to common genetic variants that have been associated to sporadic AD. Besides APOE, that presents a strong association with the disease (OR~4, the rest of these genes have moderate or low degrees of association, with OR ranging from 0.88 to 1.23. Taking together, these genes may account only for a fraction of the attributable AD risk and therefore, rare variants and epistastic gene interactions should be taken into account in order to get the full picture of the genetic risks associated to AD. Here, we review recent whole-exome studies looking for rare variants, somatic brain mutations with a strong association to the disease, and several studies dealing with epistasis as additional mechanisms conferring genetic susceptibility to AD. Altogether, recent evidence underlines the importance of defining molecular and genetic pathways and networks rather than the contribution of specific genes.

  14. Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma.

    Science.gov (United States)

    Khor, Chiea Chuen; Do, Tan; Jia, Hongyan; Nakano, Masakazu; George, Ronnie; Abu-Amero, Khaled; Duvesh, Roopam; Chen, Li Jia; Li, Zheng; Nongpiur, Monisha E; Perera, Shamira A; Qiao, Chunyan; Wong, Hon-Tym; Sakai, Hiroshi; Barbosa de Melo, Mônica; Lee, Mei-Chin; Chan, Anita S; Azhany, Yaakub; Dao, Thi Lam Huong; Ikeda, Yoko; Perez-Grossmann, Rodolfo A; Zarnowski, Tomasz; Day, Alexander C; Jonas, Jost B; Tam, Pancy O S; Tran, Tuan Anh; Ayub, Humaira; Akhtar, Farah; Micheal, Shazia; Chew, Paul T K; Aljasim, Leyla A; Dada, Tanuj; Luu, Tam Thi; Awadalla, Mona S; Kitnarong, Naris; Wanichwecharungruang, Boonsong; Aung, Yee Yee; Mohamed-Noor, Jelinar; Vijayan, Saravanan; Sarangapani, Sripriya; Husain, Rahat; Jap, Aliza; Baskaran, Mani; Goh, David; Su, Daniel H; Wang, Huaizhou; Yong, Vernon K; Yip, Leonard W; Trinh, Tuyet Bach; Makornwattana, Manchima; Nguyen, Thanh Thu; Leuenberger, Edgar U; Park, Ki-Ho; Wiyogo, Widya Artini; Kumar, Rajesh S; Tello, Celso; Kurimoto, Yasuo; Thapa, Suman S; Pathanapitoon, Kessara; Salmon, John F; Sohn, Yong Ho; Fea, Antonio; Ozaki, Mineo; Lai, Jimmy S M; Tantisevi, Visanee; Khaing, Chaw Chaw; Mizoguchi, Takanori; Nakano, Satoko; Kim, Chan-Yun; Tang, Guangxian; Fan, Sujie; Wu, Renyi; Meng, Hailin; Nguyen, Thi Thuy Giang; Tran, Tien Dat; Ueno, Morio; Martinez, Jose Maria; Ramli, Norlina; Aung, Yin Mon; Reyes, Rigo Daniel; Vernon, Stephen A; Fang, Seng Kheong; Xie, Zhicheng; Chen, Xiao Yin; Foo, Jia Nee; Sim, Kar Seng; Wong, Tina T; Quek, Desmond T; Venkatesh, Rengaraj; Kavitha, Srinivasan; Krishnadas, Subbiah R; Soumittra, Nagaswamy; Shantha, Balekudaru; Lim, Boon-Ang; Ogle, Jeanne; de Vasconcellos, José P C; Costa, Vital P; Abe, Ricardo Y; de Souza, Bruno B; Sng, Chelvin C; Aquino, Maria C; Kosior-Jarecka, Ewa; Fong, Guillermo Barreto; Tamanaja, Vania Castro; Fujita, Ricardo; Jiang, Yuzhen; Waseem, Naushin; Low, Sancy; Pham, Huan Nguyen; Al-Shahwan, Sami; Craven, E Randy; Khan, Muhammad Imran; Dada, Rrima; Mohanty, Kuldeep; Faiq, Muneeb A; Hewitt, Alex W; Burdon, Kathryn P; Gan, Eng Hui; Prutthipongsit, Anuwat; Patthanathamrongkasem, Thipnapa; Catacutan, Mary Ann T; Felarca, Irene R; Liao, Chona S; Rusmayani, Emma; Istiantoro, Vira Wardhana; Consolandi, Giulia; Pignata, Giulia; Lavia, Carlo; Rojanapongpun, Prin; Mangkornkanokpong, Lerprat; Chansangpetch, Sunee; Chan, Jonathan C H; Choy, Bonnie N K; Shum, Jennifer W H; Than, Hlaing May; Oo, Khin Thida; Han, Aye Thi; Yong, Victor H; Ng, Xiao-Yu; Goh, Shuang Ru; Chong, Yaan Fun; Hibberd, Martin L; Seielstad, Mark; Png, Eileen; Dunstan, Sarah J; Chau, Nguyen Van Vinh; Bei, Jinxin; Zeng, Yi Xin; Karkey, Abhilasha; Basnyat, Buddha; Pasutto, Francesca; Paoli, Daniela; Frezzotti, Paolo; Wang, Jie Jin; Mitchell, Paul; Fingert, John H; Allingham, R Rand; Hauser, Michael A; Lim, Soon Thye; Chew, Soo Hong; Ebstein, Richard P; Sakuntabhai, Anavaj; Park, Kyu Hyung; Ahn, Jeeyun; Boland, Greet; Snippe, Harm; Stead, Richard; Quino, Raquel; Zaw, Su Nyunt; Lukasik, Urszula; Shetty, Rohit; Zahari, Mimiwati; Bae, Hyoung Won; Oo, Nay Lin; Kubota, Toshiaki; Manassakorn, Anita; Ho, Wing Lau; Dallorto, Laura; Hwang, Young Hoon; Kiire, Christine A; Kuroda, Masako; Djamal, Zeiras Eka; Peregrino, Jovell Ian M; Ghosh, Arkasubhra; Jeoung, Jin Wook; Hoan, Tung S; Srisamran, Nuttamon; Sandragasu, Thayanithi; Set, Saw Htoo; Doan, Vi Huyen; Bhattacharya, Shomi S; Ho, Ching-Lin; Tan, Donald T; Sihota, Ramanjit; Loon, Seng-Chee; Mori, Kazuhiko; Kinoshita, Shigeru; Hollander, Anneke I den; Qamar, Raheel; Wang, Ya-Xing; Teo, Yik Y; Tai, E-Shyong; Hartleben-Matkin, Curt; Lozano-Giral, David; Saw, Seang Mei; Cheng, Ching-Yu; Zenteno, Juan C; Pang, Chi Pui; Bui, Huong T T; Hee, Owen; Craig, Jamie E; Edward, Deepak P; Yonahara, Michiko; Neto, Jamil Miguel; Guevara-Fujita, Maria L; Xu, Liang; Ritch, Robert; Liza-Sharmini, Ahmad Tajudin; Wong, Tien Y; Al-Obeidan, Saleh; Do, Nhu Hon; Sundaresan, Periasamy; Tham, Clement C; Foster, Paul J; Vijaya, Lingam; Tashiro, Kei; Vithana, Eranga N; Wang, Ningli; Aung, Tin

    2016-05-01

    Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

  15. Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia

    Science.gov (United States)

    Ellinghaus, E; Stanulla, M; Richter, G; Ellinghaus, D; te Kronnie, G; Cario, G; Cazzaniga, G; Horstmann, M; Panzer Grümayer, R; Cavé, H; Trka, J; Cinek, O; Teigler-Schlegel, A; ElSharawy, A; Häsler, R; Nebel, A; Meissner, B; Bartram, T; Lescai, F; Franceschi, C; Giordan, M; Nürnberg, P; Heinzow, B; Zimmermann, M; Schreiber, S; Schrappe, M; Franke, A

    2012-01-01

    Acute lymphoblastic leukemia (ALL) is a malignant disease of the white blood cells. The etiology of ALL is believed to be multifactorial and likely to involve an interplay of environmental and genetic variables. We performed a genome-wide association study of 355 750 single-nucleotide polymorphisms (SNPs) in 474 controls and 419 childhood ALL cases characterized by a t(12;21)(p13;q22) — the most common chromosomal translocation observed in childhood ALL — which leads to an ETV6–RUNX1 gene fusion. The eight most strongly associated SNPs were followed-up in 951 ETV6-RUNX1-positive cases and 3061 controls from Germany/Austria and Italy, respectively. We identified a novel, genome-wide significant risk locus at 3q28 (TP63, rs17505102, PCMH=8.94 × 10−9, OR=0.65). The separate analysis of the combined German/Austrian sample only, revealed additional genome-wide significant associations at 11q11 (OR8U8, rs1945213, P=9.14 × 10−11, OR=0.69) and 8p21.3 (near INTS10, rs920590, P=6.12 × 10−9, OR=1.36). These associations and another association at 11p11.2 (PTPRJ, rs3942852, P=4.95 × 10−7, OR=0.72) remained significant in the German/Austrian replication panel after correction for multiple testing. Our findings demonstrate that germline genetic variation can specifically contribute to the risk of ETV6–RUNX1-positive childhood ALL. The identification of TP63 and PTPRJ as susceptibility genes emphasize the role of the TP53 gene family and the importance of proteins regulating cellular processes in connection with tumorigenesis. PMID:22076464

  16. Replication analysis of 15 susceptibility loci for nonsyndromic cleft lip with or without cleft palate in an italian population.

    Science.gov (United States)

    Cura, Francesca; Böhmer, Anne C; Klamt, Johanna; Schünke, Hannah; Scapoli, Luca; Martinelli, Marcella; Carinci, Francesco; Nöthen, Markus M; Knapp, Michael; Ludwig, Kerstin U; Mangold, Elisabeth

    2016-02-01

    Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is one of the most common congenital malformations in humans. Its average global incidence is 1.7 per 1000 live births, with wide variation according to geographical location and ethnicity. Its etiology involves both genetic and environmental factors. The aim of the present study was to confirm genetic association of a selection of 15 candidate nsCL/P loci using an independent sample of the Italian population. At least one single-nucleotide polymorphism (SNP) for each locus was genotyped in 380 nuclear trios. Transmission disequilibrium analysis revealed significant associations for three variants at two loci (8q24 and 1p22). Two SNPs at 8q24 showed the strongest level of association, the rs987525 (PTDT  = 6.81 × 10(-6) ; homozygous relative risk = 3.60 [95% confidence interval, 2.12-6.13]), and the rs17241253 (PTDT  = 1.03 × 10(-5) ; homozygous relative risk = 3.75 [95% confidence interval, 2.10-6.67]). Four additional loci (at 1q32, 3q12, 8q21, and 10q25) achieved nominally significant p-values. Two SNPs at 1p36 achieved p-values of < 0.1. The present data suggest that 6 of the 15 analyzed nsCL/P risk loci contribute significantly to nsCL/P risk in the Italian population. These include the 1p22 locus, which previous research has implicated predominantly in Asian populations. Different loci, including 8q24 and 1p22 have been found associated with nsCL/P in multiple populations. Further efforts are needed to identify causative variants and transfer knowledge to clinical application, such as personal genetic risk assessment. © 2015 Wiley Periodicals, Inc.

  17. Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer.

    Science.gov (United States)

    Lesseur, Corina; Diergaarde, Brenda; Olshan, Andrew F; Wünsch-Filho, Victor; Ness, Andrew R; Liu, Geoffrey; Lacko, Martin; Eluf-Neto, José; Franceschi, Silvia; Lagiou, Pagona; Macfarlane, Gary J; Richiardi, Lorenzo; Boccia, Stefania; Polesel, Jerry; Kjaerheim, Kristina; Zaridze, David; Johansson, Mattias; Menezes, Ana M; Curado, Maria Paula; Robinson, Max; Ahrens, Wolfgang; Canova, Cristina; Znaor, Ariana; Castellsagué, Xavier; Conway, David I; Holcátová, Ivana; Mates, Dana; Vilensky, Marta; Healy, Claire M; Szeszenia-Dąbrowska, Neonila; Fabiánová, Eleonóra; Lissowska, Jolanta; Grandis, Jennifer R; Weissler, Mark C; Tajara, Eloiza H; Nunes, Fabio D; de Carvalho, Marcos B; Thomas, Steve; Hung, Rayjean J; Peters, Wilbert H M; Herrero, Rolando; Cadoni, Gabriella; Bueno-de-Mesquita, H Bas; Steffen, Annika; Agudo, Antonio; Shangina, Oxana; Xiao, Xiangjun; Gaborieau, Valérie; Chabrier, Amélie; Anantharaman, Devasena; Boffetta, Paolo; Amos, Christopher I; McKay, James D; Brennan, Paul

    2016-12-01

    We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10-8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2-TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci-9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10-9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10-6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.

  18. Genomewide Scan for Affective Disorder Susceptibility Loci in Families of a Northern Swedish Isolated Population

    OpenAIRE

    Venken, Tine; Claes, Stephan; Sluijs, Samuël; Paterson, Andrew D; Van Duijn, Cornelia,; Adolfsson, Rolf; Del-Favero, Jurgen; Van Broeckhoven, Christine

    2004-01-01

    We analyzed nine multigenerational families with ascertained affective spectrum disorders in northern Sweden's geographically isolated population of Västerbotten. This northern Swedish population, which originated from a limited number of early settlers ∼8,000 years ago, is genetically more homogeneous than outbred populations. In a genomewide linkage analysis, we identified three chromosomal loci with multipoint LOD scores (MPLOD) ⩾2 at 9q31.1-q34.1 (MPLOD 3.24), 6q22.2-q24.2 (MPLOD 2.48), a...

  19. Obesity-susceptibility loci and their influence on adiposity-related traits in transition from adolescence to adulthood--the HUNT study.

    Science.gov (United States)

    Cuypers, Koenraad Frans; Loos, Ruth J F; Kvaløy, Kirsti; Kulle, Bettina; Romundstad, Pål; Holmen, Turid Lingaas

    2012-01-01

    Obesity-susceptibility loci have been related to adiposity traits in adults and may affect body fat estimates in adolescence. There are indications that different sets of obesity-susceptibility loci influence level of and change in obesity-related traits from adolescence to adulthood. To investigate whether previously reported obesity-susceptible loci in adults influence adiposity traits in adolescence and change in BMI and waist circumference (WC) from adolescence into young adulthood. We also examined whether physical activity modifies the effects of these genetic loci on adiposity-related traits. Nine obesity-susceptibility variants were genotyped in 1 643 adolescents (13-19 years old) from the HUNT study, Norway, who were followed-up into young adulthood. Lifestyle was assessed using questionnaires and anthropometric measurements were taken. The effects of genetic variants individually and combined in a genetic predisposition score (GPS) on obesity-related traits were studied cross-sectionally and longitudinally. A modifying effect of physical activity was tested. The GPS was significantly associated to BMI (B: 0.046 SD/allele [0.020, 0.073], p = 0.001) in adolescence and in young adulthood (B: 0.041 SD/allele [0.015, 0.067], p = 0.002) as it was to waist circumference (WC). The GPS was not associated to change in BMI (p = 0.762) or WC (p = 0.726). We found no significant interaction effect between the GPS and physical activity. Our observations suggest that obesity-susceptibility loci established in adults affect BMI and WC already in adolescence. However, an association with change in adiposity-related traits from adolescence to adulthood could not be verified for these loci. Neither could an attenuating effect of physical activity on the association between the obesity-susceptibility genes and body fat estimates be revealed.

  20. Obesity-Susceptibility Loci and Their Influence on Adiposity-Related Traits in Transition from Adolescence to Adulthood - The HUNT Study

    Science.gov (United States)

    Cuypers, Koenraad Frans; Loos, Ruth J. F.; Kvaløy, Kirsti; Kulle, Bettina; Romundstad, Pål; Holmen, Turid Lingaas

    2012-01-01

    Introduction Obesity-susceptibility loci have been related to adiposity traits in adults and may affect body fat estimates in adolescence. There are indications that different sets of obesity-susceptibility loci influence level of and change in obesity-related traits from adolescence to adulthood. Objectives To investigate whether previously reported obesity-susceptible loci in adults influence adiposity traits in adolescence and change in BMI and waist circumference (WC) from adolescence into young adulthood. We also examined whether physical activity modifies the effects of these genetic loci on adiposity-related traits. Methods Nine obesity-susceptibility variants were genotyped in 1 643 adolescents (13–19 years old) from the HUNT study, Norway, who were followed-up into young adulthood. Lifestyle was assessed using questionnaires and anthropometric measurements were taken. The effects of genetic variants individually and combined in a genetic predisposition score (GPS) on obesity-related traits were studied cross-sectionally and longitudinally. A modifying effect of physical activity was tested. Results The GPS was significantly associated to BMI (B: 0.046 SD/allele [0.020, 0.073], p = 0.001) in adolescence and in young adulthood (B: 0.041 SD/allele [0.015, 0.067], p = 0.002) as it was to waist circumference (WC). The GPS was not associated to change in BMI (p = 0.762) or WC (p = 0.726). We found no significant interaction effect between the GPS and physical activity. Conclusions Our observations suggest that obesity-susceptibility loci established in adults affect BMI and WC already in adolescence. However, an association with change in adiposity-related traits from adolescence to adulthood could not be verified for these loci. Neither could an attenuating effect of physical activity on the association between the obesity-susceptibility genes and body fat estimates be revealed. PMID:23094032

  1. Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors.

    Directory of Open Access Journals (Sweden)

    Stefan Nickels

    Full Text Available Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene-environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4 × 10(-6 and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1 × 10(-4. Overall, the per-allele odds ratio (95% confidence interval for LSP1-rs3817198 was 1.08 (1.01-1.16 in nulliparous women and ranged from 1.03 (0.96-1.10 in parous women with one birth to 1.26 (1.16-1.37 in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85-0.98 in those with an alcohol intake of <20 g/day and 1.45 (1.14-1.85 in those who drank ≥ 20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3 × 10(-5, with a per-allele OR of 1.14 (1.11-1.17 in parous women and 0.98 (0.92-1.05 in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.

  2. Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

    Science.gov (United States)

    Mahajan, Anubha; Locke, Adam; Rayner, N William; Robertson, Neil; Scott, Robert A; Prokopenko, Inga; Scott, Laura J; Green, Todd; Sparso, Thomas; Thuillier, Dorothee; Yengo, Loic; Grallert, Harald; Wahl, Simone; Frånberg, Mattias; Strawbridge, Rona J; Kestler, Hans; Chheda, Himanshu; Eisele, Lewin; Gustafsson, Stefan; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Qi, Lu; Karssen, Lennart C; van Leeuwen, Elisabeth M; Willems, Sara M; Li, Man; Chen, Han; Fuchsberger, Christian; Kwan, Phoenix; Ma, Clement; Linderman, Michael; Lu, Yingchang; Thomsen, Soren K; Rundle, Jana K; Beer, Nicola L; van de Bunt, Martijn; Chalisey, Anil; Kang, Hyun Min; Voight, Benjamin F; Abecasis, Goncalo R; Almgren, Peter; Baldassarre, Damiano; Balkau, Beverley; Benediktsson, Rafn; Blüher, Matthias; Boeing, Heiner; Bonnycastle, Lori L; Borringer, Erwin P; Burtt, Noël P; Carey, Jason; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Doney, Alex SF; Dorkhan, Mozhgan; Edkins, Sarah; Eriksson, Johan G; Esko, Tonu; Eury, Elodie; Fadista, João; Flannick, Jason; Fontanillas, Pierre; Fox, Caroline; Franks, Paul W; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Gottesman, Omri; Grant, George B; Grarup, Niels; Groves, Christopher J; Hassinen, Maija; Have, Christian T; Herder, Christian; Holmen, Oddgeir L; Hreidarsson, Astradur B; Humphries, Steve E; Hunter, David J; Jackson, Anne U; Jonsson, Anna; Jørgensen, Marit E; Jørgensen, Torben; Kerrison, Nicola D; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Kovacs, Peter; Kraft, Peter; Kravic, Jasmina; Langford, Cordelia; Leander, Karin; Liang, Liming; Lichtner, Peter; Lindgren, Cecilia M; Lindholm, Eero; Linneberg, Allan; Liu, Ching-Ti; Lobbens, Stéphane; Luan, Jian’an; Lyssenko, Valeriya; Männistö, Satu; McLeod, Olga; Meyer, Julia; Mihailov, Evelin; Mirza, Ghazala; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Navarro, Carmen; Nöthen, Markus M; Oskolkov, Nikolay N; Owen, Katharine R; Palli, Domenico; Pechlivanis, Sonali; Perry, John RB; Platou, Carl GP; Roden, Michael; Ruderfer, Douglas; Rybin, Denis; van der Schouw, Yvonne T; Sennblad, Bengt; Sigurðsson, Gunnar; Stančáková, Alena; Steinbach, Gerald; Storm, Petter; Strauch, Konstantin; Stringham, Heather M; Sun, Qi; Thorand, Barbara; Tikkanen, Emmi; Tonjes, Anke; Trakalo, Joseph; Tremoli, Elena; Tuomi, Tiinamaija; Wennauer, Roman; Wood, Andrew R; Zeggini, Eleftheria; Dunham, Ian; Birney, Ewan; Pasquali, Lorenzo; Ferrer, Jorge; Loos, Ruth JF; Dupuis, Josée; Florez, Jose C; Boerwinkle, Eric; Pankow, James S; van Duijn, Cornelia; Sijbrands, Eric; Meigs, James B; Hu, Frank B; Thorsteinsdottir, Unnur; Stefansson, Kari; Lakka, Timo A; Rauramaa, Rainer; Stumvoll, Michael; Pedersen, Nancy L; Lind, Lars; Keinanen-Kiukaanniemi, Sirkka M; Korpi-Hyövälti, Eeva; Saaristo, Timo E; Saltevo, Juha; Kuusisto, Johanna; Laakso, Markku; Metspalu, Andres; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne; Ripatti, Samuli; Salomaa, Veikko; Ingelsson, Erik; Boehm, Bernhard O; Bergman, Richard N; Collins, Francis S; Mohlke, Karen L; Koistinen, Heikki; Tuomilehto, Jaakko; Hveem, Kristian; Njølstad, Inger; Deloukas, Panagiotis; Donnelly, Peter J; Frayling, Timothy M; Hattersley, Andrew T; de Faire, Ulf; Hamsten, Anders; Illig, Thomas; Peters, Annette; Cauchi, Stephane; Sladek, Rob; Froguel, Philippe; Hansen, Torben; Pedersen, Oluf; Morris, Andrew D; Palmer, Collin NA; Kathiresan, Sekar; Melander, Olle; Nilsson, Peter M; Groop, Leif C; Barroso, Inês; Langenberg, Claudia; Wareham, Nicholas J; O’Callaghan, Christopher A; Gloyn, Anna L; Altshuler, David; Boehnke, Michael; Teslovich, Tanya M; McCarthy, Mark I; Morris, Andrew P

    2015-01-01

    We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. PMID:26551672

  3. Two obesity susceptibility loci in LYPLAL1 and ETV5 independently associated with childhood hypertension in Chinese population.

    Science.gov (United States)

    Lv, Duo; Zhou, Dan; Zhang, Yan; Zhang, Shuai; Zhu, Yi-Min

    2017-09-05

    Genome-wide association studies have identified novel obesity-associated susceptibility loci. Associations of these variants with childhood obesity have been studied in our previous research. The purpose of this study is to investigate if these loci are associated with hypertension being independent of obesity in Chinese children and adolescents. Nineteen candidate SNPs were genotyped using Sequenom MassARRAY platform among Chinese children (N=2954, 514 hypertension and 2440 controls, aged 7-17years). Dietary behaviors were assessed through face to face investigations. Of the nineteen obese related SNPs, ten SNPs were found to be associated with systolic blood pressure (SBP) or diastolic blood pressure (DBP) in Chinese children. After adjusting for age, sex and WHtR, rs2605100 in LYPLAL1was found to be associated with high blood pressure (HBP) under dominant model (P=0.024) with the OR of 1.274 (95% CI =1.033-1.572, effect genotype=GG). The distribution of genotype of rs7647305 in ETV5 showed significant difference between HBP and non-HBP subjects under dominant model (P=0.011) with the OR of 0.654 (95% CI=0.471-0.909, effect genotype=CC). Using rs2605100 and rs7647305, the genetic risk score (GRS) analysis showed that, after adjusted for age, sex and WHtR, subjects carrying one or two risk alleles had the risks of hypertension with the ORs 1.797 (95% CI, 1.168-2.765), 2.149 (95% CI, 1.375-3.357) comparing with the subjects with non-risk-allele. Genetic variations of obesity-associated loci, LYPLAL1 rs2605100 and ETV5 rs7647305 independently associate with the risk of childhood hypertension in China. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci

    DEFF Research Database (Denmark)

    Amin Al Olama, Ali; Benlloch, Sara; Antoniou, Antonis C

    2015-01-01

    prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum......BACKGROUND: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. METHODS: We genotyped 25...... and family history. RESULTS: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man...

  5. IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci

    DEFF Research Database (Denmark)

    Sørensen, Per Soelberg

    2010-01-01

    the replication collections and a joint analysis with the discovery data set were performed. The possible functional consequences of the validated susceptibility loci were explored using RNA expression data. For all of the tested SNPs, the effect observed in the replication phase involved the same allele...... and the same direction of effect observed in the discovery phase. Three loci exceeded genome-wide significance in the joint analysis: RGS1 (P value=3.55 x 10(-9)), IL12A (P=3.08 x 10(-8)) and MPHOSPH9/CDK2AP1 (P=3.96 x 10(-8)). The RGS1 risk allele is shared with celiac disease (CD), and the IL12A risk allele...... seems to be protective for celiac disease. Within the MPHOSPH9/CDK2AP1 locus, the risk allele correlates with diminished RNA expression of the cell cycle regulator CDK2AP1; this effect is seen in both lymphoblastic cell lines (P=1.18 x 10(-5)) and in peripheral blood mononuclear cells from subjects...

  6. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array

    DEFF Research Database (Denmark)

    Eeles, Rosalind A; Olama, Ali Amin Al; Benlloch, Sara

    2013-01-01

    Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the internationa...

  7. A genome-wide association study identifies novel and functionally related susceptibility loci for Kawasaki Disease

    NARCIS (Netherlands)

    Burgner, D.; Davila, S.; Breunis, W.B.; Ng, S.B.; Li, Y.; Bonnard, C.; Ling, L.; Wright, V.J.; Thalamuthu, A.; Odam, M.; Shimizu, C.; Burns, J.C.; Levin, M.; Kuijpers, T.W.; Hibberd, M.L.

    2009-01-01

    Kawasaki disease (KD) is a pediatric vasculitis that damages the coronary arteries in 25% of untreated and approximately 5% of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s) in genetically susceptible children. To investigate genetic determinants of KD

  8. A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease

    NARCIS (Netherlands)

    Burgner, David; Davila, Sonia; Breunis, Willemijn B.; Ng, Sarah B.; Li, Yi; Bonnard, Carine; Ling, Ling; Wright, Victoria J.; Thalamuthu, Anbupalam; Odam, Miranda; Shimizu, Chisato; Burns, Jane C.; Levin, Michael; Kuijpers, Taco W.; Hibberd, Martin L.; Christiansen, Frank; Goldwater, Paul; Curtis, Nigel; Palasanthiran, Pamela; Ziegler, John; Nissan, Michael; Kuipers, Irene M.; Ottenkamp, Jaap J.; Geissler, Judy; Biezeveld, Maarten; Filippini, Luc; Brogan, Paul; Klein, Nigel; Shah, Vanita; Dillon, Michael; Booy, Robert; Shingadia, Delane; Bose, Anu; Mukasa, Thomas; Tulloh, Robert; Michie, Colin; Shike, Hiroko; Nievergelt, Caroline M.; Schork, Nicholas J.; Newburger, Jane W.; Baker, Annette L.; Sundel, Robert P.; Rowley, Anne H.; Shulman, Stanford T.

    2009-01-01

    Kawasaki disease (KD) is a pediatric vasculitis that damages the coronary arteries in 25% of untreated and approximately 5% of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s) in genetically susceptible children. To investigate genetic determinants of KD

  9. Sequential Elimination of Major-Effect Contributors Identifies Additional Quantitative Trait Loci Conditioning High-Temperature Growth in Yeast

    Science.gov (United States)

    Sinha, Himanshu; David, Lior; Pascon, Renata C.; Clauder-Münster, Sandra; Krishnakumar, Sujatha; Nguyen, Michelle; Shi, Getao; Dean, Jed; Davis, Ronald W.; Oefner, Peter J.; McCusker, John H.; Steinmetz, Lars M.

    2008-01-01

    Several quantitative trait loci (QTL) mapping strategies can successfully identify major-effect loci, but often have poor success detecting loci with minor effects, potentially due to the confounding effects of major loci, epistasis, and limited sample sizes. To overcome such difficulties, we used a targeted backcross mapping strategy that genetically eliminated the effect of a previously identified major QTL underlying high-temperature growth (Htg) in yeast. This strategy facilitated the mapping of three novel QTL contributing to Htg of a clinically derived yeast strain. One QTL, which is linked to the previously identified major-effect QTL, was dissected, and NCS2 was identified as the causative gene. The interaction of the NCS2 QTL with the first major-effect QTL was background dependent, revealing a complex QTL architecture spanning these two linked loci. Such complex architecture suggests that more genes than can be predicted are likely to contribute to quantitative traits. The targeted backcrossing approach overcomes the difficulties posed by sample size, genetic linkage, and epistatic effects and facilitates identification of additional alleles with smaller contributions to complex traits. PMID:18780730

  10. Investigation of Caucasian rheumatoid arthritis susceptibility loci in African patients with the same disease

    Science.gov (United States)

    2012-01-01

    Introduction The largest genetic risk to develop rheumatoid arthritis (RA) arises from a group of alleles of the HLA DRB1 locus ('shared epitope', SE). Over 30 non-HLA single nucleotide polymorphisms (SNPs) predisposing to disease have been identified in Caucasians, but they have never been investigated in West/Central Africa. We previously reported a lower prevalence of the SE in RA patients in Cameroon compared to European patients and aimed in the present study to investigate the contribution of Caucasian non-HLA RA SNPs to disease susceptibility in Black Africans. Methods RA cases and controls from Cameroon were genotyped for Caucasian RA susceptibility SNPs using Sequenom MassArray technology. Genotype data were also available for 5024 UK cases and 4281 UK controls and for 119 Yoruba individuals in Ibadan, Nigeria (YRI, HapMap). A Caucasian aggregate genetic-risk score (GRS) was calculated as the sum of the weighted risk-allele counts. Results After genotyping quality control procedures were performed, data on 28 Caucasian non-HLA susceptibility SNPs were available in 43 Cameroonian RA cases and 44 controls. The minor allele frequencies (MAF) were tightly correlated between Cameroonian controls and YRI individuals (correlation coefficient 93.8%, p = 1.7E-13), and they were pooled together. There was no correlation between MAF of UK and African controls; 13 markers differed by more than 20%. The MAF for markers at PTPN22, IL2RA, FCGR2A and IL2/IL21 was below 2% in Africans. The GRS showed a strong association with RA in the UK. However, the GRS did not predict RA in Africans (OR = 0.71, 95% CI 0.29 - 1.74, p = 0.456). Random sampling from the UK cohort showed that this difference in association is unlikely to be explained by small sample size or chance, but is statistically significant with p<0.001. Conclusions The MAFs of non-HLA Caucasian RA susceptibility SNPs are different between Caucasians and Africans, and several polymorphisms are barely detectable in

  11. A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11

    Science.gov (United States)

    Siddiq, Afshan; Couch, Fergus J.; Chen, Gary K.; Lindström, Sara; Eccles, Diana; Millikan, Robert C.; Michailidou, Kyriaki; Stram, Daniel O.; Beckmann, Lars; Rhie, Suhn Kyong; Ambrosone, Christine B.; Aittomäki, Kristiina; Amiano, Pilar; Apicella, Carmel; Baglietto, Laura; Bandera, Elisa V.; Beckmann, Matthias W.; Berg, Christine D.; Bernstein, Leslie; Blomqvist, Carl; Brauch, Hiltrud; Brinton, Louise; Bui, Quang M.; Buring, Julie E.; Buys, Saundra S.; Campa, Daniele; Carpenter, Jane E.; Chasman, Daniel I.; Chang-Claude, Jenny; Chen, Constance; Clavel-Chapelon, Françoise; Cox, Angela; Cross, Simon S.; Czene, Kamila; Deming, Sandra L.; Diasio, Robert B.; Diver, W. Ryan; Dunning, Alison M.; Durcan, Lorraine; Ekici, Arif B.; Fasching, Peter A.; Feigelson, Heather Spencer; Fejerman, Laura; Figueroa, Jonine D.; Fletcher, Olivia; Flesch-Janys, Dieter; Gaudet, Mia M.; Gerty, Susan M.; Rodriguez-Gil, Jorge L.; Giles, Graham G.; van Gils, Carla H.; Godwin, Andrew K.; Graham, Nikki; Greco, Dario; Hall, Per; Hankinson, Susan E.; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Hoover, Robert N.; Hopper, John L.; Hu, Jennifer J.; Huntsman, Scott; Ingles, Sue A.; Irwanto, Astrid; Isaacs, Claudine; Jacobs, Kevin B.; John, Esther M.; Justenhoven, Christina; Kaaks, Rudolf; Kolonel, Laurence N.; Coetzee, Gerhard A.; Lathrop, Mark; Le Marchand, Loic; Lee, Adam M.; Lee, I-Min; Lesnick, Timothy; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Martin, Nicholas G.; McLean, Catriona A.; Meijers-Heijboer, Hanne; Meindl, Alfons; Miron, Penelope; Monroe, Kristine R.; Montgomery, Grant W.; Müller-Myhsok, Bertram; Nickels, Stefan; Nyante, Sarah J.; Olswold, Curtis; Overvad, Kim; Palli, Domenico; Park, Daniel J.; Palmer, Julie R.; Pathak, Harsh; Peto, Julian; Pharoah, Paul; Rahman, Nazneen; Rivadeneira, Fernando; Schmidt, Daniel F.; Schmutzler, Rita K.; Slager, Susan; Southey, Melissa C.; Stevens, Kristen N.; Sinn, Hans-Peter; Press, Michael F.; Ross, Eric; Riboli, Elio; Ridker, Paul M.; Schumacher, Fredrick R.; Severi, Gianluca; dos Santos Silva, Isabel; Stone, Jennifer; Sund, Malin; Tapper, William J.; Thun, Michael J.; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Waisfisz, Quinten; Wang, Xianshu; Wang, Zhaoming; Weaver, JoEllen; Schulz-Wendtland, Rüdiger; Wilkens, Lynne R.; Van Den Berg, David; Zheng, Wei; Ziegler, Regina G.; Ziv, Elad; Nevanlinna, Heli; Easton, Douglas F.; Hunter, David J.; Henderson, Brian E.; Chanock, Stephen J.; Garcia-Closas, Montserrat; Kraft, Peter; Haiman, Christopher A.; Vachon, Celine M.

    2012-01-01

    Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10-5 in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10−8) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10–6) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10−9), and with both ER-positive (OR = 1.09; P = 1.5 × 10−5) and ER-negative (OR = 1.16, P = 2.5 × 10−7) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci. PMID:22976474

  12. Significant overlap between human genome-wide association-study nominated breast cancer risk alleles and rat mammary cancer susceptibility loci.

    Science.gov (United States)

    Sanders, Jennifer; Samuelson, David J

    2014-01-27

    Human population-based genome-wide association (GWA) studies identify low penetrance breast cancer risk alleles; however, GWA studies alone do not definitively determine causative genes or mechanisms. Stringent genome- wide statistical significance level requirements, set to avoid false-positive associations, yield many false-negative associations. Laboratory rats (Rattus norvegicus) are useful to study many aspects of breast cancer, including genetic susceptibility. Several rat mammary cancer associated loci have been identified using genetic linkage and congenic strain based-approaches. Here, we sought to determine the amount of overlap between GWA study nominated human breast and rat mammary cancer susceptibility loci. We queried published GWA studies to identify two groups of SNPs, one that reached genome-wide significance and one comprised of SNPs failing a validation step and not reaching genome- wide significance. Human genome locations of these SNPs were compared to known rat mammary carcinoma susceptibility loci to determine if risk alleles existed in both species. Rat genome regions not known to associate with mammary cancer risk were randomly selected as control regions. Significantly more human breast cancer risk GWA study nominated SNPs mapped at orthologs of rat mammary cancer loci than to regions not known to contain rat mammary cancer loci. The rat genome was useful to predict associations that had met human genome-wide significance criteria and weaker associations that had not. Integration of human and rat comparative genomics may be useful to parse out false-negative associations in GWA studies of breast cancer risk.

  13. Genome-wide association studies identify susceptibility loci affecting respiratory disease in Chinese Erhualian pigs under natural conditions.

    Science.gov (United States)

    Huang, X; Huang, T; Deng, W; Yan, G; Qiu, H; Huang, Y; Ke, S; Hou, Y; Zhang, Y; Zhang, Z; Fang, S; Zhou, L; Yang, B; Ren, J; Ai, H; Huang, L

    2017-02-01

    Prevalence of swine respiratory disease causes poor growth performance in and serious economic losses to the swine industry. In this study, a categorical trait of enzootic pneumonia-like (EPL) score representing the infection gradient of a respiratory disease, more likely enzootic pneumonia, was recorded in a herd of 332 Chinese Erhualian pigs. According to their EPL scores and the disease effect on weight gains, these pigs were grouped into controls (EPL score ≤ 1) and cases (EPL score > 1). The weight gain of the case group reduced significantly at days 180, 210, 240 and 300 as compared to the control group. The heritability of EPL score was estimated to be 0.24 based on the pedigree information using a linear mixed model. All 332 Erhualian pigs and their nine sire parents were genotyped with Illumina Porcine 60K SNP chips. Two genome-wide association studies were performed under a generalized linear mixed model and a case-control model respectively. In total, five loci surpassed the suggestive significance level (P = 2.98 × 10(-5) ) on chromosomes 2, 8, 12 and 14. CXCL6, CXCL8, KIT and CTBP2 were highlighted as candidate genes that might play important roles in determining resistance/susceptibility to swine EP-like respiratory disease. The findings advance understanding of the genetic basis of resistance/susceptibility to respiratory disease in pigs. © 2016 Stichting International Foundation for Animal Genetics.

  14. Complex interactions between new loci, Sluc1, Sluc2, Sluc3 and Sluc4, that influence the susceptibility to lung cancer in the mouse

    NARCIS (Netherlands)

    Fijneman, R.J.A.; Vries, de S.S.; Jansen, R.C.; Demant, P.

    1996-01-01

    Many complex traits, including susceptibility to lung cancer, are controlled by multiple genes - quantitative trait loci (QTLs). We facilitated the mapping of QTLs by making use of recombinant congenic strains (RCS), a system of mouse inbred strains in which the genetic complexity is reduced, and by

  15. Complex interactions of new quantitative trait loci, Sluc1, Sluc2, Sluc3, and Sluc4, that influence the susceptibility to lung cancer in the mouse

    NARCIS (Netherlands)

    Fijneman, Remond J.A.; Vries, Sandra S. de; Jansen, Ritsert C.; Demant, Peter

    1996-01-01

    Many complex traits, including susceptibility to lung cancer, are controlled by multiple genes - quantitative trait loci (QTLs). We facilitated the mapping of QTLs by making use of recombinant congenic strains (RCS), a system of mouse inbred strains in which the genetic complexity is reduced, and by

  16. A genome-wide association study identifies novel and functionally related susceptibility Loci for Kawasaki disease.

    Directory of Open Access Journals (Sweden)

    David Burgner

    2009-01-01

    Full Text Available Kawasaki disease (KD is a pediatric vasculitis that damages the coronary arteries in 25% of untreated and approximately 5% of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s in genetically susceptible children. To investigate genetic determinants of KD susceptibility, we performed a genome-wide association study (GWAS in 119 Caucasian KD cases and 135 matched controls with stringent correction for possible admixture, followed by replication in an independent cohort and subsequent fine-mapping, for a total of 893 KD cases plus population and family controls. Significant associations of 40 SNPs and six haplotypes, identifying 31 genes, were replicated in an independent cohort of 583 predominantly Caucasian KD families, with NAALADL2 (rs17531088, p(combined = 1.13 x 10(-6 and ZFHX3 (rs7199343, p(combined = 2.37 x 10(-6 most significantly associated. Sixteen associated variants with a minor allele frequency of >0.05 that lay within or close to known genes were fine-mapped with HapMap tagging SNPs in 781 KD cases, including 590 from the discovery and replication stages. Original or tagging SNPs in eight of these genes replicated the original findings, with seven genes having further significant markers in adjacent regions. In four genes (ZFHX3, NAALADL2, PPP1R14C, and TCP1, the neighboring markers were more significantly associated than the originally associated variants. Investigation of functional relationships between the eight fine-mapped genes using Ingenuity Pathway Analysis identified a single functional network (p = 10(-13 containing five fine-mapped genes-LNX1, CAMK2D, ZFHX3, CSMD1, and TCP1-with functional relationships potentially related to inflammation, apoptosis, and cardiovascular pathology. Pair-wise blood transcript levels were measured during acute and convalescent KD for all fine-mapped genes, revealing a consistent trend of significantly reduced transcript levels prior to treatment

  17. A Genome-Wide Association Study Identifies Novel and Functionally Related Susceptibility Loci for Kawasaki Disease

    Science.gov (United States)

    Breunis, Willemijn B.; Ng, Sarah B.; Li, Yi; Bonnard, Carine; Ling, Ling; Wright, Victoria J.; Thalamuthu, Anbupalam; Odam, Miranda; Shimizu, Chisato; Burns, Jane C.; Levin, Michael; Kuijpers, Taco W.; Hibberd, Martin L.

    2009-01-01

    Kawasaki disease (KD) is a pediatric vasculitis that damages the coronary arteries in 25% of untreated and approximately 5% of treated children. Epidemiologic data suggest that KD is triggered by unidentified infection(s) in genetically susceptible children. To investigate genetic determinants of KD susceptibility, we performed a genome-wide association study (GWAS) in 119 Caucasian KD cases and 135 matched controls with stringent correction for possible admixture, followed by replication in an independent cohort and subsequent fine-mapping, for a total of 893 KD cases plus population and family controls. Significant associations of 40 SNPs and six haplotypes, identifying 31 genes, were replicated in an independent cohort of 583 predominantly Caucasian KD families, with NAALADL2 (rs17531088, p combined = 1.13×10−6) and ZFHX3 (rs7199343, p combined = 2.37×10−6) most significantly associated. Sixteen associated variants with a minor allele frequency of >0.05 that lay within or close to known genes were fine-mapped with HapMap tagging SNPs in 781 KD cases, including 590 from the discovery and replication stages. Original or tagging SNPs in eight of these genes replicated the original findings, with seven genes having further significant markers in adjacent regions. In four genes (ZFHX3, NAALADL2, PPP1R14C, and TCP1), the neighboring markers were more significantly associated than the originally associated variants. Investigation of functional relationships between the eight fine-mapped genes using Ingenuity Pathway Analysis identified a single functional network (p = 10−13) containing five fine-mapped genes—LNX1, CAMK2D, ZFHX3, CSMD1, and TCP1—with functional relationships potentially related to inflammation, apoptosis, and cardiovascular pathology. Pair-wise blood transcript levels were measured during acute and convalescent KD for all fine-mapped genes, revealing a consistent trend of significantly reduced transcript levels prior to treatment

  18. Genome-wide association study identifies new prostate cancer susceptibility loci

    DEFF Research Database (Denmark)

    Schumacher, Fredrick R.; Berndt, Sonja I.; Siddiq, Afshan

    2011-01-01

    published GWAS with 7358 PrCa cases and 6732 controls, we identified a new susceptibility locus associated with overall PrCa risk at 2q37.3 (rs2292884, P= 4.3 x 10–8). We also confirmed a locus suggested by an earlier GWAS at 12q13 (rs902774, P= 8.6 x 10–9). The estimated per-allele odds ratios......Prostate cancer (PrCa) is the most common non-skin cancer diagnosed among males in developed countries and the second leading cause of cancer mortality, yet little is known regarding its etiology and factors that influence clinical outcome. Genome-wide association studies (GWAS) of PrCa have...

  19. Novel genetic susceptibility loci for diabetic end-stage renal disease identified through robust naive Bayes classification.

    Science.gov (United States)

    Sambo, Francesco; Malovini, Alberto; Sandholm, Niina; Stavarachi, Monica; Forsblom, Carol; Mäkinen, Ville-Petteri; Harjutsalo, Valma; Lithovius, Raija; Gordin, Daniel; Parkkonen, Maija; Saraheimo, Markku; Thorn, Lena M; Tolonen, Nina; Wadén, Johan; He, Bing; Osterholm, Anne-May; Tuomilehto, Jaako; Lajer, Maria; Salem, Rany M; McKnight, Amy Jayne; Tarnow, Lise; Panduru, Nicolae M; Barbarini, Nicola; Di Camillo, Barbara; Toffolo, Gianna M; Tryggvason, Karl; Bellazzi, Riccardo; Cobelli, Claudio; Groop, Per-Henrik

    2014-08-01

    Diabetic nephropathy is a major diabetic complication, and diabetes is the leading cause of end-stage renal disease (ESRD). Family studies suggest a hereditary component for diabetic nephropathy. However, only a few genes have been associated with diabetic nephropathy or ESRD in diabetic patients. Our aim was to detect novel genetic variants associated with diabetic nephropathy and ESRD. We exploited a novel algorithm, 'Bag of Naive Bayes', whose marker selection strategy is complementary to that of conventional genome-wide association models based on univariate association tests. The analysis was performed on a genome-wide association study of 3,464 patients with type 1 diabetes from the Finnish Diabetic Nephropathy (FinnDiane) Study and subsequently replicated with 4,263 type 1 diabetes patients from the Steno Diabetes Centre, the All Ireland-Warren 3-Genetics of Kidneys in Diabetes UK collection (UK-Republic of Ireland) and the Genetics of Kidneys in Diabetes US Study (GoKinD US). Five genetic loci (WNT4/ZBTB40-rs12137135, RGMA/MCTP2-rs17709344, MAPRE1P2-rs1670754, SEMA6D/SLC24A5-rs12917114 and SIK1-rs2838302) were associated with ESRD in the FinnDiane study. An association between ESRD and rs17709344, tagging the previously identified rs12437854 and located between the RGMA and MCTP2 genes, was replicated in independent case-control cohorts. rs12917114 near SEMA6D was associated with ESRD in the replication cohorts under the genotypic model (p < 0.05), and rs12137135 upstream of WNT4 was associated with ESRD in Steno. This study supports the previously identified findings on the RGMA/MCTP2 region and suggests novel susceptibility loci for ESRD. This highlights the importance of applying complementary statistical methods to detect novel genetic variants in diabetic nephropathy and, in general, in complex diseases.

  20. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

    Directory of Open Access Journals (Sweden)

    Montserrat Garcia-Closas

    2008-04-01

    Full Text Available A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs in five loci (fibroblast growth receptor 2 (FGFR2, trinucleotide repeat containing 9 (TNRC9, mitogen-activated protein kinase 3 K1 (MAP3K1, 8q24, and lymphocyte-specific protein 1 (LSP1 associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI = 1.31 (1.27-1.36 than ER-negative (1.08 (1.03-1.14 disease (P for heterogeneity = 10(-13. This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5, 10(-8, 0.013, respectively. The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4, respectively. The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312 showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21. rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97. The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding

  1. A genome-wide screen for acrophobia susceptibility loci in a Finnish isolate

    Science.gov (United States)

    Misiewicz, Zuzanna; Hiekkalinna, Tero; Paunio, Tiina; Varilo, Teppo; Terwilliger, Joseph D.; Partonen, Timo; Hovatta, Iiris

    2016-01-01

    Acrophobia, an abnormal fear of heights, is a specific phobia characterized as apprehension cued by the occurrence or anticipation of elevated spaces. It is considered a complex trait with onset influenced by both genetic and environmental factors. Identification of genetic risk variants would provide novel insight into the genetic basis of the fear of heights phenotype and contribute to the molecular-level understanding of its aetiology. Genetic isolates may facilitate identification of susceptibility alleles due to reduced genetic heterogeneity. We took advantage of an internal genetic isolate in Finland in which a distinct acrophobia phenotype appears to be segregating in pedigrees originally ascertained for schizophrenia. We conducted parametric, nonparametric, joint linkage and linkage disequilibrium analyses using a microsatellite marker panel, genotyped in families to search for chromosomal regions correlated with acrophobia. Our results implicated a few regions with suggestive evidence for linkage on chromosomes 4q28 (LOD = 2.17), 8q24 (LOD = 2.09) and 13q21-q22 (LOD = 2.22). We observed no risk haplotypes shared between different families. These results suggest that genetic predisposition to acrophobia in this genetic isolate is unlikely to be mediated by a small number of shared high-risk alleles, but rather has a complex genetic architecture. PMID:27996024

  2. New susceptibility loci associated with kidney disease in type 1 diabetes

    National Research Council Canada - National Science Library

    Sandholm, Niina; Salem, Rany M; McKnight, Amy Jayne; Brennan, Eoin P; Forsblom, Carol; Isakova, Tamara; McKay, Gareth J; Williams, Winfred W; Sadlier, Denise M; Mäkinen, Ville-Petteri; Swan, Elizabeth J; Palmer, Cameron; Boright, Andrew P; Ahlqvist, Emma; Deshmukh, Harshal A; Keller, Benjamin J; Huang, Huateng; Ahola, Aila J; Fagerholm, Emma; Gordin, Daniel; Harjutsalo, Valma; He, Bing; Heikkilä, Outi; Hietala, Kustaa; Kytö, Janne; Lahermo, Päivi; Lehto, Markku; Lithovius, Raija; Osterholm, Anne-May; Parkkonen, Maija; Pitkäniemi, Janne; Rosengård-Bärlund, Milla; Saraheimo, Markku; Sarti, Cinzia; Söderlund, Jenny; Soro-Paavonen, Aino; Syreeni, Anna; Thorn, Lena M; Tikkanen, Heikki; Tolonen, Nina; Tryggvason, Karl; Tuomilehto, Jaakko; Wadén, Johan; Gill, Geoffrey V; Prior, Sarah; Guiducci, Candace; Mirel, Daniel B; Taylor, Andrew; Hosseini, S Mohsen; Parving, Hans-Henrik; Rossing, Peter; Tarnow, Lise; Ladenvall, Claes; Alhenc-Gelas, François; Lefebvre, Pierre; Rigalleau, Vincent; Roussel, Ronan; Tregouet, David-Alexandre; Maestroni, Anna; Maestroni, Silvia; Falhammar, Henrik; Gu, Tianwei; Möllsten, Anna; Cimponeriu, Danut; Ioana, Mihai; Mota, Maria; Mota, Eugen; Serafinceanu, Cristian; Stavarachi, Monica; Hanson, Robert L; Nelson, Robert G; Kretzler, Matthias; Colhoun, Helen M; Panduru, Nicolae Mircea; Gu, Harvest F; Brismar, Kerstin; Zerbini, Gianpaolo; Hadjadj, Samy; Marre, Michel; Groop, Leif; Lajer, Maria; Bull, Shelley B; Waggott, Daryl; Paterson, Andrew D; Savage, David A; Bain, Stephen C; Martin, Finian; Hirschhorn, Joel N; Godson, Catherine; Florez, Jose C; Groop, Per-Henrik; Maxwell, Alexander P

    2012-01-01

    ...) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion of the excess mortality associated with type 1 diabetes (T1D...

  3. Susceptibility quantitative trait loci for pathogenic leucocytosis in SCG/Kj mice, a spontaneously occurring crescentic glomerulonephritis and vasculitis model

    Science.gov (United States)

    Hamano, Y; Abe, M; Matsuoka, S; Zhang, D; Kondo, Y; Kagami, Y; Ishigami, A; Maruyama, N; Tsuruta, Y; Yumura, W; Suzuki, K

    2014-01-01

    The spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mouse, a model of human crescentic glomerulonephritis (CrGN) and systemic vasculitis, is characterized by the production of myeloperoxidase-specific anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) and marked leucocytosis. This study was performed to identify the specific populations of leucocytes associated with CrGN and susceptibility loci for pathogenic leucocytosis. Four hundred and twenty female (C57BL/6 × SCG/Kj) F2 intercross mice were subjected to serial flow cytometry examination of the peripheral blood (PB). Kidney granulocytes and monocytes were examined histopathologically. Linkage analyses were performed with 109 polymorphic microsatellite markers. Correlation studies revealed that increase of the granulocytes, F4/80+ cells, CD3+CD4−CD8− T cells and dendritic cells (DCs) in peripheral blood (PB) were associated significantly with glomerulonephritis, crescent formation and vasculitis. In kidney sections, F4/80low cells were observed in crescent, while F4/80high cells were around the Bowman's capsules and in the interstitium. Numbers of F4/80+ cells in crescents correlated significantly with F4/80+ cell numbers in PB, but not with numbers of F4/80+ cells in the interstitium. Genome-wide quantitative trait locus (QTL) mapping revealed three SCG/Kj-derived non-Fas QTLs for leucocytosis, two on chromosome 1 and one on chromosome 17. QTLs on chromosome 1 affected DCs, granulocytes and F4/80+ cells, but QTL on chromosome 17 affected DCs and granulocytes. We found CrGN-associated leucocytes and susceptibility QTLs with their positional candidate genes. F4/80+ cells in crescents are considered as recruited inflammatory macrophages. The results provide information for leucocytes to be targeted and genetic elements in CrGN and vasculitis. PMID:24654803

  4. Association of eleven common, low-penetrance colorectal cancer susceptibility genetic variants at six risk loci with clinical outcome.

    Directory of Open Access Journals (Sweden)

    Janelle M Hoskins

    Full Text Available Low-penetrance genetic variants have been increasingly recognized to influence the risk of tumor development. Risk variants for colorectal cancer (CRC have been mapped to chromosome positions 8q23.3, 8q24, 9p24.1, 10p14, 11q23, 14q22.2, 15q13, 16q22.1, 18q21, 19q13.1 and 20p12.3. In particular, the 8q24 single nucleotide polymorphism (SNP, rs6983267, has reproducibly been associated with the risk of developing CRC. As the CRC risk SNPs may also influence disease outcome, thus in this study, we evaluated whether they influence patient survival.DNA samples from 583 CRC patients enrolled in the prospective, North Carolina Cancer Care Outcomes Research and Surveillance Consortium Study (NC CanCORS were genotyped for 11 CRC susceptibility SNPs at 6 CRC risk loci. Relationships between genotypes and patient survival were examined using Cox regression analysis. In multivariate analysis, patients homozygous for the CRC risk allele of rs7013278 or rs7014346 (both at 8 q24 were only nominally significant for poorer overall survival compared to patients homozygous for the protective allele (hazard ratio = 2.20 and 1.96, respectively; P<0.05. None of these associations, however, remained statistically significant after correction for multiple testing. The other nine susceptibility SNPs tested were not significantly associated with survival.We did not find evidence of association of CRC risk variants with patient survival.

  5. Crosstalk between the gut and the liver via susceptibility loci: Novel advances in inflammatory bowel disease and autoimmune liver disease.

    Science.gov (United States)

    Li, Xinyang; Shen, Jun; Ran, Zhihua

    2017-02-01

    Inflammatory bowel disease (IBD) is an autoimmune disorder characterized by chronic, relapsing intestinal inflammation. Autoimmune liver disease (AILD) may be involved in IBD as an extra-intestinal manifestation (EIM). Epidemiologic and anatomic evidence have demonstrated an intimate crosstalk between the gut and the liver. In this review, we briefly introduced nine groups of susceptibility loci shared by inflammatory bowel and autoimmune liver disease for the first time. The genome-wide association studies (GWAS) evidence of pathways involving crosstalk between the gut and the liver is clarified and explained. It has been found that HNF4-α, GPR35, MST1R, CARD9, IL2/IL21/IL2R, BACH2, TNFRSF14, MAdCAM-1, and FUT2 are the genes involved in tight junction formation, macrophage function, T helper cell or Treg cell cycle and function, TNF secretion, lymphocyte homing or intestinal dysbiosis, respectively. The intimate crosstalk between the gut and liver in immunity is also highlighted and discussed in this review. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Ian P M Tomlinson

    2011-06-01

    Full Text Available Genome-wide association studies (GWAS have identified 14 tagging single nucleotide polymorphisms (tagSNPs that are associated with the risk of colorectal cancer (CRC, and several of these tagSNPs are near bone morphogenetic protein (BMP pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3, BMP4 (14q22.2, and BMP2 (20p12.3 using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10 and BMP2 (rs4813802, P = 4.65×10(-11. Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8 and rs11632715 (P = 2.30×10(-10. As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.

  7. Τhe genetics of juvenile idiopathic arthritis: Searching for new susceptibility loci.

    Science.gov (United States)

    Zervou, Maria I; Dimopoulou, Despoina G; Eliopoulos, Elias; Trachana, Maria; Pratsidou-Gkertsi, Polyxeni; Andreou, Athena; Sidiropoulos, Prodromos; Spandidos, Demetrios A; Garyfallos, Alexandros; Goulielmos, George N

    2017-12-01

    ) mutation on TYK2 protein, bioinformatics analysis was performed. Combining three‑dimensional (3D)‑modeling and molecular dynamics simulations we identified changes in structural flexibility, affecting the functionality of the kinase domain of TYK2. To the best of our knowledge, this is the first time that eNOS VNTR polymorphism is associated with susceptibility to JIA, suggesting a differential role of allele 'a' in various complex diseases. The current data emphasize the importance of comparative studies in populations of a different ancestral background towards the clarification of the role of specific alleles in the development of JIA.

  8. New susceptibility loci associated with kidney disease in type 1 diabetes

    DEFF Research Database (Denmark)

    Sandholm, Niina; Salem, Rany M; McKnight, Amy Jayne

    2012-01-01

    Diabetic kidney disease, or diabetic nephropathy (DN), is a major complication of diabetes and the leading cause of end-stage renal disease (ESRD) that requires dialysis treatment or kidney transplantation. In addition to the decrease in the quality of life, DN accounts for a large proportion...... mechanisms behind the disease remain poorly understood, and current therapeutic strategies rarely result in reversal of DN. In the GEnetics of Nephropathy: an International Effort (GENIE) consortium, we have undertaken a meta-analysis of genome-wide association studies (GWAS) of T1D DN comprising ~2...

  9. Adult adiposity susceptibility loci, early growth and general and abdominal fatness in childhood: the Generation R Study.

    Science.gov (United States)

    Vogelezang, S; Monnereau, C; Gaillard, R; Renders, C M; Hofman, A; Jaddoe, V W V; Felix, J F

    2015-06-01

    Genome-wide association studies in adults have identified genetic loci associated with adiposity measures. Little is known about the effects of these loci on growth and body fat distribution from early childhood onwards. In a population-based prospective cohort study among 4144 children, we examined the associations of weighted risk scores combining 29 known genetic markers of adult body mass index (BMI) and 14 known genetic markers of adult waist-hip ratio (WHR) with peak weight velocity, peak height velocity, age at adiposity peak and BMI at adiposity peak in early infancy and additionally with BMI, total fat mass, android/gynoid fat ratio and preperitoneal fat area at the median age of 6.0 years (95% range 5.7, 7.8). A higher adult BMI genetic risk score was associated with a higher age at adiposity peak in infancy and a higher BMI, total fat mass, android/gynoid fat ratio and preperitoneal fat area in childhood (P=0.05, 1.5 × 10(-24), 3.6 × 10(-18), 4.0 × 10(-11) and 1.3 × 10(-5), respectively), with the strongest association for childhood BMI with a 0.04 higher s.d. score BMI (95% confidence interval 0.03, 0.05) per additional risk allele. A higher adult WHR genetic risk score was not associated with infant growth measures or childhood BMI and total fat mass, but was associated with childhood android/gynoid fat ratio and preperitoneal fat area (PBMI and WHR in adults influence growth patterns and general and abdominal fat development from early childhood onwards.

  10. Functional annotations of diabetes nephropathy susceptibility loci through analysis of genome-wide renal gene expression in rat models of diabetes mellitus

    DEFF Research Database (Denmark)

    Hu, Yaomin; Kaisaki, Pamela J; Argoud, Karène

    2009-01-01

    of spontaneous (genetically determined) mild hyperglycaemia and insulin resistance (Goto-Kakizaki-GK) and experimentally induced severe hyperglycaemia (Wistar-Kyoto-WKY rats injected with streptozotocin [STZ]). RESULTS: Different patterns of transcription regulation in the two rat models of diabetes likely...... that are responsive to hyperglycaemia and may contribute to renal functional and/or structural alterations. CONCLUSION: Combining transcriptomics in animal models and comparative genomics provides important information to improve functional annotations of disease susceptibility loci in humans and experimental support...

  11. Candidate high myopia loci on chromosomes 18p and 12q do not play a major role in susceptibility to common myopia

    Science.gov (United States)

    Ibay, Grace; Doan, Betty; Reider, Lauren; Dana, Debra; Schlifka, Melissa; Hu, Heping; Holmes, Taura; O'Neill, Jennifer; Owens, Robert; Ciner, Elise; Bailey–Wilson, Joan E; Stambolian, Dwight

    2004-01-01

    Background To determine whether previously reported loci predisposing to nonsyndromic high myopia show linkage to common myopia in pedigrees from two ethnic groups: Ashkenazi Jewish and Amish. We hypothesized that these high myopia loci might exhibit allelic heterogeneity and be responsible for moderate /mild or common myopia. Methods Cycloplegic and manifest refraction were performed on 38 Jewish and 40 Amish families. Individuals with at least -1.00 D in each meridian of both eyes were classified as myopic. Genomic DNA was genotyped with 12 markers on chromosomes 12q21-23 and 18p11.3. Parametric and nonparametric linkage analyses were conducted to determine whether susceptibility alleles at these loci are important in families with less severe, clinical forms of myopia. Results There was no strong evidence of linkage of common myopia to these candidate regions: all two-point and multipoint heterogeneity LOD scores were .0 and non-parametric linkage p-values were > 0.01. However, one Amish family showed slight evidence of linkage (LOD>1.0) on 12q; another 3 Amish families each gave LOD >1.0 on 18p; and 3 Jewish families each gave LOD >1.0 on 12q. Conclusions Significant evidence of linkage (LOD> 3) of myopia was not found on chromosome 18p or 12q loci in these families. These results suggest that these loci do not play a major role in the causation of common myopia in our families studied. PMID:15291966

  12. Candidate high myopia loci on chromosomes 18p and 12q do not play a major role in susceptibility to common myopia

    Directory of Open Access Journals (Sweden)

    Ciner Elise

    2004-08-01

    Full Text Available Abstract Background To determine whether previously reported loci predisposing to nonsyndromic high myopia show linkage to common myopia in pedigrees from two ethnic groups: Ashkenazi Jewish and Amish. We hypothesized that these high myopia loci might exhibit allelic heterogeneity and be responsible for moderate /mild or common myopia. Methods Cycloplegic and manifest refraction were performed on 38 Jewish and 40 Amish families. Individuals with at least -1.00 D in each meridian of both eyes were classified as myopic. Genomic DNA was genotyped with 12 markers on chromosomes 12q21-23 and 18p11.3. Parametric and nonparametric linkage analyses were conducted to determine whether susceptibility alleles at these loci are important in families with less severe, clinical forms of myopia. Results There was no strong evidence of linkage of common myopia to these candidate regions: all two-point and multipoint heterogeneity LOD scores were 0.01. However, one Amish family showed slight evidence of linkage (LOD>1.0 on 12q; another 3 Amish families each gave LOD >1.0 on 18p; and 3 Jewish families each gave LOD >1.0 on 12q. Conclusions Significant evidence of linkage (LOD> 3 of myopia was not found on chromosome 18p or 12q loci in these families. These results suggest that these loci do not play a major role in the causation of common myopia in our families studied.

  13. Replication and meta-analysis of GWAS identified susceptibility loci in Kawasaki disease confirm the importance of B lymphoid tyrosine kinase (BLK) in disease susceptibility

    NARCIS (Netherlands)

    Chang, Chia-Jung; Kuo, Ho-Chang; Chang, Jeng-Sheng; Lee, Jong-Keuk; Tsai, Fuu-Jen; Khor, Chiea Chuen; Chang, Li-Ching; Chen, Shih-Ping; Ko, Tai-Ming; Liu, Yi-Min; Chen, Ying-Ju; Hong, Young Mi; Jang, Gi Young; Hibberd, Martin L.; Kuijpers, Taco; Burgner, David; Levin, Michael; Burns, Jane C.; Davila, Sonia; Chen, Yuan-Tsong; Chen, Chien-Hsiun; Wu, Jer-Yuarn; Lee, Yi-Ching; Liang, Chi-Di; Hwang, Kao-Pin; Chang, Luan-Yin; Huang, Li-Min; Chen, Ming-Ren; Chi, Hsin; Huang, Fu-Yuan; Chiu, Nan-Chang; Lee, Meng-Luen; Huang, Yhu-Chering; Hwang, Betau; Lee, Pi-Chang; Yoo, Jeong-Jin; Park, In-Sook; Hong, Soo-Jong; Kim, Kwi-Joo; Kim, Jae-Jung; Sohn, Saejung; Young Jang, Gi; Ha, Kee-Soo; Nam, Hyo-Kyoung; Byeon, Jung-Hye; Yun, Sin Weon; Han, Myung Ki; Lee, Kyung-Yil; Hwang, Ja-Young; Rhim, Jung-Woo; Song, Min Seob; Lee, Hyoung Doo; Kim, Dong Soo; Kil, Hong-Ryang; Kim, Gi-Beom; Yoon, Kyung Lim; Kim, Jong-Duk; Lee, Jae-Moo; Odam, Miranda; Christiansen, Frank; Goldwater, Paul; Curtis, Nigel; Palasanthiran, Pamela; Ziegler, John; Nissan, Michael; Kuipers, Irene M.; Ottenkamp, Jaap J.; Geissler, Judy; Biezeveld, Maarten; Filippini, Luc; Ling, Ling; Wright, Victoria J.; Brogan, Paul; Klein, Nigel; Shah, Vanita; Dillon, Michael; Booy, Robert; Shingadia, Delane; Bose, Anu; Mukasa, Thomas; Tulloh, Robert; Michie, Colin

    2013-01-01

    The BLK and CD40 loci have been associated with Kawasaki disease (KD) in two genome-wide association studies (GWAS) conducted in a Taiwanese population of Han Chinese ancestry (Taiwanese) and in Japanese cohorts. Here we build on these findings with replication studies of the BLK and CD40 loci in

  14. An investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors

    Science.gov (United States)

    Rudolph, Anja; Milne, Roger L.; Truong, Thérèse; Knight, Julia A.; Seibold, Petra; Flesch-Janys, Dieter; Behrens, Sabine; Eilber, Ursula; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Dunning, Alison M.; Shah, Mitul; Munday, Hannah R.; Darabi, Hatef; Eriksson, Mikael; Brand, Judith S.; Olson, Janet; Vachon, Celine M.; Hallberg, Emily; Castelao, J. Esteban; Carracedo, Angel; Torres, Maria; Li, Jingmei; Humphreys, Keith; Cordina-Duverger, Emilie; Menegaux, Florence; Flyger, Henrik; Nordestgaard, Børge G.; Nielsen, Sune F.; Yesilyurt, Betul T.; Floris, Giuseppe; Leunen, Karin; Engelhardt, Ellen G.; Broeks, Annegien; Rutgers, Emiel J.; Glendon, Gord; Mulligan, Anna Marie; Cross, Simon; Reed, Malcolm; Gonzalez-Neira, Anna; Perez, José Ignacio Arias; Provenzano, Elena; Apicella, Carmel; Southey, Melissa C.; Spurdle, Amanda; Investigators, kConFab; Group, AOCS; Häberle, Lothar; Beckmann, Matthias W.; Ekici, Arif B.; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; McLean, Catriona; Baglietto, Laura; Chanock, Stephen J.; Lissowska, Jolanta; Sherman, Mark E.; Brüning, Thomas; Hamann, Ute; Ko, Yon-Dschun; Orr, Nick; Schoemaker, Minouk; Ashworth, Alan; Kosma, Veli-Matti; Kataja, Vesa; Hartikainen, Jaana M.; Mannermaa, Arto; Swerdlow, Anthony; Giles, Graham G.; Brenner, Hermann; Fasching, Peter A.; Chenevix-Trench, Georgia; Hopper, John; Benítez, Javier; Cox, Angela; Andrulis, Irene L.; Lambrechts, Diether; Gago-Dominguez, Manuela; Couch, Fergus; Czene, Kamila; Bojesen, Stig E.; Easton, Doug F.; Schmidt, Marjanka K.; Guénel, Pascal; Hall, Per; Pharoah, Paul D. P.; Garcia-Closas, Montserrat; Chang-Claude, Jenny

    2014-01-01

    A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint) risk in women ≥170cm (OR=1.22, p=0.017), but inversely associated with ER-negative BC risk in women risk was stronger for women who had had four or more pregnancies (OR=0.85, p=2.0×10−4), and absent in women who had had just one (OR=0.96, p=0.19, pint = 6.1×10−4). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR=0.93, p=2.8×10−5), but no association was observed in current smokers (OR=1.07, p=0.14, pint = 3.4×10−4). In conclusion, recently identified breast cancer susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies. PMID:25227710

  15. Identification of novel susceptibility Loci for kawasaki disease in a Han chinese population by a genome-wide association study.

    Directory of Open Access Journals (Sweden)

    Fuu-Jen Tsai

    Full Text Available Kawasaki disease (KD is an acute systemic vasculitis syndrome that primarily affects infants and young children. Its etiology is unknown; however, epidemiological findings suggest that genetic predisposition underlies disease susceptibility. Taiwan has the third-highest incidence of KD in the world, after Japan and Korea. To investigate novel mechanisms that might predispose individuals to KD, we conducted a genome-wide association study (GWAS in 250 KD patients and 446 controls in a Han Chinese population residing in Taiwan, and further validated our findings in an independent Han Chinese cohort of 208 cases and 366 controls. The most strongly associated single-nucleotide polymorphisms (SNPs detected in the joint analysis corresponded to three novel loci. Among these KD-associated SNPs three were close to the COPB2 (coatomer protein complex beta-2 subunit gene: rs1873668 (p = 9.52×10⁻⁵, rs4243399 (p = 9.93×10⁻⁵, and rs16849083 (p = 9.93×10⁻⁵. We also identified a SNP in the intronic region of the ERAP1 (endoplasmic reticulum amino peptidase 1 gene (rs149481, p(best = 4.61×10⁻⁵. Six SNPs (rs17113284, rs8005468, rs10129255, rs2007467, rs10150241, and rs12590667 clustered in an area containing immunoglobulin heavy chain variable regions genes, with p(best-values between 2.08×10⁻⁵ and 8.93×10⁻⁶, were also identified. This is the first KD GWAS performed in a Han Chinese population. The novel KD candidates we identified have been implicated in T cell receptor signaling, regulation of proinflammatory cytokines, as well as antibody-mediated immune responses. These findings may lead to a better understanding of the underlying molecular pathogenesis of KD.

  16. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3

    Science.gov (United States)

    Purdue, Mark P.; Johansson, Mattias; Zelenika, Diana; Toro, Jorge R.; Scelo, Ghislaine; Moore, Lee E.; Prokhortchouk, Egor; Wu, Xifeng; Kiemeney, Lambertus A; Gaborieau, Valerie; Jacobs, Kevin B; Chow, Wong-Ho; Zaridze, David; Matveev, Vsevolod; Lubinski, Jan; Trubicka, Joanna; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Rudnai, Péter; Fabianova, Eleonora; Bucur, Alexandru; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Boffetta, Paolo; Colt, Joanne S.; Davis, Faith G.; Schwartz, Kendra L.; Banks, Rosamonde E; Selby, Peter J; Harnden, Patricia; Berg, Christine D.; Hsing, Ann W.; Grubb, Robert L.; Boeing, Heiner; Vineis, Paolo; Clavel-Chapelon, Françoise; Palli, Domenico; Tumino, Rosario; Krogh, Vittorio; Panico, Salvatore; Duell, Eric J.; Ramón Quirós, José; Sanchez, Maria-José; Navarro, Carmen; Ardanaz, Eva; Dorronsoro, Miren; Khaw, Kay-Tee; Allen, Naomi E; Bueno-de-Mesquita, H Bas; Peeters, Petra HM; Trichopoulos, Dimitrios; Linseisen, Jakob; Ljungberg, Börje; Overvad, Kim; Tjønneland, Anne; Romieu, Isabelle; Riboli, Elio; Mukeria, Anush; Shangina, Oxana; Stevens, Victoria L; Thun, Michael J; Diver, W. Ryan; Gapstur, Susan M; Pharoah, Paul D; Easton, Douglas F; Albanes, Demetrius; Weinstein, Stephanie J.; Virtamo, Jarmo; Vatten, Lars; Hveem, Kristian; Njølstad, Inger; Tell, Grethe; Stoltenberg, Camilla; Kumar, Rajiv; Koppova, Kvetoslava; Cussenot, Olivier; Benhamou, Simone; Oosterwijk, Egbert; Vermeulen, Sita H.; Aben, Katja K.H.; van der Marel, Saskia L.; Ye, Yuanqing; Wood, Christopher G.; Pu, Xia; Mazur, Alexander M; Bulygina, Eugenia S; Chekanov, Nikolai N; Foglio, Mario; Lechner, Doris; Gut, Ivo; Heath, Simon; Blanche, Hélène; Hutchinson, Amy; Thomas, Gilles; Wang, Zhaoming; Yeager, Meredith; Fraumeni, Joseph F.; Skryabin, Konstantin G; McKay, James D; Rothman, Nathaniel; Chanock, Stephen J.; Lathrop, Mark; Brennan, Paul

    2011-01-01

    We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 cases and 8,505 controls of European background from 11 studies, and followed up 6 SNPs in three replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r2 = 0.99 in controls), rs11894252 (P = 1.8×10−8) and rs7579899 (P = 2.3×10−9), map to EPAS1 on 2p21, which encodes hypoxia-inducible- factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13, contains no characterized genes (P = 7.8×10−14). In addition, we observed a promising association on 12q24.31 for rs4765623 which maps to the scavenger receptor class B, member 1 (SCARB1) gene (P = 2.6×10−8). Our study reports novel genomic regions associated with RCC risk that may lead to new etiological insights. PMID:21131975

  17. Association of 8q23-24 region (8q23.3 loci and 8q24.21 loci) with susceptibility to colorectal cancer: a systematic and updated meta-analysis.

    Science.gov (United States)

    Li, Linlin; Lv, Li; Liang, Yuan; Shen, Xiaoyu; Zhou, Shishi; Zhu, Jia; Ma, Rui

    2015-01-01

    Several single nucleotide polymorphisms (SNPs), rs16892766 in the 8q23.3 region and rs6983267, rs10505477, rs7014346 and rs7837328 in the 8q24.21 region, have been identified by genome-wide association studies (GWAS) and a number of case-control studies to be closely associated with risk of colorectal cancer (CRC). In the present study, a meta-analysis was performed to confirm if these loci are risk factors for susceptibility to CRC, taking heterogeneity of population into consideration. The whole literature search was conducted via database of MEDLINE and Embase, through which 33 articles with 49 studies (141,899 cases and 157,536 controls) were finally included in this meta-analysis to evaluate the association between the 5 polymorphisms and risk of CRC under allelic model. A meta-analysis of the pooled data showed that the G allele of rs6983267, the A allele of rs7014346, the T allele of rs10505477, the C allele of rs16892766 and the A allele of rs7837328 were associated with significantly increased risk of CRC under allelic model. Additionally, subgroup analyses of four SNPs (rs7837328 excluded) by ethnicity witnessed a notable association between the G allele of rs6983267 and increased risk of CRC among Caucasians, Asians and Africans. Furthermore, the C allele of rs16892766 was strongly linked with elevated risk of CRC among Caucasians and Africans. However, the A allele of rs7014346 and T allele of rs10505477 only heightened risk for CRC among Caucasians and showed no effects among Asians. In summary, rs6983267 is a risk factor for CRC among Caucasians, Asians and Africans; rs7014346 and rs10505477 are risky genetic polymorphisms only among Caucasians; rs16892766 is a hazardous element among populations with Caucasian and African ancestry; and rs7837328 could elevate the susceptibility to CRC in a multinational group. However, more potential factors related with CRC risk should be investigated in further studies.

  18. A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci

    Science.gov (United States)

    Pillai, Sreekumar G.; Shianna, Kevin V.; Need, Anna C.; Feng, Sheng; Hersh, Craig P.; Bakke, Per; Gulsvik, Amund; Ruppert, Andreas; Lødrup Carlsen, Karin C.; Roses, Allen; Anderson, Wayne; Rennard, Stephen I.; Lomas, David A.; Silverman, Edwin K.; Goldstein, David B.

    2009-01-01

    There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue

  19. A genome-wide association study in chronic obstructive pulmonary disease (COPD: identification of two major susceptibility loci.

    Directory of Open Access Journals (Sweden)

    Sreekumar G Pillai

    2009-03-01

    Full Text Available There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD. The only known genetic risk factor is severe deficiency of alpha(1-antitrypsin, which is present in 1-2% of individuals with COPD. We conducted a genome-wide association study (GWAS in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls and evaluated the top 100 single nucleotide polymorphisms (SNPs in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT and 472 controls from the Normative Aging Study (NAS and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the alpha-nicotinic acetylcholine receptor (CHRNA 3/5 locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48 x 10(-10, (rs8034191 and 5.74 x 10(-10 (rs1051730. Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article

  20. Novel loci controlling lymphocyte proliferative response to cytokines and their clustering with loci controlling autoimmune reactions, macrophage function and lung tumor susceptibility

    Czech Academy of Sciences Publication Activity Database

    Lipoldová, Marie; Havelková, Helena; Badalová, Jana; Demant, P.

    2005-01-01

    Roč. 114, č. 3 (2005), s. 394-399 ISSN 0020-7136 R&D Projects: GA ČR(CZ) GA310/03/1381 Grant - others:European Commission(XE) CIPA-CT940040; Howard Hughes Medical Institute(US) 55000323 Institutional research plan: CEZ:AV0Z5052915 Keywords : lymphocyte activation * interleukin * lung cancer susceptibility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.700, year: 2005

  1. A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3)

    DEFF Research Database (Denmark)

    Enciso-Mora, Victor; Broderick, Peter; Ma, Yussanne

    2010-01-01

    To identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility l...

  2. Haplotype-based analysis of ulcerative colitis risk loci identifies both IL2 and IL21 as susceptibility genes in Han Chinese.

    Science.gov (United States)

    Shi, Jihua; Zhou, Lu; Zhernakova, Alexandra; Qian, Jiaming; Zhu, Feng; Sun, Gang; Zhu, Liming; Ma, Xuejun; Dijkstra, Gerard; Wijmenga, Cisca; Faber, Klaas Nico; Lu, Xinghua; Weersma, Rinse K

    2011-12-01

    The incidence of ulcerative colitis (UC) varies between Western and Eastern ethnicities. A distinct genetic background may play a role in the differences. Until now, very little was known of the UC genetics in Asian populations. Here we performed a haplotype-based analysis of six known UC susceptibility loci in Han Chinese patients. In all, 245 UC patients and 300 healthy controls of Han Chinese descent were genotyped for 27 single nucleotide polymorphisms (SNPs), which cover the major haplotypes of the chromosome regions containing IL10, IL2/IL21, MYO9B, ECM1, MST1, and IL23R in Han Chinese. In contrast to the tight linkage disequilibrium (LD) block of the IL2/IL21 region in Caucasians, IL2 and IL21 reside in two independent LD blocks in Han Chinese. The IL2 SNP rs2069762 (P = 7.0 × 10(-4) , odds ratio [OR] = 1.54, 95% confidence interval [CI] 1.20-1.99) and the IL21 SNP rs2055979 (P = 1.2 × 10(-4) , OR = 1.50, 95% CI 1.17-1.92) were independently associated with UC. We identified one risk haplotype in IL2 and another independent risk haplotype in IL21. In addition to the IL2/IL21 locus, we observed association of the TT genotype of SNP rs1545620 in MYO9B with UC (P = 0.0169; OR = 0.29, 95% CI 0.11-0.78) and association of rs17375018 in IL23R with pancolitis in Chinese UC patients (P = 0.002; OR = 2.38, 95% CI 1.41-4.02). Our study confirmed the association of the IL2/IL21 region with UC in Han Chinese patients, and further implied both IL2 and IL21 as genetic risk factors for UC. Han Chinese UC patients share part of their genetic susceptibility with Caucasian patients. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.

  3. Functional annotations of diabetes nephropathy susceptibility loci through analysis of genome-wide renal gene expression in rat models of diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Farrall Martin

    2009-07-01

    Full Text Available Abstract Background Hyperglycaemia in diabetes mellitus (DM alters gene expression regulation in various organs and contributes to long term vascular and renal complications. We aimed to generate novel renal genome-wide gene transcription data in rat models of diabetes in order to test the responsiveness to hyperglycaemia and renal structural changes of positional candidate genes at selected diabetic nephropathy (DN susceptibility loci. Methods Both Affymetrix and Illumina technologies were used to identify significant quantitative changes in the abundance of over 15,000 transcripts in kidney of models of spontaneous (genetically determined mild hyperglycaemia and insulin resistance (Goto-Kakizaki-GK and experimentally induced severe hyperglycaemia (Wistar-Kyoto-WKY rats injected with streptozotocin [STZ]. Results Different patterns of transcription regulation in the two rat models of diabetes likely underlie the roles of genetic variants and hyperglycaemia severity. The impact of prolonged hyperglycaemia on gene expression changes was more profound in STZ-WKY rats than in GK rats and involved largely different sets of genes. These included genes already tested in genetic studies of DN and a large number of protein coding sequences of unknown function which can be considered as functional and, when they map to DN loci, positional candidates for DN. Further expression analysis of rat orthologs of human DN positional candidate genes provided functional annotations of known and novel genes that are responsive to hyperglycaemia and may contribute to renal functional and/or structural alterations. Conclusion Combining transcriptomics in animal models and comparative genomics provides important information to improve functional annotations of disease susceptibility loci in humans and experimental support for testing candidate genes in human genetics.

  4. Genome-wide association study using the ethnicity-specific Japonica array: identification of new susceptibility loci for cold medicine-related Stevens-Johnson syndrome with severe ocular complications.

    Science.gov (United States)

    Ueta, Mayumi; Sawai, Hiromi; Shingaki, Ryosei; Kawai, Yusuke; Sotozono, Chie; Kojima, Kaname; Yoon, Kyung-Chul; Kim, Mee Kum; Seo, Kyoung Yul; Joo, Choun-Ki; Nagasaki, Masao; Kinoshita, Shigeru; Tokunaga, Katsushi

    2017-04-01

    A genome-wide association study (GWAS) for cold medicine-related Stevens-Johnson syndrome (CM-SJS) with severe ocular complications (SOC) was performed in a Japanese population. A recently developed ethnicity-specific array with genome-wide imputation that was based on the whole-genome sequences of 1070 unrelated Japanese individuals was used. Validation analysis with additional samples from Japanese individuals and replication analysis using samples from Korean individuals identified two new susceptibility loci on chromosomes 15 and 16. This study might suggest the usefulness of GWAS using the ethnicity-specific array and genome-wide imputation based on large-scale whole-genome sequences. Our findings contribute to the understanding of genetic predisposition to CM-SJS with SOC.

  5. Two-stage genome-wide association study identifies variants in CAMSAP1L1 as susceptibility loci for epilepsy in Chinese.

    Science.gov (United States)

    Guo, Youling; Baum, Larry W; Sham, Pak Chung; Wong, Virginia; Ng, Ping Wing; Lui, Colin Hiu Tung; Sin, Ngai Chuen; Tsoi, Tak Hong; Tang, Clara S M; Kwan, Johnny S H; Yip, Benjamin H K; Xiao, Su-Mei; Thomas, G Neil; Lau, Yu Lung; Yang, Wanling; Cherny, Stacey S; Kwan, Patrick

    2012-03-01

    In the majority of patients, epilepsy is a complex disorder with multiple susceptibility genes interacting with environmental factors. However, we understand little about its genetic risks. Here, we report the first genome-wide association study (GWAS) to identify common susceptibility variants of epilepsy in Chinese. This two-stage GWAS included a total of 1087 patients and 3444 matched controls. In the combined analysis of the two stages, the strongest signals were observed with two highly correlated variants, rs2292096 [G] [P= 1.0 × 10(-8), odds ratio (OR) = 0.63] and rs6660197 [T] (P= 9.9 × 10(-7), OR = 0.69), with the former reaching genome-wide significance, on 1q32.1 in the CAMSAP1L1 gene, which encodes a cytoskeletal protein. We also refined a previously reported association with rs9390754 (P= 1.7 × 10(-5)) on 6q21 in the GRIK2 gene, which encodes a glutamate receptor, and identified several other loci in genes involved in neurotransmission or neuronal networking that warrant further investigation. Our results suggest that common genetic variants may increase the susceptibility to epilepsy in Chinese.

  6. Genome-wide high-density SNP linkage search for glioma susceptibility loci: results from the Gliogene Consortium

    DEFF Research Database (Denmark)

    Shete, Sanjay; Lau, Ching C; Houlston, Richard S

    2011-01-01

    Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold i...

  7. Admixture mapping of 15,280 African Americans identifies obesity susceptibility loci on chromosomes 5 and X.

    Directory of Open Access Journals (Sweden)

    Ching-Yu Cheng

    2009-05-01

    Full Text Available The prevalence of obesity (body mass index (BMI > or =30 kg/m(2 is higher in African Americans than in European Americans, even after adjustment for socioeconomic factors, suggesting that genetic factors may explain some of the difference. To identify genetic loci influencing BMI, we carried out a pooled analysis of genome-wide admixture mapping scans in 15,280 African Americans from 14 epidemiologic studies. Samples were genotyped at a median of 1,411 ancestry-informative markers. After adjusting for age, sex, and study, BMI was analyzed both as a dichotomized (top 20% versus bottom 20% and a continuous trait. We found that a higher percentage of European ancestry was significantly correlated with lower BMI (rho = -0.042, P = 1.6x10(-7. In the dichotomized analysis, we detected two loci on chromosome X as associated with increased African ancestry: the first at Xq25 (locus-specific LOD = 5.94; genome-wide score = 3.22; case-control Z = -3.94; and the second at Xq13.1 (locus-specific LOD = 2.22; case-control Z = -4.62. Quantitative analysis identified a third locus at 5q13.3 where higher BMI was highly significantly associated with greater European ancestry (locus-specific LOD = 6.27; genome-wide score = 3.46. Further mapping studies with dense sets of markers will be necessary to identify the alleles in these regions of chromosomes X and 5 that may be associated with variation in BMI.

  8. Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

    DEFF Research Database (Denmark)

    Zhao, Wei; Rasheed, Asif; Tikkanen, Emmi

    2017-01-01

    To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2......D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD...... associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein....

  9. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

    Science.gov (United States)

    Aung, Tin; Ozaki, Mineo; Lee, Mei Chin; Schlötzer-Schrehardt, Ursula; Thorleifsson, Gudmar; Mizoguchi, Takanori; Igo, Robert P; Haripriya, Aravind; Williams, Susan E; Astakhov, Yury S; Orr, Andrew C; Burdon, Kathryn P; Nakano, Satoko; Mori, Kazuhiko; Abu-Amero, Khaled; Hauser, Michael; Li, Zheng; Prakadeeswari, Gopalakrishnan; Bailey, Jessica N Cooke; Cherecheanu, Alina Popa; Kang, Jae H; Nelson, Sarah; Hayashi, Ken; Manabe, Shin-Ichi; Kazama, Shigeyasu; Zarnowski, Tomasz; Inoue, Kenji; Irkec, Murat; Coca-Prados, Miguel; Sugiyama, Kazuhisa; Järvelä, Irma; Schlottmann, Patricio; Lerner, S Fabian; Lamari, Hasnaa; Nilgün, Yildirim; Bikbov, Mukharram; Park, Ki Ho; Cha, Soon Cheol; Yamashiro, Kenji; Zenteno, Juan C; Jonas, Jost B; Kumar, Rajesh S; Perera, Shamira A; Chan, Anita S Y; Kobakhidze, Nino; George, Ronnie; Vijaya, Lingam; Do, Tan; Edward, Deepak P; de Juan Marcos, Lourdes; Pakravan, Mohammad; Moghimi, Sasan; Ideta, Ryuichi; Bach-Holm, Daniella; Kappelgaard, Per; Wirostko, Barbara; Thomas, Samuel; Gaston, Daniel; Bedard, Karen; Greer, Wenda L; Yang, Zhenglin; Chen, Xueyi; Huang, Lulin; Sang, Jinghong; Jia, Hongyan; Jia, Liyun; Qiao, Chunyan; Zhang, Hui; Liu, Xuyang; Zhao, Bowen; Wang, Ya-Xing; Xu, Liang; Leruez, Stéphanie; Reynier, Pascal; Chichua, George; Tabagari, Sergo; Uebe, Steffen; Zenkel, Matthias; Berner, Daniel; Mossböck, Georg; Weisschuh, Nicole; Hoja, Ursula; Welge-Luessen, Ulrich-Christoph; Mardin, Christian; Founti, Panayiota; Chatzikyriakidou, Anthi; Pappas, Theofanis; Anastasopoulos, Eleftherios; Lambropoulos, Alexandros; Ghosh, Arkasubhra; Shetty, Rohit; Porporato, Natalia; Saravanan, Vijayan; Venkatesh, Rengaraj; Shivkumar, Chandrashekaran; Kalpana, Narendran; Sarangapani, Sripriya; Kanavi, Mozhgan R; Beni, Afsaneh Naderi; Yazdani, Shahin; Lashay, Alireza; Naderifar, Homa; Khatibi, Nassim; Fea, Antonio; Lavia, Carlo; Dallorto, Laura; Rolle, Teresa; Frezzotti, Paolo; Paoli, Daniela; Salvi, Erika; Manunta, Paolo; Mori, Yosai; Miyata, Kazunori; Higashide, Tomomi; Chihara, Etsuo; Ishiko, Satoshi; Yoshida, Akitoshi; Yanagi, Masahide; Kiuchi, Yoshiaki; Ohashi, Tsutomu; Sakurai, Toshiya; Sugimoto, Takako; Chuman, Hideki; Aihara, Makoto; Inatani, Masaru; Miyake, Masahiro; Gotoh, Norimoto; Matsuda, Fumihiko; Yoshimura, Nagahisa; Ikeda, Yoko; Ueno, Morio; Sotozono, Chie; Jeoung, Jin Wook; Sagong, Min; Park, Kyu Hyung; Ahn, Jeeyun; Cruz-Aguilar, Marisa; Ezzouhairi, Sidi M; Rafei, Abderrahman; Chong, Yaan Fun; Ng, Xiao Yu; Goh, Shuang Ru; Chen, Yueming; Yong, Victor H K; Khan, Muhammad Imran; Olawoye, Olusola O; Ashaye, Adeyinka O; Ugbede, Idakwo; Onakoya, Adeola; Kizor-Akaraiwe, Nkiru; Teekhasaenee, Chaiwat; Suwan, Yanin; Supakontanasan, Wasu; Okeke, Suhanya; Uche, Nkechi J; Asimadu, Ifeoma; Ayub, Humaira; Akhtar, Farah; Kosior-Jarecka, Ewa; Lukasik, Urszula; Lischinsky, Ignacio; Castro, Vania; Grossmann, Rodolfo Perez; Megevand, Gordana Sunaric; Roy, Sylvain; Dervan, Edward; Silke, Eoin; Rao, Aparna; Sahay, Priti; Fornero, Pablo; Cuello, Osvaldo; Sivori, Delia; Zompa, Tamara; Mills, Richard A; Souzeau, Emmanuelle; Mitchell, Paul; Wang, Jie Jin; Hewitt, Alex W; Coote, Michael; Crowston, Jonathan G; Astakhov, Sergei Y; Akopov, Eugeny L; Emelyanov, Anton; Vysochinskaya, Vera; Kazakbaeva, Gyulli; Fayzrakhmanov, Rinat; Al-Obeidan, Saleh A; Owaidhah, Ohoud; Aljasim, Leyla Ali; Chowbay, Balram; Foo, Jia Nee; Soh, Raphael Q; Sim, Kar Seng; Xie, Zhicheng; Cheong, Augustine W O; Mok, Shi Qi; Soo, Hui Meng; Chen, Xiao Yin; Peh, Su Qin; Heng, Khai Koon; Husain, Rahat; Ho, Su-Ling; Hillmer, Axel M; Cheng, Ching-Yu; Escudero-Domínguez, Francisco A; González-Sarmiento, Rogelio; Martinon-Torres, Frederico; Salas, Antonio; Pathanapitoon, Kessara; Hansapinyo, Linda; Wanichwecharugruang, Boonsong; Kitnarong, Naris; Sakuntabhai, Anavaj; Nguyn, Hip X; Nguyn, Giang T T; Nguyn, Trình V; Zenz, Werner; Binder, Alexander; Klobassa, Daniela S; Hibberd, Martin L; Davila, Sonia; Herms, Stefan; Nöthen, Markus M; Moebus, Susanne; Rautenbach, Robyn M; Ziskind, Ari; Carmichael, Trevor R; Ramsay, Michele; Álvarez, Lydia; García, Montserrat; González-Iglesias, Héctor; Rodríguez-Calvo, Pedro P; Fernández-Vega Cueto, Luis; Oguz, Çilingir; Tamcelik, Nevbahar; Atalay, Eray; Batu, Bilge; Aktas, Dilek; Kasım, Burcu; Wilson, M Roy; Coleman, Anne L; Liu, Yutao; Challa, Pratap; Herndon, Leon; Kuchtey, Rachel W; Kuchtey, John; Curtin, Karen; Chaya, Craig J; Crandall, Alan; Zangwill, Linda M; Wong, Tien Yin; Nakano, Masakazu; Kinoshita, Shigeru; den Hollander, Anneke I; Vesti, Eija; Fingert, John H; Lee, Richard K; Sit, Arthur J; Shingleton, Bradford J; Wang, Ningli; Cusi, Daniele; Qamar, Raheel; Kraft, Peter; Pericak-Vance, Margaret A; Raychaudhuri, Soumya; Heegaard, Steffen; Kivelä, Tero; Reis, André; Kruse, Friedrich E; Weinreb, Robert N; Pasquale, Louis R; Haines, Jonathan L; Thorsteinsdottir, Unnur; Jonasson, Fridbert; Allingham, R Rand; Milea, Dan; Ritch, Robert; Kubota, Toshiaki; Tashiro, Kei; Vithana, Eranga N; Micheal, Shazia; Topouzis, Fotis; Craig, Jamie E; Dubina, Michael; Sundaresan, Periasamy; Stefansson, Kari; Wiggs, Janey L; Pasutto, Francesca; Khor, Chiea Chuen

    2017-07-01

    Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

  10. GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers.

    Directory of Open Access Journals (Sweden)

    Shengping Li

    Full Text Available Genome-wide association studies (GWAS have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV-related hepatocellular carcinoma (HCC. To further identify novel susceptibility loci associated with HBV-related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV-positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1 on 6p21.32 (OR = 1.30, P = 1.13×10⁻¹⁹ and rs455804 (GRIK1 on 21q21.3 (OR = 0.84, P = 1.86×10⁻⁸, which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10⁻⁴; rs455804: OR = 0.84, P = 6.92×10⁻³. We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV-related HCC, suggesting the involvement of glutamate signaling in the development of HBV-related HCC.

  11. Longitudinal exome-wide association study to identify genetic susceptibility loci for hypertension in a Japanese population.

    Science.gov (United States)

    Yasukochi, Yoshiki; Sakuma, Jun; Takeuchi, Ichiro; Kato, Kimihiko; Oguri, Mitsutoshi; Fujimaki, Tetsuo; Horibe, Hideki; Yamada, Yoshiji

    2017-12-08

    Genome-wide association studies have identified various genetic variants associated with complex disorders. However, these studies have commonly been conducted in a cross-sectional manner. Therefore, we performed a longitudinal exome-wide association study (EWAS) in a Japanese cohort. We aimed to identify genetic variants that confer susceptibility to hypertension using ~244 000 single-nucleotide variants (SNVs) and physiological data from 6026 Japanese individuals who underwent annual health check-ups for several years. After quality control, the association of hypertension with SNVs was tested using a generalized estimating equation model. Finally, our longitudinal EWAS detected seven hypertension-related SNVs that passed strict criteria. Among these variants, six SNVs were densely located at 12q24.1, and an East Asian-specific motif (haplotype) 'CAAAA' comprising five derived alleles was identified. Statistical analyses showed that the prevalence of hypertension in individuals with the East Asian-specific haplotype was significantly lower than that in individuals with the common haplotype 'TGGGT'. Furthermore, individuals with the East Asian haplotype may be less susceptible to the adverse effects of smoking on hypertension. The longitudinal EWAS for the recessive model showed that a novel SNV, rs11917356 of COL6A5, was significantly associated with systolic blood pressure, and the derived allele at the SNV may have spread throughout East Asia in recent evolutionary time.

  12. Validation of obesity susceptibility loci identified by genome-wide association studies in early childhood in South Brazilian children.

    Science.gov (United States)

    Zandoná, M R; Sangalli, C N; Campagnolo, P D B; Vitolo, M R; Almeida, S; Mattevi, V S

    2017-02-01

    The prevalence of childhood obesity has been dramatically increasing in developing countries as it has been reported for developed nations. Identifying susceptibility genes in early life could provide the foundations for interventions in lifestyle to prevent obese children to become obese adults. The objective of this study was to evaluate the influence of genetic variants related to obesity identified by genome-wide association studies (MC4R, TMEM18, KCTD15, SH2B1, SEC16B, BDNF, NEGR1, OLFM4 and HOXB5 genes) on anthropometric and dietary phenotypes in two Brazilian cohorts followed-up since birth. There were 745 children examined at birth, after 1 year and after 3.5 years of follow-up. Ten single nucleotide polymorphisms were genotyped. Anthropometric and dietary parameters were compared among genotypes. Children were classified as overweight when body mass index Z-score was >+1. Overweight prevalence was 30.7% at 3.5 years old. Significant associations were identified at 3.5 years old for TMEM18 rs6548238, NEGR1 rs2815752, BDNF rs10767664 and rs6265 (1 year old and 3.5 years old) with anthropometric phenotypes and at 3.5 years old for SEC16B rs10913469 with dietary parameters. Our results indicate that genetic variants in/near these genes contribute to obesity susceptibility in childhood and highlight the age at which they begin to affect obesity-related phenotypes. © 2016 World Obesity Federation.

  13. Meta-analysis of gene–environment-wide association scans accounting for education level identifies additional loci for refractive error

    Science.gov (United States)

    Fan, Qiao; Verhoeven, Virginie J. M.; Wojciechowski, Robert; Barathi, Veluchamy A.; Hysi, Pirro G.; Guggenheim, Jeremy A.; Höhn, René; Vitart, Veronique; Khawaja, Anthony P.; Yamashiro, Kenji; Hosseini, S Mohsen; Lehtimäki, Terho; Lu, Yi; Haller, Toomas; Xie, Jing; Delcourt, Cécile; Pirastu, Mario; Wedenoja, Juho; Gharahkhani, Puya; Venturini, Cristina; Miyake, Masahiro; Hewitt, Alex W.; Guo, Xiaobo; Mazur, Johanna; Huffman, Jenifer E.; Williams, Katie M.; Polasek, Ozren; Campbell, Harry; Rudan, Igor; Vatavuk, Zoran; Wilson, James F.; Joshi, Peter K.; McMahon, George; St Pourcain, Beate; Evans, David M.; Simpson, Claire L.; Schwantes-An, Tae-Hwi; Igo, Robert P.; Mirshahi, Alireza; Cougnard-Gregoire, Audrey; Bellenguez, Céline; Blettner, Maria; Raitakari, Olli; Kähönen, Mika; Seppala, Ilkka; Zeller, Tanja; Meitinger, Thomas; Ried, Janina S.; Gieger, Christian; Portas, Laura; van Leeuwen, Elisabeth M.; Amin, Najaf; Uitterlinden, André G.; Rivadeneira, Fernando; Hofman, Albert; Vingerling, Johannes R.; Wang, Ya Xing; Wang, Xu; Tai-Hui Boh, Eileen; Ikram, M. Kamran; Sabanayagam, Charumathi; Gupta, Preeti; Tan, Vincent; Zhou, Lei; Ho, Candice E. H.; Lim, Wan'e; Beuerman, Roger W.; Siantar, Rosalynn; Tai, E-Shyong; Vithana, Eranga; Mihailov, Evelin; Khor, Chiea-Chuen; Hayward, Caroline; Luben, Robert N.; Foster, Paul J.; Klein, Barbara E. K.; Klein, Ronald; Wong, Hoi-Suen; Mitchell, Paul; Metspalu, Andres; Aung, Tin; Young, Terri L.; He, Mingguang; Pärssinen, Olavi; van Duijn, Cornelia M.; Jin Wang, Jie; Williams, Cathy; Jonas, Jost B.; Teo, Yik-Ying; Mackey, David A.; Oexle, Konrad; Yoshimura, Nagahisa; Paterson, Andrew D.; Pfeiffer, Norbert; Wong, Tien-Yin; Baird, Paul N.; Stambolian, Dwight; Wilson, Joan E. Bailey; Cheng, Ching-Yu; Hammond, Christopher J.; Klaver, Caroline C. W.; Saw, Seang-Mei; Rahi, Jugnoo S.; Korobelnik, Jean-François; Kemp, John P.; Timpson, Nicholas J.; Smith, George Davey; Craig, Jamie E.; Burdon, Kathryn P.; Fogarty, Rhys D.; Iyengar, Sudha K.; Chew, Emily; Janmahasatian, Sarayut; Martin, Nicholas G.; MacGregor, Stuart; Xu, Liang; Schache, Maria; Nangia, Vinay; Panda-Jonas, Songhomitra; Wright, Alan F.; Fondran, Jeremy R.; Lass, Jonathan H.; Feng, Sheng; Zhao, Jing Hua; Khaw, Kay-Tee; Wareham, Nick J.; Rantanen, Taina; Kaprio, Jaakko; Pang, Chi Pui; Chen, Li Jia; Tam, Pancy O.; Jhanji, Vishal; Young, Alvin L.; Döring, Angela; Raffel, Leslie J.; Cotch, Mary-Frances; Li, Xiaohui; Yip, Shea Ping; Yap, Maurice K.H.; Biino, Ginevra; Vaccargiu, Simona; Fossarello, Maurizio; Fleck, Brian; Yazar, Seyhan; Tideman, Jan Willem L.; Tedja, Milly; Deangelis, Margaret M.; Morrison, Margaux; Farrer, Lindsay; Zhou, Xiangtian; Chen, Wei; Mizuki, Nobuhisa; Meguro, Akira; Mäkelä, Kari Matti

    2016-01-01

    Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10−5), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia. PMID:27020472

  14. Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.

    Science.gov (United States)

    Fan, Qiao; Verhoeven, Virginie J M; Wojciechowski, Robert; Barathi, Veluchamy A; Hysi, Pirro G; Guggenheim, Jeremy A; Höhn, René; Vitart, Veronique; Khawaja, Anthony P; Yamashiro, Kenji; Hosseini, S Mohsen; Lehtimäki, Terho; Lu, Yi; Haller, Toomas; Xie, Jing; Delcourt, Cécile; Pirastu, Mario; Wedenoja, Juho; Gharahkhani, Puya; Venturini, Cristina; Miyake, Masahiro; Hewitt, Alex W; Guo, Xiaobo; Mazur, Johanna; Huffman, Jenifer E; Williams, Katie M; Polasek, Ozren; Campbell, Harry; Rudan, Igor; Vatavuk, Zoran; Wilson, James F; Joshi, Peter K; McMahon, George; St Pourcain, Beate; Evans, David M; Simpson, Claire L; Schwantes-An, Tae-Hwi; Igo, Robert P; Mirshahi, Alireza; Cougnard-Gregoire, Audrey; Bellenguez, Céline; Blettner, Maria; Raitakari, Olli; Kähönen, Mika; Seppala, Ilkka; Zeller, Tanja; Meitinger, Thomas; Ried, Janina S; Gieger, Christian; Portas, Laura; van Leeuwen, Elisabeth M; Amin, Najaf; Uitterlinden, André G; Rivadeneira, Fernando; Hofman, Albert; Vingerling, Johannes R; Wang, Ya Xing; Wang, Xu; Tai-Hui Boh, Eileen; Ikram, M Kamran; Sabanayagam, Charumathi; Gupta, Preeti; Tan, Vincent; Zhou, Lei; Ho, Candice E H; Lim, Wan'e; Beuerman, Roger W; Siantar, Rosalynn; Tai, E-Shyong; Vithana, Eranga; Mihailov, Evelin; Khor, Chiea-Chuen; Hayward, Caroline; Luben, Robert N; Foster, Paul J; Klein, Barbara E K; Klein, Ronald; Wong, Hoi-Suen; Mitchell, Paul; Metspalu, Andres; Aung, Tin; Young, Terri L; He, Mingguang; Pärssinen, Olavi; van Duijn, Cornelia M; Jin Wang, Jie; Williams, Cathy; Jonas, Jost B; Teo, Yik-Ying; Mackey, David A; Oexle, Konrad; Yoshimura, Nagahisa; Paterson, Andrew D; Pfeiffer, Norbert; Wong, Tien-Yin; Baird, Paul N; Stambolian, Dwight; Wilson, Joan E Bailey; Cheng, Ching-Yu; Hammond, Christopher J; Klaver, Caroline C W; Saw, Seang-Mei; Rahi, Jugnoo S; Korobelnik, Jean-François; Kemp, John P; Timpson, Nicholas J; Smith, George Davey; Craig, Jamie E; Burdon, Kathryn P; Fogarty, Rhys D; Iyengar, Sudha K; Chew, Emily; Janmahasatian, Sarayut; Martin, Nicholas G; MacGregor, Stuart; Xu, Liang; Schache, Maria; Nangia, Vinay; Panda-Jonas, Songhomitra; Wright, Alan F; Fondran, Jeremy R; Lass, Jonathan H; Feng, Sheng; Zhao, Jing Hua; Khaw, Kay-Tee; Wareham, Nick J; Rantanen, Taina; Kaprio, Jaakko; Pang, Chi Pui; Chen, Li Jia; Tam, Pancy O; Jhanji, Vishal; Young, Alvin L; Döring, Angela; Raffel, Leslie J; Cotch, Mary-Frances; Li, Xiaohui; Yip, Shea Ping; Yap, Maurice K H; Biino, Ginevra; Vaccargiu, Simona; Fossarello, Maurizio; Fleck, Brian; Yazar, Seyhan; Tideman, Jan Willem L; Tedja, Milly; Deangelis, Margaret M; Morrison, Margaux; Farrer, Lindsay; Zhou, Xiangtian; Chen, Wei; Mizuki, Nobuhisa; Meguro, Akira; Mäkelä, Kari Matti

    2016-03-29

    Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

  15. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

    DEFF Research Database (Denmark)

    Kar, Siddhartha P; Beesley, Jonathan; Amin Al Olama, Ali

    2016-01-01

    -type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P

  16. Distinct high resolution genome profiles of early onset and late onset colorectal cancer integrated with gene expression data identify candidate susceptibility loci

    Directory of Open Access Journals (Sweden)

    Merok Marianne A

    2010-05-01

    Full Text Available Abstract Background Estimates suggest that up to 30% of colorectal cancers (CRC may develop due to an increased genetic risk. The mean age at diagnosis for CRC is about 70 years. Time of disease onset 20 years younger than the mean age is assumed to be indicative of genetic susceptibility. We have compared high resolution tumor genome copy number variation (CNV (Roche NimbleGen, 385 000 oligo CGH array in microsatellite stable (MSS tumors from two age groups, including 23 young at onset patients without known hereditary syndromes and with a median age of 44 years (range: 28-53 and 17 elderly patients with median age 79 years (range: 69-87. Our aim was to identify differences in the tumor genomes between these groups and pinpoint potential susceptibility loci. Integration analysis of CNV and genome wide mRNA expression data, available for the same tumors, was performed to identify a restricted candidate gene list. Results The total fraction of the genome with aberrant copy number, the overall genomic profile and the TP53 mutation spectrum were similar between the two age groups. However, both the number of chromosomal aberrations and the number of breakpoints differed significantly between the groups. Gains of 2q35, 10q21.3-22.1, 10q22.3 and 19q13.2-13.31 and losses from 1p31.3, 1q21.1, 2q21.2, 4p16.1-q28.3, 10p11.1 and 19p12, positions that in total contain more than 500 genes, were found significantly more often in the early onset group as compared to the late onset group. Integration analysis revealed a covariation of DNA copy number at these sites and mRNA expression for 107 of the genes. Seven of these genes, CLC, EIF4E, LTBP4, PLA2G12A, PPAT, RG9MTD2, and ZNF574, had significantly different mRNA expression comparing median expression levels across the transcriptome between the two groups. Conclusions Ten genomic loci, containing more than 500 protein coding genes, are identified as more often altered in tumors from early onset versus late

  17. Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population.

    Science.gov (United States)

    Zanetti, Krista A; Wang, Zhaoming; Aldrich, Melinda; Amos, Christopher I; Blot, William J; Bowman, Elise D; Burdette, Laurie; Cai, Qiuyin; Caporaso, Neil; Chung, Charles C; Gillanders, Elizabeth M; Haiman, Christopher A; Hansen, Helen M; Henderson, Brian E; Kolonel, Laurence N; Marchand, Loic Le; Li, Shengchao; McNeill, Lorna Haughton; Ryan, Bríd M; Schwartz, Ann G; Sison, Jennette D; Spitz, Margaret R; Tucker, Margaret; Wenzlaff, Angela S; Wiencke, John K; Wilkens, Lynne; Wrensch, Margaret R; Wu, Xifeng; Zheng, Wei; Zhou, Weiyin; Christiani, David; Palmer, Julie R; Penning, Trevor M; Rieber, Alyssa G; Rosenberg, Lynn; Ruiz-Narvaez, Edward A; Su, Li; Vachani, Anil; Wei, Yongyue; Whitehead, Alexander S; Chanock, Stephen J; Harris, Curtis C

    2016-08-01

    Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping. We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p<1.51×10(-5)) in an independent set of 866 cases and 796 controls in stage 2. In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p=1.3×10(-9); OR=1.32; 95% CI=1.20-1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p=2.8×10(-9); OR=1.28; 95% CI=1.18-1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p=1.3×10(-8); OR=1.37; 95% CI=1.23-1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans. Published by Elsevier Ireland Ltd.

  18. Genome-wide association study confirms lung cancer susceptibility loci on chromosome 5p15 and 15q25 in an African-American population

    Science.gov (United States)

    Zanetti, Krista A.; Wang, Zhaoming; Aldrich, Melinda; Amos, Christopher I.; Blot, William J.; Bowman, Elise D.; Burdette, Laurie; Cai, Quiyin; Caporaso, Neil; Chung, Charles C.; Gillanders, Elizabeth M.; Haiman, Christopher A.; Hansen, Helen M.; Henderson, Brian E.; Kolonel, Laurence N.; Le Marchand, Loic; Li, Shengchao; McNeill, Lorna Haughton; Ryan, Bríd M.; Schwartz, Ann G.; Sison, Jennette D.; Spitz, Margaret R.; Tucker, Margaret; Wenzlaff, Angela S.; Wiencke, John K.; Wilkens, Lynne; Wrensch, Margaret R.; Wu, Xifeng; Zheng, Wei; Zhou, Weiyin; Christiani, David; Palmer, Julie R.; Penning, Trevor M.; Rieber, Alyssa G.; Rosenberg, Lynn; Ruiz-Narvaez, Edward A.; Su, Li; Vachani, Anil; Wei, Yongyue; Whitehead, Alexander S.; Chanock, Stephen J.; Harris, Curtis C.

    2016-01-01

    Objectives Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping. Materials and Methods We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs (p<1.51×10−5) in an independent set of 866 cases and 796 controls in stage 2. Results and Conclusion In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 (p = 1.3 × 10−9; OR = 1.32; 95% CI = 1.20–1.44) near CHRNA5, and 5p15.33 marked by rs2853677 (p = 2.8 × 10−9; OR = 1.28; 95% CI = 1.18–1.39) near TERT. The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer (p = 1.3 × 10−8; OR = 1.37; 95% CI = 1.23–1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking - cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT, on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans. PMID:27393504

  19. Orosomucoid (ORM) typing by isoelectric focusing: evidence for an additional duplicated ORM1 locus haplotype and close linkage of two ORM loci.

    Science.gov (United States)

    Yuasa, I; Umetsu, K; Suenaga, K

    1988-01-01

    Human serum orosomucoid (ORM) exhibits a high variability. Several alleles including a duplicated ORM1 gene (ORM1*2.1) have been identified at two functional ORM loci, ORM1 and ORM2. In this study a modified isoelectric focusing, in which glycerin was omitted from gels, was used to differentiate a new variant ORM1 5 from ORM2 3. The ORM1 5 band was always observed together with the ORM1 2 band. The simultaneous expression could be explained in terms of an additional duplicated ORM1 locus haplotype, ORM1*5.2, whose average frequency was .016 in two Japanese populations. The ORM2*6 found at a polymorphic frequency (.023) was demonstrated to be in association with ORM1*2, indicating the close proximity between ORM1 and ORM2 loci. Images Figure 1 PMID:3400642

  20. Evolution of multiple additive loci caused divergence between Drosophila yakuba and D. santomea in wing rowing during male courtship.

    Directory of Open Access Journals (Sweden)

    Jessica Cande

    Full Text Available In Drosophila, male flies perform innate, stereotyped courtship behavior. This innate behavior evolves rapidly between fly species, and is likely to have contributed to reproductive isolation and species divergence. We currently understand little about the neurobiological and genetic mechanisms that contributed to the evolution of courtship behavior. Here we describe a novel behavioral difference between the two closely related species D. yakuba and D. santomea: the frequency of wing rowing during courtship. During courtship, D. santomea males repeatedly rotate their wing blades to face forward and then back (rowing, while D. yakuba males rarely row their wings. We found little intraspecific variation in the frequency of wing rowing for both species. We exploited multiplexed shotgun genotyping (MSG to genotype two backcross populations with a single lane of Illumina sequencing. We performed quantitative trait locus (QTL mapping using the ancestry information estimated by MSG and found that the species difference in wing rowing mapped to four or five genetically separable regions. We found no evidence that these loci display epistasis. The identified loci all act in the same direction and can account for most of the species difference.

  1. Four Susceptibility Loci for Gallstone Disease Identified in a Meta-analysis of Genome-Wide Association Studies

    DEFF Research Database (Denmark)

    Joshi, Amit D; Andersson, Charlotte; Buch, Stephan

    2016-01-01

    BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta-analysis o......BACKGROUND & AIMS: A genome-wide association study (GWAS) of 280 cases identified the hepatic cholesterol transporter ABCG8 as a locus associated with risk for gallstone disease, but findings have not been reported from any other GWAS of this phenotype. We performed a large-scale, meta......-analysis of GWASs of individuals of European ancestry with available prior genotype data, to identify additional genetic risk factors for gallstone disease. METHODS: We obtained per-allele odds ratio (OR) and standard error estimates using age- and sex-adjusted logistic regression models within each of the 10...... discovery studies (8720 cases and 55,152 controls). We performed an inverse variance weighted, fixed-effects meta-analysis of study-specific estimates to identify single-nucleotide polymorphisms that were associated independently with gallstone disease. Associations were replicated in 6489 cases and 62...

  2. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.

    Directory of Open Access Journals (Sweden)

    Heather C Mefford

    2010-05-01

    Full Text Available Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Several genes have been identified in rare autosomal dominant and severe sporadic forms of epilepsy, but the genetic cause is unknown in the vast majority of cases. Copy number variants (CNVs are known to play an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID, autism, and schizophrenia. Genome-wide studies of copy number variation in epilepsy have not been performed. We have applied whole-genome oligonucleotide array comparative genomic hybridization to a cohort of 517 individuals with various idiopathic, non-lesional epilepsies. We detected one or more rare genic CNVs in 8.9% of affected individuals that are not present in 2,493 controls; five individuals had two rare CNVs. We identified CNVs in genes previously implicated in other neurodevelopmental disorders, including two deletions in AUTS2 and one deletion in CNTNAP2. Therefore, our findings indicate that rare CNVs are likely to contribute to a broad range of generalized and focal epilepsies. In addition, we find that 2.9% of patients carry deletions at 15q11.2, 15q13.3, or 16p13.11, genomic hotspots previously associated with ID, autism, or schizophrenia. In summary, our findings suggest common etiological factors for seemingly diverse diseases such as ID, autism, schizophrenia, and epilepsy.

  3. Fine-mapping of the 5p15.33, 6p22.1-p21.31, and 15q25.1 regions identifies functional and histology-specific lung cancer susceptibility loci in African-Americans.

    Science.gov (United States)

    Walsh, Kyle M; Gorlov, Ivan P; Hansen, Helen M; Wu, Xifeng; Spitz, Margaret R; Zhang, Huifeng; Lu, Emily Y; Wenzlaff, Angela S; Sison, Jennette D; Wei, Chongjuan; Lloyd, Stacy M; Chen, Wei; Frazier, Marsha L; Seldin, Michael F; Bierut, Laura J; Bracci, Paige M; Wrensch, Margaret R; Schwartz, Ann G; Wiencke, John K; Amos, Christopher I

    2013-02-01

    Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans. 1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate. The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25-1.97; P, 1.1 × 10(-4)) and variants in the 5'-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48-0.85; P, 1.82 × 10(-3)). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73-0.93; P, 1.1 × 10(-3)). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65-0.86; P, 8.1 × 10(-5)). Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma. Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies.

  4. Orosomucoid (ORM) typing by isoelectric focusing: evidence for an additional duplicated ORM1 locus haplotype and close linkage of two ORM loci.

    OpenAIRE

    Yuasa, I; Umetsu, K; Suenaga, K

    1988-01-01

    Human serum orosomucoid (ORM) exhibits a high variability. Several alleles including a duplicated ORM1 gene (ORM1*2.1) have been identified at two functional ORM loci, ORM1 and ORM2. In this study a modified isoelectric focusing, in which glycerin was omitted from gels, was used to differentiate a new variant ORM1 5 from ORM2 3. The ORM1 5 band was always observed together with the ORM1 2 band. The simultaneous expression could be explained in terms of an additional duplicated ORM1 locus hapl...

  5. Associations of Genetic Variants at Nongenic Susceptibility Loci with Breast Cancer Risk and Heterogeneity by Tumor Subtype in Southern Han Chinese Women

    Directory of Open Access Journals (Sweden)

    Huiying Liang

    2016-01-01

    Full Text Available Current understanding of cancer genomes is mainly “gene centric.” However, GWAS have identified some nongenic breast cancer susceptibility loci. Validation studies showed inconsistent results among different populations. To further explore this inconsistency and to investigate associations by intrinsic subtype (Luminal-A, Luminal-B, ER−&PR−&HER2+, and triple negative among Southern Han Chinese women, we genotyped five nongenic polymorphisms (2q35: rs13387042, 5p12: rs981782 and rs4415084, and 8q24: rs1562430 and rs13281615 using MassARRAY IPLEX platform in 609 patients and 882 controls. Significant associations with breast cancer were observed for rs13387042 and rs4415084 with OR (95% CI per-allele 1.29 (1.00–1.66 and 0.83 (0.71–0.97, respectively. In subtype specific analysis, rs13387042 (per-allele adjusted OR = 1.36, 95% CI = 1.00–1.87 and rs4415084 (per-allele adjusted OR = 0.82, 95% CI = 0.66–1.00 showed slightly significant association with Luminal-A subtype; however, only rs13387042 was associated with ER−&PR−&HER2+ tumors (per-allele adjusted OR = 1.55, 95% CI = 1.00–2.40, and none of them were linked to Luminal-B and triple negative subtype. Collectively, nongenic SNPs were heterogeneous according to the intrinsic subtype. Further studies with larger datasets along with intrinsic subtype categorization should explore and confirm the role of these variants in increasing breast cancer risk.

  6. Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease

    NARCIS (Netherlands)

    van der Harst, Pim; Verweij, Niek

    2018-01-01

    Rationale: Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic

  7. Multicenter dizygotic twin cohort study confirms two linkage susceptibility loci for body mass index at 3q29 and 7q36 and identifies three further potential novel loci

    DEFF Research Database (Denmark)

    Kettunen, J; Perola, M; Martin, N G

    2009-01-01

    OBJECTIVE: To identify common loci and potential genetic variants affecting body mass index (BMI, kg m(-2)) in study populations originating from Europe. DESIGN: We combined genome-wide linkage scans of six cohorts from Australia, Denmark, Finland, the Netherlands, Sweden and the United Kingdom...

  8. Susceptibility of Clostridium difficile Toward Antimicrobial Agents Used as Feed Additives for Food Animals

    DEFF Research Database (Denmark)

    Aarestrup, Frank Møller; Tvede, Michael

    2011-01-01

    A total of 65 toxigenic Clostridium difficile strains isolated from patients with antibiotic-associated diarrhea were tested for susceptibility to avilamycin, flavomycin, monensin, and salinomycin. Except for flavomycin the substances showed in vitro efficacy comparable to reports of the currently...

  9. Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index

    Science.gov (United States)

    Speliotes, Elizabeth K.; Willer, Cristen J.; Berndt, Sonja I.; Monda, Keri L.; Thorleifsson, Gudmar; Jackson, Anne U.; Allen, Hana Lango; Lindgren, Cecilia M.; Luan, Jian’an; Mägi, Reedik; Randall, Joshua C.; Vedantam, Sailaja; Winkler, Thomas W.; Qi, Lu; Workalemahu, Tsegaselassie; Heid, Iris M.; Steinthorsdottir, Valgerdur; Stringham, Heather M.; Weedon, Michael N.; Wheeler, Eleanor; Wood, Andrew R.; Ferreira, Teresa; Weyant, Robert J.; Segré, Ayellet V.; Estrada, Karol; Liang, Liming; Nemesh, James; Park, Ju-Hyun; Gustafsson, Stefan; Kilpeläinen, Tuomas O.; Yang, Jian; Bouatia-Naji, Nabila; Esko, Tõnu; Feitosa, Mary F.; Kutalik, Zoltán; Mangino, Massimo; Raychaudhuri, Soumya; Scherag, Andre; Smith, Albert Vernon; Welch, Ryan; Zhao, Jing Hua; Aben, Katja K.; Absher, Devin M.; Amin, Najaf; Dixon, Anna L.; Fisher, Eva; Glazer, Nicole L.; Goddard, Michael E.; Heard-Costa, Nancy L.; Hoesel, Volker; Hottenga, Jouke-Jan; Johansson, Åsa; Johnson, Toby; Ketkar, Shamika; Lamina, Claudia; Li, Shengxu; Moffatt, Miriam F.; Myers, Richard H.; Narisu, Narisu; Perry, John R.B.; Peters, Marjolein J.; Preuss, Michael; Ripatti, Samuli; Rivadeneira, Fernando; Sandholt, Camilla; Scott, Laura J.; Timpson, Nicholas J.; Tyrer, Jonathan P.; van Wingerden, Sophie; Watanabe, Richard M.; White, Charles C.; Wiklund, Fredrik; Barlassina, Christina; Chasman, Daniel I.; Cooper, Matthew N.; Jansson, John-Olov; Lawrence, Robert W.; Pellikka, Niina; Prokopenko, Inga; Shi, Jianxin; Thiering, Elisabeth; Alavere, Helene; Alibrandi, Maria T. S.; Almgren, Peter; Arnold, Alice M.; Aspelund, Thor; Atwood, Larry D.; Balkau, Beverley; Balmforth, Anthony J.; Bennett, Amanda J.; Ben-Shlomo, Yoav; Bergman, Richard N.; Bergmann, Sven; Biebermann, Heike; Blakemore, Alexandra I.F.; Boes, Tanja; Bonnycastle, Lori L.; Bornstein, Stefan R.; Brown, Morris J.; Buchanan, Thomas A.; Busonero, Fabio; Campbell, Harry; Cappuccio, Francesco P.; Cavalcanti-Proença, Christine; Chen, Yii-Der Ida; Chen, Chih-Mei; Chines, Peter S.; Clarke, Robert; Coin, Lachlan; Connell, John; Day, Ian N.M.; den Heijer, Martin; Duan, Jubao; Ebrahim, Shah; Elliott, Paul; Elosua, Roberto; Eiriksdottir, Gudny; Erdos, Michael R.; Eriksson, Johan G.; Facheris, Maurizio F.; Felix, Stephan B.; Fischer-Posovszky, Pamela; Folsom, Aaron R.; Friedrich, Nele; Freimer, Nelson B.; Fu, Mao; Gaget, Stefan; Gejman, Pablo V.; Geus, Eco J.C.; Gieger, Christian; Gjesing, Anette P.; Goel, Anuj; Goyette, Philippe; Grallert, Harald; Gräßler, Jürgen; Greenawalt, Danielle M.; Groves, Christopher J.; Gudnason, Vilmundur; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Hall, Alistair S.; Havulinna, Aki S.; Hayward, Caroline; Heath, Andrew C.; Hengstenberg, Christian; Hicks, Andrew A.; Hinney, Anke; Hofman, Albert; Homuth, Georg; Hui, Jennie; Igl, Wilmar; Iribarren, Carlos; Isomaa, Bo; Jacobs, Kevin B.; Jarick, Ivonne; Jewell, Elizabeth; John, Ulrich; Jørgensen, Torben; Jousilahti, Pekka; Jula, Antti; Kaakinen, Marika; Kajantie, Eero; Kaplan, Lee M.; Kathiresan, Sekar; Kettunen, Johannes; Kinnunen, Leena; Knowles, Joshua W.; Kolcic, Ivana; König, Inke R.; Koskinen, Seppo; Kovacs, Peter; Kuusisto, Johanna; Kraft, Peter; Kvaløy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lanzani, Chiara; Launer, Lenore J.; Lecoeur, Cecile; Lehtimäki, Terho; Lettre, Guillaume; Liu, Jianjun; Lokki, Marja-Liisa; Lorentzon, Mattias; Luben, Robert N.; Ludwig, Barbara; Manunta, Paolo; Marek, Diana; Marre, Michel; Martin, Nicholas G.; McArdle, Wendy L.; McCarthy, Anne; McKnight, Barbara; Meitinger, Thomas; Melander, Olle; Meyre, David; Midthjell, Kristian; Montgomery, Grant W.; Morken, Mario A.; Morris, Andrew P.; Mulic, Rosanda; Ngwa, Julius S.; Nelis, Mari; Neville, Matt J.; Nyholt, Dale R.; O’Donnell, Christopher J.; O’Rahilly, Stephen; Ong, Ken K.; Oostra, Ben; Paré, Guillaume; Parker, Alex N.; Perola, Markus; Pichler, Irene; Pietiläinen, Kirsi H.; Platou, Carl G.P.; Polasek, Ozren; Pouta, Anneli; Rafelt, Suzanne; Raitakari, Olli; Rayner, Nigel W.; Ridderstråle, Martin; Rief, Winfried; Ruokonen, Aimo; Robertson, Neil R.; Rzehak, Peter; Salomaa, Veikko; Sanders, Alan R.; Sandhu, Manjinder S.; Sanna, Serena; Saramies, Jouko; Savolainen, Markku J.; Scherag, Susann; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Silander, Kaisa; Sinisalo, Juha; Siscovick, David S.; Smit, Jan H.; Soranzo, Nicole; Sovio, Ulla; Stephens, Jonathan; Surakka, Ida; Swift, Amy J.; Tammesoo, Mari-Liis; Tardif, Jean-Claude; Teder-Laving, Maris; Teslovich, Tanya M.; Thompson, John R.; Thomson, Brian; Tönjes, Anke; Tuomi, Tiinamaija; van Meurs, Joyce B.J.; van Ommen, Gert-Jan; Vatin, Vincent; Viikari, Jorma; Visvikis-Siest, Sophie; Vitart, Veronique; Vogel, Carla I. G.; Voight, Benjamin F.; Waite, Lindsay L.; Wallaschofski, Henri; Walters, G. Bragi; Widen, Elisabeth; Wiegand, Susanna; Wild, Sarah H.; Willemsen, Gonneke; Witte, Daniel R.; Witteman, Jacqueline C.; Xu, Jianfeng; Zhang, Qunyuan; Zgaga, Lina; Ziegler, Andreas; Zitting, Paavo; Beilby, John P.; Farooqi, I. Sadaf; Hebebrand, Johannes; Huikuri, Heikki V.; James, Alan L.; Kähönen, Mika; Levinson, Douglas F.; Macciardi, Fabio; Nieminen, Markku S.; Ohlsson, Claes; Palmer, Lyle J.; Ridker, Paul M.; Stumvoll, Michael; Beckmann, Jacques S.; Boeing, Heiner; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Collins, Francis S.; Cupples, L. Adrienne; Smith, George Davey; Erdmann, Jeanette; Froguel, Philippe; Grönberg, Henrik; Gyllensten, Ulf; Hall, Per; Hansen, Torben; Harris, Tamara B.; Hattersley, Andrew T.; Hayes, Richard B.; Heinrich, Joachim; Hu, Frank B.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Kaprio, Jaakko; Karpe, Fredrik; Khaw, Kay-Tee; Kiemeney, Lambertus A.; Krude, Heiko; Laakso, Markku; Lawlor, Debbie A.; Metspalu, Andres; Munroe, Patricia B.; Ouwehand, Willem H.; Pedersen, Oluf; Penninx, Brenda W.; Peters, Annette; Pramstaller, Peter P.; Quertermous, Thomas; Reinehr, Thomas; Rissanen, Aila; Rudan, Igor; Samani, Nilesh J.; Schwarz, Peter E.H.; Shuldiner, Alan R.; Spector, Timothy D.; Tuomilehto, Jaakko; Uda, Manuela; Uitterlinden, André; Valle, Timo T.; Wabitsch, Martin; Waeber, Gérard; Wareham, Nicholas J.; Watkins, Hugh; Wilson, James F.; Wright, Alan F.; Zillikens, M. Carola; Chatterjee, Nilanjan; McCarroll, Steven A.; Purcell, Shaun; Schadt, Eric E.; Visscher, Peter M.; Assimes, Themistocles L.; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Groop, Leif C.; Haritunians, Talin; Hunter, David J.; Kaplan, Robert C.; Mohlke, Karen L.; O’Connell, Jeffrey R.; Peltonen, Leena; Schlessinger, David; Strachan, David P.; van Duijn, Cornelia M.; Wichmann, H.-Erich; Frayling, Timothy M.; Thorsteinsdottir, Unnur; Abecasis, Gonçalo R.; Barroso, Inês; Boehnke, Michael; Stefansson, Kari; North, Kari E.; McCarthy, Mark I.; Hirschhorn, Joel N.; Ingelsson, Erik; Loos, Ruth J.F.

    2010-01-01

    Obesity is globally prevalent and highly heritable, but the underlying genetic factors remain largely elusive. To identify genetic loci for obesity-susceptibility, we examined associations between body mass index (BMI) and ~2.8 million SNPs in up to 123,865 individuals, with targeted follow-up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity-susceptibility loci and identified 18 new loci associated with BMI (P<5×10−8), one of which includes a copy number variant near GPRC5B. Some loci (MC4R, POMC, SH2B1, BDNF) map near key hypothalamic regulators of energy balance, and one is near GIPR, an incretin receptor. Furthermore, genes in other newly-associated loci may provide novel insights into human body weight regulation. PMID:20935630

  10. Thyroid cancer GWAS identifies 10q26.12 and 6q14.1 as novel susceptibility loci and reveals genetic heterogeneity among populations.

    Science.gov (United States)

    Mancikova, Veronika; Cruz, Raquel; Inglada-Pérez, Lucía; Fernández-Rozadilla, Ceres; Landa, Iñigo; Cameselle-Teijeiro, José; Celeiro, Catuxa; Pastor, Susana; Velázquez, Antonia; Marcos, Ricard; Andía, Victor; Álvarez-Escolá, Cristina; Meoro, Amparo; Schiavi, Francesca; Opocher, Giuseppe; Quintela, Inés; Ansede-Bermejo, Juan; Ruiz-Ponte, Clara; Santisteban, Pilar; Robledo, Mercedes; Carracedo, Angel

    2015-10-15

    Thyroid cancer is the most heritable cancer of all those not displaying typical Mendelian inheritance. However, most of the genetic factors that would explain the high heritability remain unknown. Our aim was to identify additional common genetic variants associated with susceptibility to this disease. In order to do so, we performed a genome-wide association study in a series of 398 cases and 502 controls from Spain, followed by a replication in four well-defined Southern European case-control collections contributing a total of 1,422 cases and 1,908 controls. The association between the variation at the 9q22 locus near FOXE1 and thyroid cancer risk was consistent across all series, with several SNPs identified (rs7028661: OR = 1.64, p = 1.0 × 10(-22) , rs7037324: OR = 1.54, p = 1.2 × 10(-17) ). Moreover, the rare alleles of three SNPs (rs2997312, rs10788123 and rs1254167) at 10q26.12 showed suggestive evidence of association with higher risk of the disease (OR = 1.35, p = 1.2 × 10(-04) , OR = 1.26, p = 5.2 × 10(-04) and OR = 1.38, p = 5.9 × 10(-05) , respectively). Finally, the rare allele of rs4075570 at 6q14.1 conferred protection in the series studied (OR = 0.82, p = 2.0 × 10(-04) ). This study suggests that heterogeneity in genetic susceptibility between populations is a key feature to take into account when exploring genetic risk factors related to this disease. © 2015 UICC.

  11. Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3

    NARCIS (Netherlands)

    Purdue, Mark P.; Johansson, Mattias; Zelenika, Diana; Toro, Jorge R.; Scelo, Ghislaine; Moore, Lee E.; Prokhortchouk, Egor; Wu, Xifeng; Kiemeney, Lambertus A.; Gaborieau, Valerie; Jacobs, Kevin B.; Chow, Wong-Ho; Zaridze, David; Matveev, Vsevolod; Lubinski, Jan; Trubicka, Joanna; Szeszenia-Dabrowska, Neonila; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Bucur, Alexandru; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Boffetta, Paolo; Colt, Joanne S.; Davis, Faith G.; Schwartz, Kendra L.; Banks, Rosamonde E.; Selby, Peter J.; Harnden, Patricia; Berg, Christine D.; Hsing, Ann W.; Grubb, Robert L.; Boeing, Heiner; Vineis, Paolo; Clavel-Chapelon, Francoise; Palli, Domenico; Tumino, Rosario; Krogh, Vittorio; Panico, Salvatore; Duell, Eric J.; Quiros, Jose Ramon; Sanchez, Maria-Jose; Navarro, Carmen; Ardanaz, Eva; Dorronsoro, Miren; Khaw, Kay-Tee; Allen, Naomi E.; Bueno-de-Mesquita, H. Bas; Peeters, Petra H. M.; Trichopoulos, Dimitrios; Linseisen, Jakob; Ljungberg, Borje; Overvad, Kim; Tjonneland, Anne; Romieu, Isabelle; Riboli, Elio; Mukeria, Anush; Shangina, Oxana; Stevens, Victoria L.; Thun, Michael J.; Diver, W. Ryan; Gapstur, Susan M.; Pharoah, Paul D.; Easton, Douglas F.; Albanes, Demetrius; Weinstein, Stephanie J.; Virtamo, Jarmo; Vatten, Lars; Hveem, Kristian; Njolstad, Inger; Tell, Grethe S.; Stoltenberg, Camilla; Kumar, Rajiv; Koppova, Kvetoslava; Cussenot, Olivier; Benhamou, Simone; Oosterwijk, Egbert; Vermeulen, Sita H.; Aben, Katja K. H.; van der Marel, Saskia L.; Ye, Yuanqing; Wood, Christopher G.; Pu, Xia; Mazur, Alexander M.; Boulygina, Eugenia S.; Chekanov, Nikolai N.; Foglio, Mario; Lechner, Doris; Gut, Ivo; Heath, Simon; Blanche, Helene; Hutchinson, Amy; Thomas, Gilles; Wang, Zhaoming; Yeager, Meredith; Fraumeni, Joseph F.; Skryabin, Konstantin G.; McKay, James D.; Rothman, Nathaniel; Chanock, Stephen J.; Lathrop, Mark; Brennan, Paul

    We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and

  12. Comprehensive SNP scan of DNA repair and DNA damage response genes reveal multiple susceptibility loci conferring risk to tobacco associated leukoplakia and oral cancer.

    Science.gov (United States)

    Mondal, Pinaki; Datta, Sayantan; Maiti, Guru Prasad; Baral, Aradhita; Jha, Ganga Nath; Panda, Chinmay Kumar; Chowdhury, Shantanu; Ghosh, Saurabh; Roy, Bidyut; Roychoudhury, Susanta

    2013-01-01

    Polymorphic variants of DNA repair and damage response genes play major role in carcinogenesis. These variants are suspected as predisposition factors to Oral Squamous Cell Carcinoma (OSCC). For identification of susceptible variants affecting OSCC development in Indian population, the "maximally informative" method of SNP selection from HapMap data to non-HapMap populations was applied. Three hundred twenty-five SNPs from 11 key genes involved in double strand break repair, mismatch repair and DNA damage response pathways were genotyped on a total of 373 OSCC, 253 leukoplakia and 535 unrelated control individuals. The significantly associated SNPs were validated in an additional cohort of 144 OSCC patients and 160 controls. The rs12515548 of MSH3 showed significant association with OSCC both in the discovery and validation phases (discovery P-value: 1.43E-05, replication P-value: 4.84E-03). Two SNPs (rs12360870 of MRE11A, P-value: 2.37E-07 and rs7003908 of PRKDC, P-value: 7.99E-05) were found to be significantly associated only with leukoplakia. Stratification of subjects based on amount of tobacco consumption identified SNPs that were associated with either high or low tobacco exposed group. The study reveals a synergism between associated SNPs and lifestyle factors in predisposition to OSCC and leukoplakia.

  13. Commentary on "identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array." COGS-Cancer Research UK GWAS-ELLIPSE (part of GAME-ON) Initiative; Australian Prostate Cancer Bioresource; UK Genetic Prostate Cancer Study Collaborators/British Association, of Urological Surgeons' Section of Oncology; UK ProtecT (Prostate testing for cancer and Treatment) Study

    DEFF Research Database (Denmark)

    Olumi, Aria F; Nordestgaard, Børge G.

    2014-01-01

    Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international...... PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (Pcancer susceptibility loci, explaining ~30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred...... by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies....

  14. Association Studies and Direct DNA Sequencing Implicate Genetic Susceptibility Loci in the Etiology of Nonsyndromic Orofacial Clefts in Sub-Saharan African Populations

    Science.gov (United States)

    Gowans, L.J.J.; Adeyemo, W.L.; Eshete, M.; Mossey, P.A.; Busch, T.; Aregbesola, B.; Donkor, P.; Arthur, F.K.N.; Bello, S.A.; Martinez, A.; Li, M.; Augustine-Akpan, E.A.; Deressa, W.; Twumasi, P.; Olutayo, J.; Deribew, M.; Agbenorku, P.; Oti, A.A.; Braimah, R.; Plange-Rhule, G.; Gesses, M.; Obiri-Yeboah, S.; Oseni, G.O.; Olaitan, P.B.; Abdur-Rahman, L.; Abate, F.; Hailu, T.; Gravem, P.; Ogunlewe, M.O.; Buxó, C.J.; Marazita, M.L.; Adeyemo, A.A.; Murray, J.C.; Butali, A.

    2016-01-01

    Orofacial clefts (OFCs) are congenital dysmorphologies of the human face and oral cavity, with a global incidence of 1 per 700 live births. These anomalies exhibit a multifactorial pattern of inheritance, with genetic and environmental factors both playing crucial roles. Many loci have been implicated in the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in populations of Asian and European ancestries, through genome-wide association studies and candidate gene studies. However, few populations of African descent have been studied to date. Here, the authors show evidence of an association of some loci with NSCL/P and nonsyndromic cleft palate only (NSCPO) in cohorts from Africa (Ghana, Ethiopia, and Nigeria). The authors genotyped 48 single-nucleotide polymorphisms that were selected from previous genome-wide association studies and candidate gene studies. These markers were successfully genotyped on 701 NSCL/P and 163 NSCPO cases, 1,070 unaffected relatives, and 1,078 unrelated controls. The authors also directly sequenced 7 genes in 184 nonsyndromic OFC (NSOFC) cases and 96 controls from Ghana. Population-specific associations were observed in the case-control analyses of the subpopulations, with West African subpopulations (Ghana and Nigeria) showing a similar pattern of associations. In meta-analyses of the case-control cohort, PAX7 (rs742071, P = 5.10 × 10−3), 8q24 (rs987525, P = 1.22 × 10−3), and VAX1 (rs7078160, P = 0.04) were nominally associated with NSCL/P, and MSX1 (rs115200552, P = 0.01), TULP4 (rs651333, P = 0.04), CRISPLD2 (rs4783099, P = 0.02), and NOG1 (rs17760296, P = 0.04) were nominally associated with NSCPO. Moreover, 7 loci exhibited evidence of threshold overtransmission in NSOFC cases through the transmission disequilibrium test and through analyses of the family-based association for disease traits. Through DNA sequencing, the authors also identified 2 novel, rare, potentially pathogenic variants (p.Asn323Asp

  15. Genome-wide association study of osteochondrosis in the tarsocrural joint of Dutch Warmblood horses identifies susceptibility loci on chromosomes 3 and 10

    NARCIS (Netherlands)

    Orr, N.; Hill, E.W.; Gu, G.; Govindarajan, P.; Conroy, J.; Grevenhof, van E.M.; Ducro, B.J.; Arendonk, van J.A.M.; Knaap, J.H.; Weeren, van P.R.; Machugh, D.E.; Ennis, S.; Brama, P.A.

    2013-01-01

    Equine osteochondrosis is a developmental joint disease that is a significant source of morbidity affecting multiple breeds of horse. The genetic variants underlying osteochondrosis susceptibility have not been established. Here, we describe the results of a genome-wide association study of

  16. A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease

    DEFF Research Database (Denmark)

    Amin Al Olama, Ali; Kote-Jarai, Zsofia; Schumacher, Fredrick R

    2013-01-01

    Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS inc...

  17. Genome-wide association study of osteochondrosis in the tarsocrural joint of Dutch Warmblood horses identifies susceptibility loci on chromosomes 3 and 10

    NARCIS (Netherlands)

    Orr, N; Hill, E W; Gu, J; Govindarajan, P; Conroy, J; van Grevenhof, E M; Ducro, B J; van Arendonk, J A M; Knaap, J H; van Weeren, P R; Machugh, D E; Ennis, S; Brama, P A J

    Equine osteochondrosis is a developmental joint disease that is a significant source of morbidity affecting multiple breeds of horse. The genetic variants underlying osteochondrosis susceptibility have not been established. Here, we describe the results of a genome-wide association study of

  18. Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

    DEFF Research Database (Denmark)

    Zuber, Verena; Bettella, Francesco; Witoelar, Aree

    2017-01-01

    ) and applied to other diseases such as schizophrenia. Conclusions: This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study......Background: Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor...... progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding...

  19. Loci controlling lymphocyte production of interferon gamma after alloantigen stimulation in vitro and their co-localization with genes controlling lymphocyte infiltration of tumors and tumor susceptibility

    Czech Academy of Sciences Publication Activity Database

    Lipoldová, Marie; Havelková, Helena; Badalová, Jana; Vojtíšková, Jarmila; Quan, L.; Krulová, Magdalena; Sohrabi, Yahya; Stassen, A. P. M.; Demant, P.

    2010-01-01

    Roč. 59, č. 2 (2010), s. 203-213 ISSN 0340-7004 R&D Projects: GA MŠk(CZ) LC06009; GA AV ČR IAA500520606; GA ČR GD310/08/H077 Institutional research plan: CEZ:AV0Z50520514 Keywords : Tumor susceptibility * Genetic control of interferon gamma production * Lymphocyte infiltration of tumors Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.293, year: 2010

  20. Gene susceptibility identification in a longitudinal study confirms new loci in the development of chronic obstructive pulmonary disease and influences lung function decline.

    Science.gov (United States)

    Xie, Jungang; Wu, Hongxu; Xu, Yuzhu; Wu, Xiaojie; Liu, Xue; Shang, Jin; Zhao, Jianping; Zhao, Junling; Wang, Jianmiao; Dela Cruz, Charles S; Xiong, Weining; Xu, Yongjian

    2015-04-18

    To identify COPD associated gene susceptibility and lung function in a longitudinal cohort including COPD and subjects who were at risk for developing COPD, and to replicate this in two cross-sectional and longitudinal populations in Chinese Han population. Three cohorts were recruited in this study, including an 18-year follow-up population (306 COPD and 743 control subjects) in one village in 1992 and it changed to 409 COPD and 611 controls in 2010, a 2 year follow-up study in another village (374 COPD and 377 controls) and another 2 year follow-up one in a city (541 COPD and 560 controls) in 2010. Sixteen candidate single nucleotide polymorphisms (SNPs) were selected for genotyping. Among them, 5SNPs in or near HHIP, 1SNP in IREB2 and 1SNP in FAM13A were previously reported to be associated with COPD susceptibility or lung function decline. And another 9SNPs were selected from HapMap website as HHIP tags. In 2010, totaling 1,324 COPD patients and 1,548 healthy controls were finally included in our genetic susceptibility analyses. We identified two new regions showing an association with COPD susceptibility in the Human Hedgehog interacting protein (HHIP) rs11100865 and rs7654947, and we confirmed that the family with sequence similarity 13 member A gene (FAM13A) rs7671167 was associated with the development of COPD in Chinese Han population. And the HHIP rs7654947 and FAM13A rs7671167 were associated with lung function decline, and this result was replicated in other two populations. These results suggest an important role of the HHIP and FAM13A regions as genetic risk factors for COPD development and lung function decline in Chinese Han population. Future research on these genes should focus on the molecular mechanisms of these genes on developing COPD and creating therapies to alleviate reduced lung function.

  1. A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease.

    Science.gov (United States)

    Amin Al Olama, Ali; Kote-Jarai, Zsofia; Schumacher, Fredrick R; Wiklund, Fredrik; Berndt, Sonja I; Benlloch, Sara; Giles, Graham G; Severi, Gianluca; Neal, David E; Hamdy, Freddie C; Donovan, Jenny L; Hunter, David J; Henderson, Brian E; Thun, Michael J; Gaziano, Michael; Giovannucci, Edward L; Siddiq, Afshan; Travis, Ruth C; Cox, David G; Canzian, Federico; Riboli, Elio; Key, Timothy J; Andriole, Gerald; Albanes, Demetrius; Hayes, Richard B; Schleutker, Johanna; Auvinen, Anssi; Tammela, Teuvo L J; Weischer, Maren; Stanford, Janet L; Ostrander, Elaine A; Cybulski, Cezary; Lubinski, Jan; Thibodeau, Stephen N; Schaid, Daniel J; Sorensen, Karina D; Batra, Jyotsna; Clements, Judith A; Chambers, Suzanne; Aitken, Joanne; Gardiner, Robert A; Maier, Christiane; Vogel, Walther; Dörk, Thilo; Brenner, Hermann; Habuchi, Tomonori; Ingles, Sue; John, Esther M; Dickinson, Joanne L; Cannon-Albright, Lisa; Teixeira, Manuel R; Kaneva, Radka; Zhang, Hong-Wei; Lu, Yong-Jie; Park, Jong Y; Cooney, Kathleen A; Muir, Kenneth R; Leongamornlert, Daniel A; Saunders, Edward; Tymrakiewicz, Malgorzata; Mahmud, Nadiya; Guy, Michelle; Govindasami, Koveela; O'Brien, Lynne T; Wilkinson, Rosemary A; Hall, Amanda L; Sawyer, Emma J; Dadaev, Tokhir; Morrison, Jonathan; Dearnaley, David P; Horwich, Alan; Huddart, Robert A; Khoo, Vincent S; Parker, Christopher C; Van As, Nicholas; Woodhouse, Christopher J; Thompson, Alan; Dudderidge, Tim; Ogden, Chris; Cooper, Colin S; Lophatonanon, Artitaya; Southey, Melissa C; Hopper, John L; English, Dallas; Virtamo, Jarmo; Le Marchand, Loic; Campa, Daniele; Kaaks, Rudolf; Lindstrom, Sara; Diver, W Ryan; Gapstur, Susan; Yeager, Meredith; Cox, Angela; Stern, Mariana C; Corral, Roman; Aly, Markus; Isaacs, William; Adolfsson, Jan; Xu, Jianfeng; Zheng, S Lilly; Wahlfors, Tiina; Taari, Kimmo; Kujala, Paula; Klarskov, Peter; Nordestgaard, Børge G; Røder, M Andreas; Frikke-Schmidt, Ruth; Bojesen, Stig E; FitzGerald, Liesel M; Kolb, Suzanne; Kwon, Erika M; Karyadi, Danielle M; Orntoft, Torben Falck; Borre, Michael; Rinckleb, Antje; Luedeke, Manuel; Herkommer, Kathleen; Meyer, Andreas; Serth, Jürgen; Marthick, James R; Patterson, Briony; Wokolorczyk, Dominika; Spurdle, Amanda; Lose, Felicity; McDonnell, Shannon K; Joshi, Amit D; Shahabi, Ahva; Pinto, Pedro; Santos, Joana; Ray, Ana; Sellers, Thomas A; Lin, Hui-Yi; Stephenson, Robert A; Teerlink, Craig; Muller, Heiko; Rothenbacher, Dietrich; Tsuchiya, Norihiko; Narita, Shintaro; Cao, Guang-Wen; Slavov, Chavdar; Mitev, Vanio; Chanock, Stephen; Gronberg, Henrik; Haiman, Christopher A; Kraft, Peter; Easton, Douglas F; Eeles, Rosalind A

    2013-01-15

    Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.

  2. Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer.

    Science.gov (United States)

    Morton, Lindsay M; Sampson, Joshua N; Armstrong, Gregory T; Chen, Ting-Huei; Hudson, Melissa M; Karlins, Eric; Dagnall, Casey L; Li, Shengchao Alfred; Wilson, Carmen L; Srivastava, Deo Kumar; Liu, Wei; Kang, Guolian; Oeffinger, Kevin C; Henderson, Tara O; Moskowitz, Chaya S; Gibson, Todd M; Merino, Diana M; Wong, Jeannette R; Hammond, Sue; Neglia, Joseph P; Turcotte, Lucie M; Miller, Jeremy; Bowen, Laura; Wheeler, William A; Leisenring, Wendy M; Whitton, John A; Burdette, Laurie; Chung, Charles; Hicks, Belynda D; Jones, Kristine; Machiela, Mitchell J; Vogt, Aurelie; Wang, Zhaoming; Yeager, Meredith; Neale, Geoffrey; Lear, Matthew; Strong, Louise C; Yasui, Yutaka; Stovall, Marilyn; Weathers, Rita E; Smith, Susan A; Howell, Rebecca; Davies, Stella M; Radloff, Gretchen A; Onel, Kenan; de González, Amy Berrington; Inskip, Peter D; Rajaraman, Preetha; Fraumeni, Joseph F; Bhatia, Smita; Chanock, Stephen J; Tucker, Margaret A; Robison, Leslie L

    2017-11-01

    Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking. We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided. Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; breast cancer risk after childhood cancer.

  3. Replication and Relevance of Multiple Susceptibility Loci Discovered from Genome Wide Association Studies for Type 2 Diabetes in an Indian Population.

    Directory of Open Access Journals (Sweden)

    Nagaraja M Phani

    Full Text Available Several genetic variants for type 2 diabetes (T2D have been identified through genome wide association studies (GWAS from Caucasian population; however replication studies were not consistent across various ethnicities. Objective of the current study is to examine the possible correlation of 9 most significant GWAS single nucleotide polymorphisms (SNPs for T2D susceptibility as well as the interactive effect of these variants on the risk of T2D in an Indian population.Case-control cohorts of 1156 individuals were genotyped for 9 SNPs from an Indian population. Association analyses were performed using logistic regression after adjusting for covariates. Multifactor dimensionality reduction (MDR analysis was adopted to determine gene-gene interactions and discriminatory power of combined SNP effect was assessed by grouping individuals based on the number of risk alleles and by calculating area under the receiver-operator characteristic curve (AUC.We confirm the association of TCF7L2 (rs7903146 and SLC30A8 (rs13266634 with T2D. MDR analysis showed statistically significant interactions among four SNPs of SLC30A8 (rs13266634, IGF2BP2 (rs4402960, HHEX (rs1111875 and CDKN2A (rs10811661 genes. Cumulative analysis showed an increase in odds ratio against the baseline group of individuals carrying 5 to 6 risk alleles and discriminatory power of genetic test based on 9 variants showed higher AUC value when analyzed along with body mass index (BMI.These results provide a strong evidence for independent association between T2D and SNPs for in TCF7L2 and SLC30A8. MDR analysis demonstrates that independently non-significant variants may interact with one another resulting in increased disease susceptibility in the population tested.

  4. An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits.

    Directory of Open Access Journals (Sweden)

    Yi-Hsiang Hsu

    2010-06-01

    Full Text Available Osteoporosis is a complex disorder and commonly leads to fractures in elderly persons. Genome-wide association studies (GWAS have become an unbiased approach to identify variations in the genome that potentially affect health. However, the genetic variants identified so far only explain a small proportion of the heritability for complex traits. Due to the modest genetic effect size and inadequate power, true association signals may not be revealed based on a stringent genome-wide significance threshold. Here, we take advantage of SNP and transcript arrays and integrate GWAS and expression signature profiling relevant to the skeletal system in cellular and animal models to prioritize the discovery of novel candidate genes for osteoporosis-related traits, including bone mineral density (BMD at the lumbar spine (LS and femoral neck (FN, as well as geometric indices of the hip (femoral neck-shaft angle, NSA; femoral neck length, NL; and narrow-neck width, NW. A two-stage meta-analysis of GWAS from 7,633 Caucasian women and 3,657 men, revealed three novel loci associated with osteoporosis-related traits, including chromosome 1p13.2 (RAP1A, p = 3.6x10(-8, 2q11.2 (TBC1D8, and 18q11.2 (OSBPL1A, and confirmed a previously reported region near TNFRSF11B/OPG gene. We also prioritized 16 suggestive genome-wide significant candidate genes based on their potential involvement in skeletal metabolism. Among them, 3 candidate genes were associated with BMD in women. Notably, 2 out of these 3 genes (GPR177, p = 2.6x10(-13; SOX6, p = 6.4x10(-10 associated with BMD in women have been successfully replicated in a large-scale meta-analysis of BMD, but none of the non-prioritized candidates (associated with BMD did. Our results support the concept of our prioritization strategy. In the absence of direct biological support for identified genes, we highlighted the efficiency of subsequent functional characterization using publicly available expression profiling relevant

  5. Susceptibility to lethal cerebral malaria is regulated by epistatic interaction between chromosome 4 (Berr6) and chromosome 1 (Berr7) loci in mice.

    Science.gov (United States)

    Torre, S; van Bruggen, R; Kennedy, J M; Berghout, J; Bongfen, S E; Langat, P; Lathrop, M; Vidal, S M; Gros, P

    2013-06-01

    In humans, cerebral malaria is a rare but often lethal complication of infection with Plasmodium parasites, the occurrence of which is influenced by complex genetic factors of the host. We used a mouse model of experimental cerebral malaria (ECM) with Plasmodium berghei ANKA to study genetic factors regulating appearance of neurological symptoms and associated lethality. In a genome-wide screen of N-ethyl-N-nitrosourea-mutagenized mice derived from C57BL/6J (B6) and 129S1/SvImJ (129) mouse strains, we detected a strong interaction between the genetic backgrounds of these strains, which modulates ECM resistance. We have mapped a major gene locus to central chromosome 4 (log of the odds (LOD) 6.7; 79.6-97.3 Mb), which we designate Berr8. [corrected]. B6 alleles at Berr6 are associated with resistance, and are inherited in a co-dominant fashion. In mice heterozygous for Berr6 B6/129 alleles, resistance to ECM is strongly modulated by a second locus, Berr7, that maps to the proximal portion of chromosome 1 (LOD 4.03; 41.4 Mb). 129 alleles at Berr7 are associated with ECM resistance in a dosage-dependent fashion. Results are discussed in view of the possible role of this two-locus system in susceptibility to unrelated inflammatory conditions in mice and humans.

  6. High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci.

    Science.gov (United States)

    Kim, Kwangwoo; Bang, So-Young; Lee, Hye-Soon; Cho, Soo-Kyung; Choi, Chan-Bum; Sung, Yoon-Kyoung; Kim, Tae-Hwan; Jun, Jae-Bum; Yoo, Dae Hyun; Kang, Young Mo; Kim, Seong-Kyu; Suh, Chang-Hee; Shim, Seung-Cheol; Lee, Shin-Seok; Lee, Jisoo; Chung, Won Tae; Choe, Jung-Yoon; Shin, Hyoung Doo; Lee, Jong-Young; Han, Bok-Ghee; Nath, Swapan K; Eyre, Steve; Bowes, John; Pappas, Dimitrios A; Kremer, Joel M; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; Ärlestig, Lisbeth; Okada, Yukinori; Diogo, Dorothée; Liao, Katherine P; Karlson, Elizabeth W; Raychaudhuri, Soumya; Rantapää-Dahlqvist, Solbritt; Martin, Javier; Klareskog, Lars; Padyukov, Leonid; Gregersen, Peter K; Worthington, Jane; Greenberg, Jeffrey D; Plenge, Robert M; Bae, Sang-Cheol

    2015-03-01

    A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45,790 European case-control samples. We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  7. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

    DEFF Research Database (Denmark)

    Paternoster, Lavinia; Standl, Marie; Chen, Chih-Mei

    2011-01-01

    population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream...

  8. Genetic linkage analysis supports the presence of two susceptibility loci for alcoholism and heavy drinking on chromosome 1p22.1-11.2 and 1q21.3-24.2

    Directory of Open Access Journals (Sweden)

    Curtis David

    2005-03-01

    Full Text Available Abstract Background In order to confirm a previous finding of linkage to alcoholism on chromosome 1 we have carried out a genetic linkage study. Methods DNA from eighteen families, densely affected by alcoholism, was used to genotype a set of polymorphic microsatellite markers at loci approximately 10 centimorgans apart spanning the short arm and part of the long arm of chromosome 1. Linkage analyses were performed using the classical lod score and a model-free method. Three different definitions of affection status were defined, these were 1. Heavy Drinking (HD where affected subjects drank more than the Royal College of Psychiatrists recommended weekly amount. 2. The Research Diagnostic Criteria for alcoholism (RDCA 3. Alcohol Dependence Syndrome (ADS as defined by Edwards and Gross (1976 and now incorporated into ICD10 and DSMIV. Results Linkage analyses with the markers D1S1588, D1S2134, D1S1675 covering the cytogenetic region 1p22.1-11.2 all gave positive two point and multipoint lods with a maximum lod of 1.8 at D1S1588 (1p22.1 for the RDCA definition of alcoholism. Another lod of 1.8 was found with D1S1653 in the region 1q21.3-24.2 using the HD affection model. Conclusion These results both support the presence of linkage in the 1p22.1-11.2 region which was previously implicated by the USA Collaborative Study of the Genetics of Alcoholism (COGA study and also suggest the presence of another susceptibility locus at 1q21.3-24.2.

  9. Spatial prediction of landslide susceptibility using an adaptive neuro-fuzzy inference system combined with frequency ratio, generalized additive model, and support vector machine techniques

    Science.gov (United States)

    Chen, Wei; Pourghasemi, Hamid Reza; Panahi, Mahdi; Kornejady, Aiding; Wang, Jiale; Xie, Xiaoshen; Cao, Shubo

    2017-11-01

    The spatial prediction of landslide susceptibility is an important prerequisite for the analysis of landslide hazards and risks in any area. This research uses three data mining techniques, such as an adaptive neuro-fuzzy inference system combined with frequency ratio (ANFIS-FR), a generalized additive model (GAM), and a support vector machine (SVM), for landslide susceptibility mapping in Hanyuan County, China. In the first step, in accordance with a review of the previous literature, twelve conditioning factors, including slope aspect, altitude, slope angle, topographic wetness index (TWI), plan curvature, profile curvature, distance to rivers, distance to faults, distance to roads, land use, normalized difference vegetation index (NDVI), and lithology, were selected. In the second step, a collinearity test and correlation analysis between the conditioning factors and landslides were applied. In the third step, we used three advanced methods, namely, ANFIS-FR, GAM, and SVM, for landslide susceptibility modeling. Subsequently, the results of their accuracy were validated using a receiver operating characteristic curve. The results showed that all three models have good prediction capabilities, while the SVM model has the highest prediction rate of 0.875, followed by the ANFIS-FR and GAM models with prediction rates of 0.851 and 0.846, respectively. Thus, the landslide susceptibility maps produced in the study area can be applied for management of hazards and risks in landslide-prone Hanyuan County.

  10. Additional evidence supports association of common genetic variants in VTI1A and ETFA with increased risk of glioma susceptibility.

    Science.gov (United States)

    Wang, Ning; Deng, Zhong; Wang, Maode; Li, Ruichun; Xu, Gaofeng; Bao, Gang

    2017-04-15

    VTI1A and ETFA were identified recently as susceptibility genes for non-glioblastoma (GBM) of glioma risk in European populations, but the genetic etiology and pathogenesis of glioma have not been fully elucidated. Here, we aimed to investigate whether common genetic variants in VTI1A and ETFA predispose Han Chinese individuals to glioma. The association of thirteen common tagging single nucleotide polymorphisms (SNPs) in VTI1A and ETFA genes with glioma were assessed in a hospital-based case-control study including 473 non-GBM of glioma patients and 1046 cancer-free controls. Two SNPs (rs11196067 in VTI1A and rs1801591 in ETFA) were found to be significantly associated with non-GBM of glioma risk (rs11196067, adjusted P=0.00018, adjusted odds ratio (OR)=1.37, 95% confidence interval (CI)=1.16-1.61; rs1801591, adjusted P=0.000022, adjusted OR=1.72, 95% CI=1.34-2.20). In further stratified analysis, they were both more pronounced in the adult subgroup. In haplotype-based analysis, two haplotypes were identified to be significant association with glioma. The haplotype "TGA" (P=0.002) in VTI1A and the haplotype "ACA" (Pglioma risk respectively, compared with corresponding non-carriers. In summary, our results indicate that genetic variants in VTI1A and ETFA may modify individual susceptibility to non-GBM of glioma in the Han Chinese population and support the role of the VTI1A and ETFA genes in the occurrence of glioma. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms

    DEFF Research Database (Denmark)

    Howson, Joanna M. M.; Zhao, Wei; Barnes, Daniel R

    2017-01-01

    Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy ...... and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms....

  12. Seed colour loci, homoeology and linkage groups of the C genome chromosomes revealed in Brassica rapa–B. oleracea monosomic alien addition lines

    Science.gov (United States)

    Heneen, Waheeb K.; Geleta, Mulatu; Brismar, Kerstin; Xiong, Zhiyong; Pires, J. Chris; Hasterok, Robert; Stoute, Andrew I.; Scott, Roderick J.; King, Graham J.; Kurup, Smita

    2012-01-01

    Background and Aims Brassica rapa and B. oleracea are the progenitors of oilseed rape B. napus. The addition of each chromosome of B. oleracea to the chromosome complement of B. rapa results in a series of monosomic alien addition lines (MAALs). Analysis of MAALs determines which B. oleracea chromosomes carry genes controlling specific phenotypic traits, such as seed colour. Yellow-seeded oilseed rape is a desirable breeding goal both for food and livestock feed end-uses that relate to oil, protein and fibre contents. The aims of this study included developing a missing MAAL to complement an available series, for studies on seed colour control, chromosome homoeology and assignment of linkage groups to B. oleracea chromosomes. Methods A new batch of B. rapa–B. oleracea aneuploids was produced to generate the missing MAAL. Seed colour and other plant morphological features relevant to differentiation of MAALs were recorded. For chromosome characterization, Snow's carmine, fluorescence in situ hybridization (FISH) and genomic in situ hybridization (GISH) were used. Key Results The final MAAL was developed. Morphological traits that differentiated the MAALs comprised cotyledon number, leaf morphology, flower colour and seed colour. Seed colour was controlled by major genes on two B. oleracea chromosomes and minor genes on five other chromosomes of this species. Homoeologous pairing was largely between chromosomes with similar centromeric positions. FISH, GISH and a parallel microsatellite marker analysis defined the chromosomes in terms of their linkage groups. Conclusions A complete set of MAALs is now available for genetic, genomic, evolutionary and breeding perspectives. Defining chromosomes that carry specific genes, physical localization of DNA markers and access to established genetic linkage maps contribute to the integration of these approaches, manifested in the confirmed correspondence of linkage groups with specific chromosomes. Applications include marker

  13. Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.

    Science.gov (United States)

    den Hoed, Marcel; Eijgelsheim, Mark; Esko, Tõnu; Brundel, Bianca J J M; Peal, David S; Evans, David M; Nolte, Ilja M; Segrè, Ayellet V; Holm, Hilma; Handsaker, Robert E; Westra, Harm-Jan; Johnson, Toby; Isaacs, Aaron; Yang, Jian; Lundby, Alicia; Zhao, Jing Hua; Kim, Young Jin; Go, Min Jin; Almgren, Peter; Bochud, Murielle; Boucher, Gabrielle; Cornelis, Marilyn C; Gudbjartsson, Daniel; Hadley, David; van der Harst, Pim; Hayward, Caroline; den Heijer, Martin; Igl, Wilmar; Jackson, Anne U; Kutalik, Zoltán; Luan, Jian'an; Kemp, John P; Kristiansson, Kati; Ladenvall, Claes; Lorentzon, Mattias; Montasser, May E; Njajou, Omer T; O'Reilly, Paul F; Padmanabhan, Sandosh; St Pourcain, Beate; Rankinen, Tuomo; Salo, Perttu; Tanaka, Toshiko; Timpson, Nicholas J; Vitart, Veronique; Waite, Lindsay; Wheeler, William; Zhang, Weihua; Draisma, Harmen H M; Feitosa, Mary F; Kerr, Kathleen F; Lind, Penelope A; Mihailov, Evelin; Onland-Moret, N Charlotte; Song, Ci; Weedon, Michael N; Xie, Weijia; Yengo, Loic; Absher, Devin; Albert, Christine M; Alonso, Alvaro; Arking, Dan E; de Bakker, Paul I W; Balkau, Beverley; Barlassina, Cristina; Benaglio, Paola; Bis, Joshua C; Bouatia-Naji, Nabila; Brage, Søren; Chanock, Stephen J; Chines, Peter S; Chung, Mina; Darbar, Dawood; Dina, Christian; Dörr, Marcus; Elliott, Paul; Felix, Stephan B; Fischer, Krista; Fuchsberger, Christian; de Geus, Eco J C; Goyette, Philippe; Gudnason, Vilmundur; Harris, Tamara B; Hartikainen, Anna-Liisa; Havulinna, Aki S; Heckbert, Susan R; Hicks, Andrew A; Hofman, Albert; Holewijn, Suzanne; Hoogstra-Berends, Femke; Hottenga, Jouke-Jan; Jensen, Majken K; Johansson, Asa; Junttila, Juhani; Kääb, Stefan; Kanon, Bart; Ketkar, Shamika; Khaw, Kay-Tee; Knowles, Joshua W; Kooner, Angrad S; Kors, Jan A; Kumari, Meena; Milani, Lili; Laiho, Päivi; Lakatta, Edward G; Langenberg, Claudia; Leusink, Maarten; Liu, Yongmei; Luben, Robert N; Lunetta, Kathryn L; Lynch, Stacey N; Markus, Marcello R P; Marques-Vidal, Pedro; Mateo Leach, Irene; McArdle, Wendy L; McCarroll, Steven A; Medland, Sarah E; Miller, Kathryn A; Montgomery, Grant W; Morrison, Alanna C; Müller-Nurasyid, Martina; Navarro, Pau; Nelis, Mari; O'Connell, Jeffrey R; O'Donnell, Christopher J; Ong, Ken K; Newman, Anne B; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P; Psaty, Bruce M; Rao, Dabeeru C; Ring, Susan M; Rossin, Elizabeth J; Rudan, Diana; Sanna, Serena; Scott, Robert A; Sehmi, Jaban S; Sharp, Stephen; Shin, Jordan T; Singleton, Andrew B; Smith, Albert V; Soranzo, Nicole; Spector, Tim D; Stewart, Chip; Stringham, Heather M; Tarasov, Kirill V; Uitterlinden, André G; Vandenput, Liesbeth; Hwang, Shih-Jen; Whitfield, John B; Wijmenga, Cisca; Wild, Sarah H; Willemsen, Gonneke; Wilson, James F; Witteman, Jacqueline C M; Wong, Andrew; Wong, Quenna; Jamshidi, Yalda; Zitting, Paavo; Boer, Jolanda M A; Boomsma, Dorret I; Borecki, Ingrid B; van Duijn, Cornelia M; Ekelund, Ulf; Forouhi, Nita G; Froguel, Philippe; Hingorani, Aroon; Ingelsson, Erik; Kivimaki, Mika; Kronmal, Richard A; Kuh, Diana; Lind, Lars; Martin, Nicholas G; Oostra, Ben A; Pedersen, Nancy L; Quertermous, Thomas; Rotter, Jerome I; van der Schouw, Yvonne T; Verschuren, W M Monique; Walker, Mark; Albanes, Demetrius; Arnar, David O; Assimes, Themistocles L; Bandinelli, Stefania; Boehnke, Michael; de Boer, Rudolf A; Bouchard, Claude; Caulfield, W L Mark; Chambers, John C; Curhan, Gary; Cusi, Daniele; Eriksson, Johan; Ferrucci, Luigi; van Gilst, Wiek H; Glorioso, Nicola; de Graaf, Jacqueline; Groop, Leif; Gyllensten, Ulf; Hsueh, Wen-Chi; Hu, Frank B; Huikuri, Heikki V; Hunter, David J; Iribarren, Carlos; Isomaa, Bo; Jarvelin, Marjo-Riitta; Jula, Antti; Kähönen, Mika; Kiemeney, Lambertus A; van der Klauw, Melanie M; Kooner, Jaspal S; Kraft, Peter; Iacoviello, Licia; Lehtimäki, Terho; Lokki, Marja-Liisa L; Mitchell, Braxton D; Navis, Gerjan; Nieminen, Markku S; Ohlsson, Claes; Poulter, Neil R; Qi, Lu; Raitakari, Olli T; Rimm, Eric B; Rioux, John D; Rizzi, Federica; Rudan, Igor; Salomaa, Veikko; Sever, Peter S; Shields, Denis C; Shuldiner, Alan R; Sinisalo, Juha; Stanton, Alice V; Stolk, Ronald P; Strachan, David P; Tardif, Jean-Claude; Thorsteinsdottir, Unnur; Tuomilehto, Jaako; van Veldhuisen, Dirk J; Virtamo, Jarmo; Viikari, Jorma; Vollenweider, Peter; Waeber, Gérard; Widen, Elisabeth; Cho, Yoon Shin; Olsen, Jesper V; Visscher, Peter M; Willer, Cristen; Franke, Lude; Erdmann, Jeanette; Thompson, John R; Pfeufer, Arne; Sotoodehnia, Nona; Newton-Cheh, Christopher; Ellinor, Patrick T; Stricker, Bruno H Ch; Metspalu, Andres; Perola, Markus; Beckmann, Jacques S; Smith, George Davey; Stefansson, Kari; Wareham, Nicholas J; Munroe, Patricia B; Sibon, Ody C M; Milan, David J; Snieder, Harold; Samani, Nilesh J; Loos, Ruth J F

    2013-06-01

    Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

  14. Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders

    Science.gov (United States)

    den Hoed, Marcel; Eijgelsheim, Mark; Esko, Tõnu; Brundel, Bianca J J M; Peal, David S; Evans, David M; Nolte, Ilja M; Segrè, Ayellet V; Holm, Hilma; Handsaker, Robert E; Westra, Harm-Jan; Johnson, Toby; Isaacs, Aaron; Yang, Jian; Lundby, Alicia; Zhao, Jing Hua; Kim, Young Jin; Go, Min Jin; Almgren, Peter; Bochud, Murielle; Boucher, Gabrielle; Cornelis, Marilyn C; Gudbjartsson, Daniel; Hadley, David; Van Der Harst, Pim; Hayward, Caroline; Heijer, Martin Den; Igl, Wilmar; Jackson, Anne U; Kutalik, Zoltán; Luan, Jian’an; Kemp, John P; Kristiansson, Kati; Ladenvall, Claes; Lorentzon, Mattias; Montasser, May E; Njajou, Omer T; O’Reilly, Paul F; Padmanabhan, Sandosh; Pourcain, Beate St.; Rankinen, Tuomo; Salo, Perttu; Tanaka, Toshiko; Timpson, Nicholas J; Vitart, Veronique; Waite, Lindsay; Wheeler, William; Zhang, Weihua; Draisma, Harmen H M; Feitosa, Mary F; Kerr, Kathleen F; Lind, Penelope A; Mihailov, Evelin; Onland-Moret, N Charlotte; Song, Ci; Weedon, Michael N; Xie, Weijia; Yengo, Loic; Absher, Devin; Albert, Christine M; Alonso, Alvaro; Arking, Dan E; de Bakker, Paul I W; Balkau, Beverley; Barlassina, Cristina; Benaglio, Paola; Bis, Joshua C; Bouatia-Naji, Nabila; Brage, Søren; Chanock, Stephen J; Chines, Peter S; Chung, Mina; Darbar, Dawood; Dina, Christian; Dörr, Marcus; Elliott, Paul; Felix, Stephan B; Fischer, Krista; Fuchsberger, Christian; de Geus, Eco J C; Goyette, Philippe; Gudnason, Vilmundur; Harris, Tamara B; Hartikainen, Anna-liisa; Havulinna, Aki S; Heckbert, Susan R; Hicks, Andrew A; Hofman, Albert; Holewijn, Suzanne; Hoogstra-Berends, Femke; Hottenga, Jouke-Jan; Jensen, Majken K; Johansson, Åsa; Junttila, Juhani; Kääb, Stefan; Kanon, Bart; Ketkar, Shamika; Khaw, Kay-Tee; Knowles, Joshua W; Kooner, Angrad S; Kors, Jan A; Kumari, Meena; Milani, Lili; Laiho, Päivi; Lakatta, Edward G; Langenberg, Claudia; Leusink, Maarten; Liu, Yongmei; Luben, Robert N; Lunetta, Kathryn L; Lynch, Stacey N; Markus, Marcello R P; Marques-Vidal, Pedro; Leach, Irene Mateo; McArdle, Wendy L; McCarroll, Steven A; Medland, Sarah E; Miller, Kathryn A; Montgomery, Grant W; Morrison, Alanna C; Müller-Nurasyid, Martina; Navarro, Pau; Nelis, Mari; O’Connell, Jeffrey R; O’Donnell, Christopher J; Ong, Ken K; Newman, Anne B; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P; Psaty, Bruce M; Rao, Dabeeru C; Ring, Susan M; Rossin, Elizabeth J; Rudan, Diana; Sanna, Serena; Scott, Robert A; Sehmi, Jaban S; Sharp, Stephen; Shin, Jordan T; Singleton, Andrew B; Smith, Albert V; Soranzo, Nicole; Spector, Tim D; Stewart, Chip; Stringham, Heather M; Tarasov, Kirill V; Uitterlinden, André G; Vandenput, Liesbeth; Hwang, Shih-Jen; Whitfield, John B; Wijmenga, Cisca; Wild, Sarah H; Willemsen, Gonneke; Wilson, James F; Witteman, Jacqueline C M; Wong, Andrew; Wong, Quenna; Jamshidi, Yalda; Zitting, Paavo; Boer, Jolanda M A; Boomsma, Dorret I; Borecki, Ingrid B; Van Duijn, Cornelia M; Ekelund, Ulf; Forouhi, Nita G; Froguel, Philippe; Hingorani, Aroon; Ingelsson, Erik; Kivimaki, Mika; Kronmal, Richard A; Kuh, Diana; Lind, Lars; Martin, Nicholas G; Oostra, Ben A; Pedersen, Nancy L; Quertermous, Thomas; Rotter, Jerome I; van der Schouw, Yvonne T; Verschuren, W M Monique; Walker, Mark; Albanes, Demetrius; Arnar, David O; Assimes, Themistocles L; Bandinelli, Stefania; Boehnke, Michael; de Boer, Rudolf A; Bouchard, Claude; Caulfield, W L Mark; Chambers, John C; Curhan, Gary; Cusi, Daniele; Eriksson, Johan; Ferrucci, Luigi; van Gilst, Wiek H; Glorioso, Nicola; de Graaf, Jacqueline; Groop, Leif; Gyllensten, Ulf; Hsueh, Wen-Chi; Hu, Frank B; Huikuri, Heikki V; Hunter, David J; Iribarren, Carlos; Isomaa, Bo; Jarvelin, Marjo-Riitta; Jula, Antti; Kähönen, Mika; Kiemeney, Lambertus A; van der Klauw, Melanie M; Kooner, Jaspal S; Kraft, Peter; Iacoviello, Licia; Lehtimäki, Terho; Lokki, Marja-Liisa L; Mitchell, Braxton D; Navis, Gerjan; Nieminen, Markku S; Ohlsson, Claes; Poulter, Neil R; Qi, Lu; Raitakari, Olli T; Rimm, Eric B; Rioux, John D; Rizzi, Federica; Rudan, Igor; Salomaa, Veikko; Sever, Peter S; Shields, Denis C; Shuldiner, Alan R; Sinisalo, Juha; Stanton, Alice V; Stolk, Ronald P; Strachan, David P; Tardif, Jean-Claude; Thorsteinsdottir, Unnur; Tuomilehto, Jaako; van Veldhuisen, Dirk J; Virtamo, Jarmo; Viikari, Jorma; Vollenweider, Peter; Waeber, Gérard; Widen, Elisabeth; Cho, Yoon Shin; Olsen, Jesper V; Visscher, Peter M; Willer, Cristen; Franke, Lude; Erdmann, Jeanette; Thompson, John R; Pfeufer, Arne; Sotoodehnia, Nona; Newton-Cheh, Christopher; Ellinor, Patrick T; Stricker, Bruno H Ch; Metspalu, Andres; Perola, Markus; Beckmann, Jacques S; Smith, George Davey; Stefansson, Kari; Wareham, Nicholas J; Munroe, Patricia B; Sibon, Ody C M; Milan, David J; Snieder, Harold; Samani, Nilesh J; Loos, Ruth J F

    2013-01-01

    Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets. PMID:23583979

  15. Additive interactions between susceptibility single-nucleotide polymorphisms identified in genome-wide association studies and breast cancer risk factors in the Breast and Prostate Cancer Cohort Consortium.

    Science.gov (United States)

    Joshi, Amit D; Lindström, Sara; Hüsing, Anika; Barrdahl, Myrto; VanderWeele, Tyler J; Campa, Daniele; Canzian, Federico; Gaudet, Mia M; Figueroa, Jonine D; Baglietto, Laura; Berg, Christine D; Buring, Julie E; Chanock, Stephen J; Chirlaque, María-Dolores; Diver, W Ryan; Dossus, Laure; Giles, Graham G; Haiman, Christopher A; Hankinson, Susan E; Henderson, Brian E; Hoover, Robert N; Hunter, David J; Isaacs, Claudine; Kaaks, Rudolf; Kolonel, Laurence N; Krogh, Vittorio; Le Marchand, Loic; Lee, I-Min; Lund, Eiliv; McCarty, Catherine A; Overvad, Kim; Peeters, Petra H; Riboli, Elio; Schumacher, Fredrick; Severi, Gianluca; Stram, Daniel O; Sund, Malin; Thun, Michael J; Travis, Ruth C; Trichopoulos, Dimitrios; Willett, Walter C; Zhang, Shumin; Ziegler, Regina G; Kraft, Peter

    2014-11-15

    Additive interactions can have public health and etiological implications but are infrequently reported. We assessed departures from additivity on the absolute risk scale between 9 established breast cancer risk factors and 23 susceptibility single-nucleotide polymorphisms (SNPs) identified from genome-wide association studies among 10,146 non-Hispanic white breast cancer cases and 12,760 controls within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium. We estimated the relative excess risk due to interaction and its 95% confidence interval for each pairwise combination of SNPs and nongenetic risk factors using age- and cohort-adjusted logistic regression models. After correction for multiple comparisons, we identified a statistically significant relative excess risk due to interaction (uncorrected P = 4.51 × 10(-5)) between a SNP in the DNA repair protein RAD51 homolog 2 gene (RAD51L1; rs10483813) and body mass index (weight (kg)/height (m)(2)). We also compared additive and multiplicative polygenic risk prediction models using per-allele odds ratio estimates from previous studies for breast-cancer susceptibility SNPs and observed that the multiplicative model had a substantially better goodness of fit than the additive model. © The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  16. Genetic susceptibility for Alzheimer disease neuritic plaque pathology.

    Science.gov (United States)

    Shulman, Joshua M; Chen, Kewei; Keenan, Brendan T; Chibnik, Lori B; Fleisher, Adam; Thiyyagura, Pradeep; Roontiva, Auttawut; McCabe, Cristin; Patsopoulos, Nikolaos A; Corneveaux, Jason J; Yu, Lei; Huentelman, Matthew J; Evans, Denis A; Schneider, Julie A; Reiman, Eric M; De Jager, Philip L; Bennett, David A

    2013-09-01

    While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques. To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait. Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers. A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir. Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10-6). This polymorphism was associated with postmortem β-amyloid load as well as fibrillar β-amyloid in 2 independent cohorts of adults with normal cognition. These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.

  17. Large-scale genotyping identifies 41 new loci associated with breast cancer risk.

    Science.gov (United States)

    Michailidou, Kyriaki; Hall, Per; Gonzalez-Neira, Anna; Ghoussaini, Maya; Dennis, Joe; Milne, Roger L; Schmidt, Marjanka K; Chang-Claude, Jenny; Bojesen, Stig E; Bolla, Manjeet K; Wang, Qin; Dicks, Ed; Lee, Andrew; Turnbull, Clare; Rahman, Nazneen; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; Dos Santos Silva, Isabel; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel; van der Luijt, Rob B; Hein, Rebecca; Dahmen, Norbert; Beckman, Lars; Meindl, Alfons; Schmutzler, Rita K; Müller-Myhsok, Bertram; Lichtner, Peter; Hopper, John L; Southey, Melissa C; Makalic, Enes; Schmidt, Daniel F; Uitterlinden, Andre G; Hofman, Albert; Hunter, David J; Chanock, Stephen J; Vincent, Daniel; Bacot, François; Tessier, Daniel C; Canisius, Sander; Wessels, Lodewyk F A; Haiman, Christopher A; Shah, Mitul; Luben, Robert; Brown, Judith; Luccarini, Craig; Schoof, Nils; Humphreys, Keith; Li, Jingmei; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Couch, Fergus J; Wang, Xianshu; Vachon, Celine; Stevens, Kristen N; Lambrechts, Diether; Moisse, Matthieu; Paridaens, Robert; Christiaens, Marie-Rose; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Johnson, Nichola; Aitken, Zoe; Aaltonen, Kirsimari; Heikkinen, Tuomas; Broeks, Annegien; Veer, Laura J Van't; van der Schoot, C Ellen; Guénel, Pascal; Truong, Thérèse; Laurent-Puig, Pierre; Menegaux, Florence; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Zamora, M Pilar; Perez, Jose Ignacio Arias; Pita, Guillermo; Alonso, M Rosario; Cox, Angela; Brock, Ian W; Cross, Simon S; Reed, Malcolm W R; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Lindblom, Annika; Margolin, Sara; Hooning, Maartje J; Hollestelle, Antoinette; van den Ouweland, Ans M W; Jager, Agnes; Bui, Quang M; Stone, Jennifer; Dite, Gillian S; Apicella, Carmel; Tsimiklis, Helen; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Figueroa, Jonine; Lissowska, Jolanta; Brinton, Louise; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Brüning, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bonanni, Bernardo; Devilee, Peter; Tollenaar, Rob A E M; Seynaeve, Caroline; van Asperen, Christi J; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Bogdanova, Natalia V; Antonenkova, Natalia N; Dörk, Thilo; Kristensen, Vessela N; Anton-Culver, Hoda; Slager, Susan; Toland, Amanda E; Edge, Stephen; Fostira, Florentia; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Sueta, Aiko; Wu, Anna H; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Teo, Soo Hwang; Yip, Cheng Har; Phuah, Sze Yee; Cornes, Belinda K; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Sng, Jen-Hwei; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Ding, Shian-Ling; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Blot, William J; Signorello, Lisa B; Cai, Qiuyin; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Simard, Jacques; Garcia-Closas, Montse; Pharoah, Paul D P; Chenevix-Trench, Georgia; Dunning, Alison M; Benitez, Javier; Easton, Douglas F

    2013-04-01

    Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10(-8)). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.

  18. Large-scale genotyping identifies 41 new loci associated with breast cancer risk

    Science.gov (United States)

    Michailidou, Kyriaki; Hall, Per; Gonzalez-Neira, Anna; Ghoussaini, Maya; Dennis, Joe; Milne, Roger L; Schmidt, Marjanka K; Chang-Claude, Jenny; Bojesen, Stig E; Bolla, Manjeet K; Wang, Qin; Dicks, Ed; Lee, Andrew; Turnbull, Clare; Rahman, Nazneen; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; Silva, Isabel dos Santos; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel; van der Luijt, Rob B; Hein, Rebecca; Dahmen, Norbert; Beckman, Lars; Meindl, Alfons; Schmutzler, Rita K; Müller-Myhsok, Bertram; Lichtner, Peter; Hopper, John L; Southey, Melissa C; Makalic, Enes; Schmidt, Daniel F; Uitterlinden, Andre G; Hofman, Albert; Hunter, David J; Chanock, Stephen J; Vincent, Daniel; Bacot, François; Tessier, Daniel C; Canisius, Sander; Wessels, Lodewyk F A; Haiman, Christopher A; Shah, Mitul; Luben, Robert; Brown, Judith; Luccarini, Craig; Schoof, Nils; Humphreys, Keith; Li, Jingmei; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Couch, Fergus J; Wang, Xianshu; Vachon, Celine; Stevens, Kristen N; Lambrechts, Diether; Moisse, Matthieu; Paridaens, Robert; Christiaens, Marie-Rose; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Johnson, Nichola; Aitken, Zoe; Aaltonen, Kirsimari; Heikkinen, Tuomas; Broeks, Annegien; Van’t Veer, Laura J; van der Schoot, C Ellen; Guénel, Pascal; Truong, Thérèse; Laurent-Puig, Pierre; Menegaux, Florence; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Zamora, M Pilar; Perez, Jose Ignacio Arias; Pita, Guillermo; Alonso, M Rosario; Cox, Angela; Brock, Ian W; Cross, Simon S; Reed, Malcolm W R; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Henderson, Brian E; Schumacher, Fredrick; Le Marchand, Loic; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Lindblom, Annika; Margolin, Sara; Hooning, Maartje J; Hollestelle, Antoinette; van den Ouweland, Ans M W; Jager, Agnes; Bui, Quang M; Stone, Jennifer; Dite, Gillian S; Apicella, Carmel; Tsimiklis, Helen; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; Fasching, Peter A; Haeberle, Lothar; Ekici, Arif B; Beckmann, Matthias W; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Figueroa, Jonine; Lissowska, Jolanta; Brinton, Louise; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Brüning, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bonanni, Bernardo; Devilee, Peter; Tollenaar, Rob A E M; Seynaeve, Caroline; van Asperen, Christi J; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Bogdanova, Natalia V; Antonenkova, Natalia N; Dörk, Thilo; Kristensen, Vessela N; Anton-Culver, Hoda; Slager, Susan; Toland, Amanda E; Edge, Stephen; Fostira, Florentia; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Sueta, Aiko; Wu, Anna H; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Teo, Soo Hwang; Yip, Cheng Har; Phuah, Sze Yee; Cornes, Belinda K; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Sng, Jen-Hwei; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Ding, Shian-Ling; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Blot, William J; Signorello, Lisa B; Cai, Qiuyin; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Simard, Jacques; Garcia-Closas, Montse; Pharoah, Paul D P; Chenevix-Trench, Georgia; Dunning, Alison M; Benitez, Javier; Easton, Douglas F

    2013-01-01

    Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10−8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility. PMID:23535729

  19. Genome-wide association study identifies multiple loci associated with both mammographic density and breast cancer risk.

    Science.gov (United States)

    Lindström, Sara; Thompson, Deborah J; Paterson, Andrew D; Li, Jingmei; Gierach, Gretchen L; Scott, Christopher; Stone, Jennifer; Douglas, Julie A; dos-Santos-Silva, Isabel; Fernandez-Navarro, Pablo; Verghase, Jajini; Smith, Paula; Brown, Judith; Luben, Robert; Wareham, Nicholas J; Loos, Ruth J F; Heit, John A; Pankratz, V Shane; Norman, Aaron; Goode, Ellen L; Cunningham, Julie M; deAndrade, Mariza; Vierkant, Robert A; Czene, Kamila; Fasching, Peter A; Baglietto, Laura; Southey, Melissa C; Giles, Graham G; Shah, Kaanan P; Chan, Heang-Ping; Helvie, Mark A; Beck, Andrew H; Knoblauch, Nicholas W; Hazra, Aditi; Hunter, David J; Kraft, Peter; Pollan, Marina; Figueroa, Jonine D; Couch, Fergus J; Hopper, John L; Hall, Per; Easton, Douglas F; Boyd, Norman F; Vachon, Celine M; Tamimi, Rulla M

    2014-10-24

    Mammographic density reflects the amount of stromal and epithelial tissues in relation to adipose tissue in the breast and is a strong risk factor for breast cancer. Here we report the results from meta-analysis of genome-wide association studies (GWAS) of three mammographic density phenotypes: dense area, non-dense area and percent density in up to 7,916 women in stage 1 and an additional 10,379 women in stage 2. We identify genome-wide significant (Pbreast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (Pbreast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease-susceptibility loci.

  20. Genius loci / Madis Kõiv

    Index Scriptorium Estoniae

    Kõiv, Madis, 1929-2014

    2005-01-01

    Ettekanne 37. Kreutzwaldi päevadel Tartu Kirjandusmuuseumis 18.-19. dets. 1993, pealkirjaga "Kus on see Valga, kus on see Tartu...: Genius loci B. Kangro ja V. Uibopuu romaanides". Varem ilmunud: Akadeemia, 1994, nr. 4

  1. A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B

    DEFF Research Database (Denmark)

    Yamauchi, Toshimasa; Hara, Kazuo; Maeda, Shiro

    2010-01-01

    associations in UBE2E2 on chromosome 3 and in C2CD4A-C2CD4B on chromosome 15 at genome-wide significant levels (rs7612463 in UBE2E2, combined P = 2.27 × 10¿¿; rs7172432 in C2CD4A-C2CD4B, combined P = 3.66 × 10¿¿). The association of these two loci with T2D was replicated in other east Asian populations....... In the European populations, the C2CD4A-C2CD4B locus was significantly associated with T2D, and a combined analysis of all populations gave P = 8.78 × 10¿¹4, whereas the UBE2E2 locus did not show association to T2D. In conclusion, we identified two new loci at UBE2E2 and C2CD4A-C2CD4B associated...

  2. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32

    DEFF Research Database (Denmark)

    Steffens, M.; Leu, C.; Ruppert, A. K.

    2012-01-01

    Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3 and account for 2030 of all epilepsies. Despite their high heritability of 80, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a ...

  3. Involvement of multiple genetic loci in Staphylococcus aureus teicoplanin resistance

    OpenAIRE

    Bischoff, Markus; Roos, Martin; Putnik, Jasmina; Wada, Akihito; Glanzmann, Philipp; Giachino, Philipp; Vaudaux, Pierre; Berger-Bächi, B.

    2017-01-01

    Teicoplanin resistance was transformed from a teicoplanin-resistant Staphylococcus aureus into the susceptible strain BB255 to give strain BB938. The cell wall composition, amidation of the iD-glutamate, and peptide crosslinking were identical in BB938 as in BB255 except for a 60% increased length of the glycan chain. Transductional crosses revealed that at least two distinct loci contributed in a cumulative fashion to teicoplanin resistance. One of these loci correlated with a mutation inact...

  4. Susceptibility Genes in Thyroid Autoimmunity

    Directory of Open Access Journals (Sweden)

    Yoshiyuki Ban

    2005-01-01

    Full Text Available The autoimmune thyroid diseases (AITD are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD and Hashimoto's thyroiditis (HT and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4 and thyroid specific genes (e.g. TSHR, Tg. Most likely, these loci interact and their interactions may influence disease phenotype and severity.

  5. New Genetic Loci Associated with Preharvest Sprouting and Its Evaluation Based on the Model Equation in Rice

    Directory of Open Access Journals (Sweden)

    Gi-An Lee

    2017-08-01

    Full Text Available Preharvest sprouting (PHS in rice panicles is an important quantitative trait that causes both yield losses and the deterioration of grain quality under unpredictable moisture conditions at the ripening stage. However, the molecular mechanism underlying PHS has not yet been elucidated. Here, we explored the genetic loci associated with PHS in rice and formulated a model regression equation for rapid screening for use in breeding programs. After re-sequencing 21 representative accessions for PHS and performing enrichment analysis, we found that approximately 20,000 SNPs revealed distinct allelic distributions between PHS resistant and susceptible accessions. Of these, 39 candidate SNP loci were selected, including previously reported QTLs. We analyzed the genotypes of 144 rice accessions to determine the association between PHS and the 39 candidate SNP loci, 10 of which were identified as significantly affecting PHS based on allele type. Based on the allele types of the SNP loci, we constructed a regression equation for evaluating PHS, accounting for an R2 value of 0.401 in japonica rice. We validated this equation using additional accessions, which exhibited a significant R2 value of 0.430 between the predicted values and actual measurements. The newly detected SNP loci and the model equation could facilitate marker-assisted selection to predict PHS in rice germplasm and breeding lines.

  6. High Frequency of Interactions between Lung Cancer Susceptibility Genes in the Mouse : Mapping of Sluc5 to Sluc14

    NARCIS (Netherlands)

    Fijneman, Remond J.A.; Jansen, Ritsert C.; Valk, Martin A. van der; Demant, Peter

    1998-01-01

    Although several genes that cause monogenic familial cancer syndromes have been identified, susceptibility to sporadic cancer remains unresolved. Animal experiments have demonstrated multigenic control of tumor susceptibility. Recently, we described four mouse lung cancer susceptibility (Sluc) loci,

  7. Recombination in immunoglobulin gene loci

    Directory of Open Access Journals (Sweden)

    Komisarenko S. V.

    2009-02-01

    Full Text Available Gene network of the lymphoid cell differentiation coordinates precisely the recombination process in immunoglobulin gene loci. In our opinion, cellular microRNAs can contribute to the allelic exclusion through microRNA-directed DNA methylation and participate in retargeting recombinases activity from the gene loci of heavy immunoglobulin chains to the gene loci of light chains

  8. Identification of allelic heterogeneity at type-2 diabetes loci and impact on prediction.

    Directory of Open Access Journals (Sweden)

    Yann C Klimentidis

    Full Text Available Although over 60 single nucleotide polymorphisms (SNPs have been identified by meta-analysis of genome-wide association studies for type-2 diabetes (T2D among individuals of European descent, much of the genetic variation remains unexplained. There are likely many more SNPs that contribute to variation in T2D risk, some of which may lie in the regions surrounding established SNPs--a phenomenon often referred to as allelic heterogeneity. Here, we use the summary statistics from the DIAGRAM consortium meta-analysis of T2D genome-wide association studies along with linkage disequilibrium patterns inferred from a large reference sample to identify novel SNPs associated with T2D surrounding each of the previously established risk loci. We then examine the extent to which the use of these additional SNPs improves prediction of T2D risk in an independent validation dataset. Our results suggest that multiple SNPs at each of 3 loci contribute to T2D susceptibility (TCF7L2, CDKN2A/B, and KCNQ1; p<5×10(-8. Using a less stringent threshold (p<5×10(-4, we identify 34 additional loci with multiple associated SNPs. The addition of these SNPs slightly improves T2D prediction compared to the use of only the respective lead SNPs, when assessed using an independent validation cohort. Our findings suggest that some currently established T2D risk loci likely harbor multiple polymorphisms which contribute independently and collectively to T2D risk. This opens a promising avenue for improving prediction of T2D, and for a better understanding of the genetic architecture of T2D.

  9. Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility

    DEFF Research Database (Denmark)

    Ram, Ramesh; Mehta, Munish; Nguyen, Tri Quang

    2016-01-01

    Genome-wide association studies have found >60 loci that confer genetic susceptibility to type 1 diabetes (T1D). Many of these are defined only by anonymous single nucleotide polymorphisms: the underlying causative genes, as well as the molecular bases by which they mediate susceptibility...... cell type. Additionally, we observed 25 loci that affected 38 transcripts in trans. In summary, our systems genetics analyses defined the effect of T1D risk alleles on levels of gene expression and provide novel insights into the complex genetics of T1D, suggesting that most of the T1D risk alleles......, are not known. Identification of how these variants affect the complex mechanisms contributing to the loss of tolerance is a challenge. In this study, we performed systematic analyses to characterize these variants. First, all known genes in strong linkage disequilibrium (r2 > 0.8) with the reported single...

  10. Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease

    Science.gov (United States)

    Harold, Denise; Jones, Lesley; Holmans, Peter; Gerrish, Amy; Vedernikov, Alexey; Richards, Alexander; DeStefano, Anita L.; Lambert, Jean-Charles; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca; Jun, Gyungah; Bis, Joshua C.; Beecham, Gary W.; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A.; Denning, Nicola; Smith, Albert V.; Chouraki, Vincent; Thomas, Charlene; Ikram, M. Arfan; Zelenika, Diana; Vardarajan, Badri N.; Kamatani, Yoichiro; Lin, Chiao-Feng; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L.; Vronskaya, Maria; Johnson, Andrew D.; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Hanon, Olivier; Fitzpatrick, Annette L.; Buxbaum, Joseph D.; Campion, Dominique; Crane, Paul K.; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L.; De Jager, Philip L.; Deramecourt, Vincent; Johnston, Janet A.; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Hernández, Isabel; Rubinsztein, David C.; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M.; Fiévet, Nathalie; Huentelman, Matthew J.; Gill, Michael; Brown, Kristelle; Kamboh, M. Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B.; Myers, Amanda J.; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; George-Hyslop, Peter St; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W.; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petra; Collinge, John; Sorbi, Sandro; Garcia, Florentino Sanchez; Fox, Nick C.; Hardy, John; Naranjo, Maria Candida Deniz; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Scarpini, Elio; Bonuccelli, Ubaldo; Mancuso, Michelangelo; Siciliano, Gabriele; Moebus, Susanne; Mecocci, Patrizia; Zompo, Maria Del; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Frank-García, Ana; Panza, Francesco; Solfrizzi, Vincenzo; Caffarra, Paolo; Nacmias, Benedetta; Perry, William; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M.; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G.; Coto, Eliecer; Hamilton-Nelson, Kara L.; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J.; Faber, Kelley M.; Jonsson, Palmi V.; Combarros, Onofre; O'Donovan, Michael C.; Cantwell, Laura B.; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H.; Bennett, David A.; Harris, Tamara B.; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee F. A. G.; Passmore, Peter; Montine, Thomas J.; Bettens, Karolien; Rotter, Jerome I.; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M.; Kukull, Walter A.; Hannequin, Didier; Powell, John F.; Nalls, Michael A.; Ritchie, Karen; Lunetta, Kathryn L.; Kauwe, John S. K.; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R.; Schmidt, Reinhold; Rujescu, Dan; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M.; Graff, Caroline; Psaty, Bruce M.; Haines, Jonathan L.; Lathrop, Mark; Pericak-Vance, Margaret A.; Launer, Lenore J.; Van Broeckhoven, Christine; Farrer, Lindsay A.; van Duijn, Cornelia M.; Ramirez, Alfredo

    2014-01-01

    Background Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10−6) and 14 (IGHV1-67 p = 7.9×10−8) which indexed novel susceptibility loci. Significance The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease. PMID:24922517

  11. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Valentina Escott-Price

    Full Text Available Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6 and 14 (IGHV1-67 p = 7.9×10-8 which indexed novel susceptibility loci.The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

  12. Novel loci associated with increased risk of sudden cardiac death in the context of coronary artery disease.

    Directory of Open Access Journals (Sweden)

    Adriana Huertas-Vazquez

    Full Text Available BACKGROUND: Recent genome-wide association studies (GWAS have identified novel loci associated with sudden cardiac death (SCD. Despite this progress, identified DNA variants account for a relatively small portion of overall SCD risk, suggesting that additional loci contributing to SCD susceptibility await discovery. The objective of this study was to identify novel DNA variation associated with SCD in the context of coronary artery disease (CAD. METHODS AND FINDINGS: Using the MetaboChip custom array we conducted a case-control association analysis of 119,117 SNPs in 948 SCD cases (with underlying CAD from the Oregon Sudden Unexpected Death Study (Oregon-SUDS and 3,050 controls with CAD from the Wellcome Trust Case-Control Consortium (WTCCC. Two newly identified loci were significantly associated with increased risk of SCD after correction for multiple comparisons at: rs6730157 in the RAB3GAP1 gene on chromosome 2 (P = 4.93×10(-12, OR = 1.60 and rs2077316 in the ZNF365 gene on chromosome 10 (P = 3.64×10(-8, OR = 2.41. CONCLUSIONS: Our findings suggest that RAB3GAP1 and ZNF365 are relevant candidate genes for SCD and will contribute to the mechanistic understanding of SCD susceptibility.

  13. Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor.

    Science.gov (United States)

    Wang, Zhaoming; McGlynn, Katherine A; Rajpert-De Meyts, Ewa; Bishop, D Timothy; Chung, Charles C; Dalgaard, Marlene D; Greene, Mark H; Gupta, Ramneek; Grotmol, Tom; Haugen, Trine B; Karlsson, Robert; Litchfield, Kevin; Mitra, Nandita; Nielsen, Kasper; Pyle, Louise C; Schwartz, Stephen M; Thorsson, Vésteinn; Vardhanabhuti, Saran; Wiklund, Fredrik; Turnbull, Clare; Chanock, Stephen J; Kanetsky, Peter A; Nathanson, Katherine L

    2017-07-01

    The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the first analysis of the X chromosome. Eight new loci mapping to 2q14.2, 3q26.2, 4q35.2, 7q36.3, 10q26.13, 15q21.3, 15q22.31, and Xq28 achieved genome-wide significance (P < 5 × 10 -8 ). Most loci harbor biologically plausible candidate genes. We refined previously reported associations at 9p24.3 and 19p12 by identifying one and three additional independent SNPs, respectively. In aggregate, the 39 independent markers identified to date explain 37% of father-to-son familial risk, 8% of which can be attributed to the 12 new signals reported here. Our findings substantially increase the number of known TGCT susceptibility alleles, move the field closer to a comprehensive understanding of the underlying genetic architecture of TGCT, and provide further clues to the etiology of TGCT.

  14. Genome-wide association study reveals two new risk loci for bipolar disorder.

    Science.gov (United States)

    Mühleisen, Thomas W; Leber, Markus; Schulze, Thomas G; Strohmaier, Jana; Degenhardt, Franziska; Treutlein, Jens; Mattheisen, Manuel; Forstner, Andreas J; Schumacher, Johannes; Breuer, René; Meier, Sandra; Herms, Stefan; Hoffmann, Per; Lacour, André; Witt, Stephanie H; Reif, Andreas; Müller-Myhsok, Bertram; Lucae, Susanne; Maier, Wolfgang; Schwarz, Markus; Vedder, Helmut; Kammerer-Ciernioch, Jutta; Pfennig, Andrea; Bauer, Michael; Hautzinger, Martin; Moebus, Susanne; Priebe, Lutz; Czerski, Piotr M; Hauser, Joanna; Lissowska, Jolanta; Szeszenia-Dabrowska, Neonila; Brennan, Paul; McKay, James D; Wright, Adam; Mitchell, Philip B; Fullerton, Janice M; Schofield, Peter R; Montgomery, Grant W; Medland, Sarah E; Gordon, Scott D; Martin, Nicholas G; Krasnow, Valery; Chuchalin, Alexander; Babadjanova, Gulja; Pantelejeva, Galina; Abramova, Lilia I; Tiganov, Alexander S; Polonikov, Alexey; Khusnutdinova, Elza; Alda, Martin; Grof, Paul; Rouleau, Guy A; Turecki, Gustavo; Laprise, Catherine; Rivas, Fabio; Mayoral, Fermin; Kogevinas, Manolis; Grigoroiu-Serbanescu, Maria; Propping, Peter; Becker, Tim; Rietschel, Marcella; Nöthen, Markus M; Cichon, Sven

    2014-03-11

    Bipolar disorder (BD) is a common and highly heritable mental illness and genome-wide association studies (GWAS) have robustly identified the first common genetic variants involved in disease aetiology. The data also provide strong evidence for the presence of multiple additional risk loci, each contributing a relatively small effect to BD susceptibility. Large samples are necessary to detect these risk loci. Here we present results from the largest BD GWAS to date by investigating 2.3 million single-nucleotide polymorphisms (SNPs) in a sample of 24,025 patients and controls. We detect 56 genome-wide significant SNPs in five chromosomal regions including previously reported risk loci ANK3, ODZ4 and TRANK1, as well as the risk locus ADCY2 (5p15.31) and a region between MIR2113 and POU3F2 (6q16.1). ADCY2 is a key enzyme in cAMP signalling and our finding provides new insights into the biological mechanisms involved in the development of BD.

  15. Genetic Susceptibility to Atherosclerosis

    Directory of Open Access Journals (Sweden)

    Sanja Kovacic

    2012-01-01

    Full Text Available Atherosclerosis is a complex multifocal arterial disease involving interactions of multiple genetic and environmental factors. Advances in techniques of molecular genetics have revealed that genetic ground significantly influences susceptibility to atherosclerotic vascular diseases. Besides further investigations of monogenetic diseases, candidate genes, genetic polymorphisms, and susceptibility loci associated with atherosclerotic diseases have been identified in recent years, and their number is rapidly increasing. This paper discusses main genetic investigations fields associated with human atherosclerotic vascular diseases. The paper concludes with a discussion of the directions and implications of future genetic research in arteriosclerosis with an emphasis on prospective prediction from an early age of individuals who are predisposed to develop premature atherosclerosis as well as to facilitate the discovery of novel drug targets.

  16. Confirmation of novel type 1 diabetes risk loci in families

    DEFF Research Database (Denmark)

    Cooper, J D; Howson, J M M; Smyth, D

    2012-01-01

    Over 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we......, the Type 1 Diabetes Genetics Consortium (T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study....

  17. Regulation of alternative splicing in human obesity loci.

    Science.gov (United States)

    Kaminska, Dorota; Käkelä, Pirjo; Nikkola, Elina; Venesmaa, Sari; Ilves, Imre; Herzig, Karl-Heinz; Kolehmainen, Marjukka; Karhunen, Leila; Kuusisto, Johanna; Gylling, Helena; Pajukanta, Päivi; Laakso, Markku; Pihlajamäki, Jussi

    2016-10-01

    Multiple obesity susceptibility loci have been identified by genome-wide association studies, yet the mechanisms by which these loci influence obesity remain unclear. Alternative splicing could contribute to obesity by regulating the transcriptomic and proteomic diversity of genes in these loci. Based on a database search, 72 of the 136 genes at the 13 obesity loci encoded multiple protein isoforms. Thus, alternative splicing of these genes in adipose tissue samples was analyzed from the Metabolic Syndrome in Men population-based study and from two weight loss intervention studies (surgical and very low calorie diet). Alternative splicing was confirmed in 11 genes with PCR capillary electrophoresis in human subcutaneous adipose tissue. Interestingly, differential splicing of TRA2B, BAG6, and MSH5 was observed between lean individuals with normoglycemia and overweight individuals with type 2 diabetes. Of these genes, we detected fat depot-dependent splicing of TRA2B and BAG6 and weight loss-induced regulation of MSH5 splicing in the intervention studies. Finally, body mass index was a major determinant of TRA2B, BAG6, and MSH5 splicing in the combined data. This study provides evidence for alternative splicing in obesity loci, suggesting that alternative splicing at least in part mediates the obesity-associated risk in these loci. © 2016 The Obesity Society.

  18. MLVA as a tool for public health surveillance of human Salmonella Typhimurium: prospective study in Belgium and evaluation of MLVA loci stability.

    Science.gov (United States)

    Wuyts, Véronique; Mattheus, Wesley; De Laminne de Bex, Guillaume; Wildemauwe, Christa; Roosens, Nancy H C; Marchal, Kathleen; De Keersmaecker, Sigrid C J; Bertrand, Sophie

    2013-01-01

    Surveillance of Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) is generally considered to benefit from molecular techniques like multiple-locus variable-number of tandem repeats analysis (MLVA), which allow earlier detection and confinement of outbreaks. Here, a surveillance study, including phage typing, antimicrobial susceptibility testing and the in Europe most commonly used 5-loci MLVA on 1,420 S. Typhimurium isolates collected between 2010 and 2012 in Belgium, was used to evaluate the added value of MLVA for public health surveillance. Phage types DT193, DT195, DT120, DT104, DT12 and U302 dominate the Belgian S. Typhimurium population. A combined resistance to ampicillin, streptomycin, sulphonamides and tetracycline (ASSuT) with or without additional resistances was observed for 42.5% of the isolates. 414 different MLVA profiles were detected, of which 14 frequent profiles included 44.4% of the S. Typhimurium population. During a serial passage experiment on selected isolates to investigate the in vitro stability of the 5 MLVA loci, variations over time were observed for loci STTR6, STTR10, STTR5 and STTR9. This study demonstrates that MLVA improves public health surveillance of S. Typhimurium. However, the 5-loci MLVA should be complemented with other subtyping methods for investigation of possible outbreaks with frequent MLVA profiles. Also, variability in these MLVA loci should be taken into account when investigating extended outbreaks and studying dynamics over longer periods.

  19. MLVA as a tool for public health surveillance of human Salmonella Typhimurium: prospective study in Belgium and evaluation of MLVA loci stability.

    Directory of Open Access Journals (Sweden)

    Véronique Wuyts

    Full Text Available Surveillance of Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium is generally considered to benefit from molecular techniques like multiple-locus variable-number of tandem repeats analysis (MLVA, which allow earlier detection and confinement of outbreaks. Here, a surveillance study, including phage typing, antimicrobial susceptibility testing and the in Europe most commonly used 5-loci MLVA on 1,420 S. Typhimurium isolates collected between 2010 and 2012 in Belgium, was used to evaluate the added value of MLVA for public health surveillance. Phage types DT193, DT195, DT120, DT104, DT12 and U302 dominate the Belgian S. Typhimurium population. A combined resistance to ampicillin, streptomycin, sulphonamides and tetracycline (ASSuT with or without additional resistances was observed for 42.5% of the isolates. 414 different MLVA profiles were detected, of which 14 frequent profiles included 44.4% of the S. Typhimurium population. During a serial passage experiment on selected isolates to investigate the in vitro stability of the 5 MLVA loci, variations over time were observed for loci STTR6, STTR10, STTR5 and STTR9. This study demonstrates that MLVA improves public health surveillance of S. Typhimurium. However, the 5-loci MLVA should be complemented with other subtyping methods for investigation of possible outbreaks with frequent MLVA profiles. Also, variability in these MLVA loci should be taken into account when investigating extended outbreaks and studying dynamics over longer periods.

  20. Characterization of microsatellite loci isolated in Mountain Plover (Charadrius montanus)

    Science.gov (United States)

    John, J. St; Kysela, R.F.; Oyler-McCance, S.J.

    2007-01-01

    Primers for 15 microsatellite loci were developed for Mountain Plover, a species whose distribution and abundance have been reduced drastically in the past 30 years. In a screen of 126 individuals collected from four breeding locales across the species' range, levels of polymorphism ranged from two to 13 alleles per locus. No two loci were found to be linked, although one locus revealed significant departures from Hardy-Weinberg equilibrium. These microsatellite loci can be used in population genetic studies, ultimately aiding in management efforts for Mountain Plover. Additionally, these markers can potentially be used in studies investigating the mating system of Mountain Plover. ?? 2007 Blackwell Publishing Ltd.

  1. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.

    Science.gov (United States)

    Hobbs, Brian D; de Jong, Kim; Lamontagne, Maxime; Bossé, Yohan; Shrine, Nick; Artigas, María Soler; Wain, Louise V; Hall, Ian P; Jackson, Victoria E; Wyss, Annah B; London, Stephanie J; North, Kari E; Franceschini, Nora; Strachan, David P; Beaty, Terri H; Hokanson, John E; Crapo, James D; Castaldi, Peter J; Chase, Robert P; Bartz, Traci M; Heckbert, Susan R; Psaty, Bruce M; Gharib, Sina A; Zanen, Pieter; Lammers, Jan W; Oudkerk, Matthijs; Groen, H J; Locantore, Nicholas; Tal-Singer, Ruth; Rennard, Stephen I; Vestbo, Jørgen; Timens, Wim; Paré, Peter D; Latourelle, Jeanne C; Dupuis, Josée; O'Connor, George T; Wilk, Jemma B; Kim, Woo Jin; Lee, Mi Kyeong; Oh, Yeon-Mok; Vonk, Judith M; de Koning, Harry J; Leng, Shuguang; Belinsky, Steven A; Tesfaigzi, Yohannes; Manichaikul, Ani; Wang, Xin-Qun; Rich, Stephen S; Barr, R Graham; Sparrow, David; Litonjua, Augusto A; Bakke, Per; Gulsvik, Amund; Lahousse, Lies; Brusselle, Guy G; Stricker, Bruno H; Uitterlinden, André G; Ampleford, Elizabeth J; Bleecker, Eugene R; Woodruff, Prescott G; Meyers, Deborah A; Qiao, Dandi; Lomas, David A; Yim, Jae-Joon; Kim, Deog Kyeom; Hawrylkiewicz, Iwona; Sliwinski, Pawel; Hardin, Megan; Fingerlin, Tasha E; Schwartz, David A; Postma, Dirkje S; MacNee, William; Tobin, Martin D; Silverman, Edwin K; Boezen, H Marike; Cho, Michael H

    2017-03-01

    Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

  2. Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease

    NARCIS (Netherlands)

    Meddens, Claartje A; Harakalova, Magdalena; van den Dungen, Noortje A M; Foroughi Asl, Hassan; Hijma, Hemme J; Cuppen, Edwin P J G; Björkegren, Johan L M; Asselbergs, Folkert W; Nieuwenhuis, Edward E S; Mokry, Michal

    2016-01-01

    BACKGROUND: Genome-wide association studies (GWAS) have revealed many susceptibility loci for complex genetic diseases. For most loci, the causal genes have not been identified. Currently, the identification of candidate genes is predominantly based on genes that localize close to or within

  3. Multiple HLA Epitopes Contribute to Type 1 Diabetes Susceptibility

    Science.gov (United States)

    Roark, Christina L.; Anderson, Kirsten M.; Simon, Lucas J.; Schuyler, Ronald P.; Aubrey, Michael T.; Freed, Brian M.

    2014-01-01

    Disease susceptibility for type 1 diabetes is strongly associated with the inheritance of specific HLA alleles. However, conventional allele frequency analysis can miss HLA associations because many alleles are rare. In addition, disparate alleles that have similar peptide-binding sites, or shared epitopes, can be missed. To identify the HLA shared epitopes associated with diabetes, we analyzed high-resolution genotyping for class I and class II loci. The HLA epitopes most strongly associated with susceptibility for disease were DQB1 A57, DQA1 V76, DRB1 H13, and DRB1 K71, whereas DPB1 YD9,57, HLA-B C67, and HLA-C YY9,116 were more weakly associated. The HLA epitopes strongly associated with resistance were DQB1 D57, DQA1 Y80, DRB1 R13, and DRB1 A71. A dominant resistance phenotype was observed for individuals bearing a protective HLA epitope, even in the presence of a susceptibility epitope. In addition, an earlier age of disease onset correlated with significantly greater numbers of susceptibility epitopes and fewer resistance epitopes (P epitopes was higher in patients than in control subjects and was not exclusively a result of linkage disequilibrium, suggesting that multiple HLA epitopes may work together to increase the risk of developing diabetes. PMID:24357703

  4. Tropical Andean Forests Are Highly Susceptible to Nutrient Inputs—Rapid Effects of Experimental N and P Addition to an Ecuadorian Montane Forest

    Science.gov (United States)

    Homeier, Jürgen; Hertel, Dietrich; Camenzind, Tessa; Cumbicus, Nixon L.; Maraun, Mark; Martinson, Guntars O.; Poma, L. Nohemy; Rillig, Matthias C.; Sandmann, Dorothee; Scheu, Stefan; Veldkamp, Edzo; Wilcke, Wolfgang; Wullaert, Hans; Leuschner, Christoph

    2012-01-01

    Tropical regions are facing increasing atmospheric inputs of nutrients, which will have unknown consequences for the structure and functioning of these systems. Here, we show that Neotropical montane rainforests respond rapidly to moderate additions of N (50 kg ha−1 yr−1) and P (10 kg ha−1 yr−1). Monitoring of nutrient fluxes demonstrated that the majority of added nutrients remained in the system, in either soil or vegetation. N and P additions led to not only an increase in foliar N and P concentrations, but also altered soil microbial biomass, standing fine root biomass, stem growth, and litterfall. The different effects suggest that trees are primarily limited by P, whereas some processes—notably aboveground productivity—are limited by both N and P. Highly variable and partly contrasting responses of different tree species suggest marked changes in species composition and diversity of these forests by nutrient inputs in the long term. The unexpectedly fast response of the ecosystem to moderate nutrient additions suggests high vulnerability of tropical montane forests to the expected increase in nutrient inputs. PMID:23071734

  5. Library Spirit and Genius Loci

    DEFF Research Database (Denmark)

    Dahlkild, Nan

    2009-01-01

    The architecture and design of Nyborg Public Library in the light of the concepts "Library Spirit" and "Genius Loci", related to contemporary social and cultural movements, the development of the early welfare state and the "Scandinavian Style".......The architecture and design of Nyborg Public Library in the light of the concepts "Library Spirit" and "Genius Loci", related to contemporary social and cultural movements, the development of the early welfare state and the "Scandinavian Style"....

  6. Two-stage genome-wide association study identifies a novel susceptibility locus associated with melanoma.

    Science.gov (United States)

    Ransohoff, Katherine J; Wu, Wenting; Cho, Hyunje G; Chahal, Harvind C; Lin, Yuan; Dai, Hong-Ji; Amos, Christopher I; Lee, Jeffrey E; Tang, Jean Y; Hinds, David A; Han, Jiali; Wei, Qingyi; Sarin, Kavita Y

    2017-03-14

    Genome-wide association studies have identified 21 susceptibility loci associated with melanoma. These loci implicate genes affecting pigmentation, nevus count, telomere maintenance, and DNA repair in melanoma risk. Here, we report the results of a two-stage genome-wide association study of melanoma. The stage 1 discovery phase consisted of 4,842 self-reported melanoma cases and 286,565 controls of European ancestry from the 23andMe research cohort and the stage 2 replication phase consisted of 1,804 melanoma cases and 1,026 controls from the University of Texas M.D. Anderson Cancer Center. We performed a combined meta-analysis totaling 6,628 melanoma cases and 287,591 controls. Our study replicates 20 of 21 previously known melanoma-loci and confirms the association of the telomerase reverse transcriptase, TERT, with melanoma susceptibility at genome-wide significance. In addition, we uncover a novel polymorphism, rs187843643 (OR = 1.96; 95% CI = [1.54, 2.48]; P = 3.53 x 10-8), associated with melanoma. The SNP rs187842643 lies within a noncoding RNA 177kb downstream of BASP1 (brain associated protein-1). We find that BASP1 expression is suppressed in melanoma as compared with benign nevi, providing additional evidence for a putative role in melanoma pathogenesis.

  7. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

    DEFF Research Database (Denmark)

    Dupuis, Josée; Langenberg, Claudia; Prokopenko, Inga

    2010-01-01

    Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up...... to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA...... proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt...

  8. Analysis of Parent-of-Origin Effects on the X Chromosome in Asian and European Orofacial Cleft Triads Identifies Associations with DMD, FGF13, EGFL6, and Additional Loci at Xp22.2

    Directory of Open Access Journals (Sweden)

    Øivind Skare

    2018-02-01

    Full Text Available Background: Although both the mother's and father's alleles are present in the offspring, they may not operate at the same level. These parent-of-origin (PoO effects have not yet been explored on the X chromosome, which motivated us to develop new methods for detecting such effects. Orofacial clefts (OFCs exhibit sex-specific differences in prevalence and are examples of traits where a search for various types of effects on the X chromosome might be relevant.Materials and Methods: We upgraded our R-package Haplin to enable genome-wide analyses of PoO effects, as well as power simulations for different statistical models. 14,486 X-chromosome SNPs in 1,291 Asian and 1,118 European case-parent triads of isolated OFCs were available from a previous GWAS. For each ethnicity, cleft lip with or without cleft palate (CL/P and cleft palate only (CPO were analyzed separately using two X-inactivation models and a sliding-window approach to haplotype analysis. In addition, we performed analyses restricted to female offspring.Results: Associations were identified in “Dystrophin” (DMD, Xp21.2-p21.1, “Fibroblast growth factor 13” (FGF13, Xq26.3-q27.1 and “EGF-like domain multiple 6” (EGFL6, Xp22.2, with biologically plausible links to OFCs. Unlike EGFL6, the other associations on chromosomal region Xp22.2 had no apparent connections to OFCs. However, the Xp22.2 region itself is of potential interest because it contains genes for clefting syndromes [for example, “Oral-facial-digital syndrome 1” (OFD1 and “Midline 1” (MID1]. Overall, the identified associations were highly specific for ethnicity, cleft subtype and X-inactivation model, except for DMD in which associations were identified in both CPO and CL/P, in the model with X-inactivation and in Europeans only.Discussion/Conclusion: The specificity of the associations for ethnicity, cleft subtype and X-inactivation model underscores the utility of conducting subanalyses, despite the

  9. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

    Science.gov (United States)

    Mahajan, Anubha; Go, Min Jin; Zhang, Weihua; Below, Jennifer E; Gaulton, Kyle J; Ferreira, Teresa; Horikoshi, Momoko; Johnson, Andrew D; Ng, Maggie C Y; Prokopenko, Inga; Saleheen, Danish; Wang, Xu; Zeggini, Eleftheria; Abecasis, Goncalo R; Adair, Linda S; Almgren, Peter; Atalay, Mustafa; Aung, Tin; Baldassarre, Damiano; Balkau, Beverley; Bao, Yuqian; Barnett, Anthony H; Barroso, Ines; Basit, Abdul; Been, Latonya F; Beilby, John; Bell, Graeme I; Benediktsson, Rafn; Bergman, Richard N; Boehm, Bernhard O; Boerwinkle, Eric; Bonnycastle, Lori L; Burtt, Noël; Cai, Qiuyin; Campbell, Harry; Carey, Jason; Cauchi, Stephane; Caulfield, Mark; Chan, Juliana C N; Chang, Li-Ching; Chang, Tien-Jyun; Chang, Yi-Cheng; Charpentier, Guillaume; Chen, Chien-Hsiun; Chen, Han; Chen, Yuan-Tsong; Chia, Kee-Seng; Chidambaram, Manickam; Chines, Peter S; Cho, Nam H; Cho, Young Min; Chuang, Lee-Ming; Collins, Francis S; Cornelis, Marylin C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Danesh, John; Das, Debashish; de Faire, Ulf; Dedoussis, George; Deloukas, Panos; Dimas, Antigone S; Dina, Christian; Doney, Alex S; Donnelly, Peter J; Dorkhan, Mozhgan; van Duijn, Cornelia; Dupuis, Josée; Edkins, Sarah; Elliott, Paul; Emilsson, Valur; Erbel, Raimund; Eriksson, Johan G; Escobedo, Jorge; Esko, Tonu; Eury, Elodie; Florez, Jose C; Fontanillas, Pierre; Forouhi, Nita G; Forsen, Tom; Fox, Caroline; Fraser, Ross M; Frayling, Timothy M; Froguel, Philippe; Frossard, Philippe; Gao, Yutang; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Grallert, Harald; Grant, George B; Grrop, Leif C; Groves, Chrisropher J; Grundberg, Elin; Guiducci, Candace; Hamsten, Anders; Han, Bok-Ghee; Hara, Kazuo; Hassanali, Neelam; Hattersley, Andrew T; Hayward, Caroline; Hedman, Asa K; Herder, Christian; Hofman, Albert; Holmen, Oddgeir L; Hovingh, Kees; Hreidarsson, Astradur B; Hu, Cheng; Hu, Frank B; Hui, Jennie; Humphries, Steve E; Hunt, Sarah E; Hunter, David J; Hveem, Kristian; Hydrie, Zafar I; Ikegami, Hiroshi; Illig, Thomas; Ingelsson, Erik; Islam, Muhammed; Isomaa, Bo; Jackson, Anne U; Jafar, Tazeen; James, Alan; Jia, Weiping; Jöckel, Karl-Heinz; Jonsson, Anna; Jowett, Jeremy B M; Kadowaki, Takashi; Kang, Hyun Min; Kanoni, Stavroula; Kao, Wen Hong L; Kathiresan, Sekar; Kato, Norihiro; Katulanda, Prasad; Keinanen-Kiukaanniemi, Kirkka M; Kelly, Ann M; Khan, Hassan; Khaw, Kay-Tee; Khor, Chiea-Chuen; Kim, Hyung-Lae; Kim, Sangsoo; Kim, Young Jin; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Korpi-Hyövälti, Eeva; Kowlessur, Sudhir; Kraft, Peter; Kravic, Jasmina; Kristensen, Malene M; Krithika, S; Kumar, Ashish; Kumate, Jesus; Kuusisto, Johanna; Kwak, Soo Heon; Laakso, Markku; Lagou, Vasiliki; Lakka, Timo A; Langenberg, Claudia; Langford, Cordelia; Lawrence, Robert; Leander, Karin; Lee, Jen-Mai; Lee, Nanette R; Li, Man; Li, Xinzhong; Li, Yun; Liang, Junbin; Liju, Samuel; Lim, Wei-Yen; Lind, Lars; Lindgren, Cecilia M; Lindholm, Eero; Liu, Ching-Ti; Liu, Jian Jun; Lobbens, Stéphane; Long, Jirong; Loos, Ruth J F; Lu, Wei; Luan, Jian'an; Lyssenko, Valeriya; Ma, Ronald C W; Maeda, Shiro; Mägi, Reedik; Männisto, Satu; Matthews, David R; Meigs, James B; Melander, Olle; Metspalu, Andres; Meyer, Julia; Mirza, Ghazala; Mihailov, Evelin; Moebus, Susanne; Mohan, Viswanathan; Mohlke, Karen L; Morris, Andrew D; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Musk, Bill; Nakamura, Jiro; Nakashima, Eitaro; Navarro, Pau; Ng, Peng-Keat; Nica, Alexandra C; Nilsson, Peter M; Njølstad, Inger; Nöthen, Markus M; Ohnaka, Keizo; Ong, Twee Hee; Owen, Katharine R; Palmer, Colin N A; Pankow, James S; Park, Kyong Soo; Parkin, Melissa; Pechlivanis, Sonali; Pedersen, Nancy L; Peltonen, Leena; Perry, John R B; Peters, Annette; Pinidiyapathirage, Janini M; Platou, Carl G; Potter, Simon; Price, Jackie F; Qi, Lu; Radha, Venkatesan; Rallidis, Loukianos; Rasheed, Asif; Rathman, Wolfgang; Rauramaa, Rainer; Raychaudhuri, Soumya; Rayner, N William; Rees, Simon D; Rehnberg, Emil; Ripatti, Samuli; Robertson, Neil; Roden, Michael; Rossin, Elizabeth J; Rudan, Igor; Rybin, Denis; Saaristo, Timo E; Salomaa, Veikko; Saltevo, Juha; Samuel, Maria; Sanghera, Dharambir K; Saramies, Jouko; Scott, James; Scott, Laura J; Scott, Robert A; Segrè, Ayellet V; Sehmi, Joban; Sennblad, Bengt; Shah, Nabi; Shah, Sonia; Shera, A Samad; Shu, Xiao Ou; Shuldiner, Alan R; Sigurđsson, Gunnar; Sijbrands, Eric; Silveira, Angela; Sim, Xueling; Sivapalaratnam, Suthesh; Small, Kerrin S; So, Wing Yee; Stančáková, Alena; Stefansson, Kari; Steinbach, Gerald; Steinthorsdottir, Valgerdur; Stirrups, Kathleen; Strawbridge, Rona J; Stringham, Heather M; Sun, Qi; Suo, Chen; Syvänen, Ann-Christine; Takayanagi, Ryoichi; Takeuchi, Fumihiko; Tay, Wan Ting; Teslovich, Tanya M; Thorand, Barbara; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tikkanen, Emmi; Trakalo, Joseph; Tremoli, Elena; Trip, Mieke D; Tsai, Fuu Jen; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Uitterlinden, Andre G; Valladares-Salgado, Adan; Vedantam, Sailaja; Veglia, Fabrizio; Voight, Benjamin F; Wang, Congrong; Wareham, Nicholas J; Wennauer, Roman; Wickremasinghe, Ananda R; Wilsgaard, Tom; Wilson, James F; Wiltshire, Steven; Winckler, Wendy; Wong, Tien Yin; Wood, Andrew R; Wu, Jer-Yuarn; Wu, Ying; Yamamoto, Ken; Yamauchi, Toshimasa; Yang, Mingyu; Yengo, Loic; Yokota, Mitsuhiro; Young, Robin; Zabaneh, Delilah; Zhang, Fan; Zhang, Rong; Zheng, Wei; Zimmet, Paul Z; Altshuler, David; Bowden, Donald W; Cho, Yoon Shin; Cox, Nancy J; Cruz, Miguel; Hanis, Craig L; Kooner, Jaspal; Lee, Jong-Young; Seielstad, Mark; Teo, Yik Ying; Boehnke, Michael; Parra, Esteban J; Chambers, Jonh C; Tai, E Shyong; McCarthy, Mark I; Morris, Andrew P

    2014-03-01

    To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.

  10. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

    NARCIS (Netherlands)

    C.J. Willer (Cristen); E.K. Speliotes (Elizabeth); R.J.F. Loos (Ruth); S. Li (Shengxu); C.M. Lindgren (Cecilia); I.M. Heid (Iris); S.I. Berndt (Sonja); A.L. Elliott (Amanda); A.U. Jackson (Anne); C. Lamina (Claudia); G. Lettre (Guillaume); N. Lim (Noha); H.N. Lyon (Helen); S.A. McCarroll (Steven); K. Papadakis (Konstantinos); L. Qi (Lu); J.C. Randall (Joshua); R.M. Roccasecca; S. Sanna (Serena); P. Scheet (Paul); M.N. Weedon (Michael); E. Wheeler (Eleanor); J.H. Zhao (Jing Hua); L.C. Jacobs (Leonie); I. Prokopenko (Inga); N. Soranzo (Nicole); T. Tanaka (Toshiko); N.J. Timpson (Nicholas); P. Almgren (Peter); A.J. Bennett (Amanda); R.N. Bergman (Richard); S. Bingham (Sheila); L.L. Bonnycastle (Lori); M.J. Brown (Morris); N.P. Burtt (Noël); P.S. Chines (Peter); L. Coin (Lachlan); F.S. Collins (Francis); J. Connell (John); C. Cooper (Charles); G.D. Smith; E.M. Dennison (Elaine); P. Deodhar (Parimal); M.R. Erdos (Michael); K. Estrada Gil (Karol); D.M. Evans (David); L. Gianniny (Lauren); C. Gieger (Christian); C.J. Gillson (Christopher); C. Guiducci (Candace); R. Hackett (Rachel); D. Hadley (David); A.S. Hall (Alistair); A.S. Havulinna (Aki); J. Hebebrand (Johannes); A. Hofman (Albert); B. Isomaa (Bo); T. Johnson (Toby); P. Jousilahti (Pekka); Z. Jovanovic (Zorica); K-T. Khaw (Kay-Tee); P. Kraft (Peter); M. Kuokkanen (Mikko); J. Kuusisto (Johanna); J. Laitinen (Jaana); E. Lakatta (Edward); J. Luan; R.N. Luben (Robert); M. Mangino (Massimo); W.L. McArdle (Wendy); T. Meitinger (Thomas); A. Mulas (Antonella); P. Munroe (Patricia); N. Narisu (Narisu); A.R. Ness (Andrew); K. Northstone (Kate); S. O'Rahilly (Stephen); C. Purmann (Carolin); M.G. Rees (Matthew); M. Ridderstråle (Martin); S.M. Ring (Susan); F. Rivadeneira Ramirez (Fernando); A. Ruokonen (Aimo); M.S. Sandhu (Manjinder); J. Saramies (Jouko); L.J. Scott (Laura); A. Scuteri (Angelo); K. Silander (Kaisa); M.A. Sims (Matthew); K. Song (Kijoung); J. Stephens (Jonathan); S. Stevens (Suzanne); H.M. Stringham (Heather); Y.C.L. Tung (Loraine); T.T. Valle (Timo); P. Tikka-Kleemola (Päivi); K.S. Vimaleswaran (Karani); P. Vollenweider (Peter); G. Waeber (Gérard); C. Wallace (Chris); R.M. Watanabe (Richard); D. Waterworth (Dawn); N. Watkins (Nicholas); J.C.M. Witteman (Jacqueline); E. Zeggini (Eleftheria); G. Zhai (Guangju); M.C. Zillikens (Carola); D. Altshuler (David); M. Caulfield (Mark); S.J. Chanock (Stephen); I.S. Farooqi (Sadaf); L. Ferrucci (Luigi); J.M. Guralnik (Jack); A.T. Hattersley (Andrew); F.B. Hu (Frank); M.-R. Jarvelin (Marjo-Riitta); M. Laakso (Markku); V. Mooser (Vincent); K.K. Ong (Ken); W.H. Ouwehand (Willem); V. Salomaa (Veikko); N.J. Samani (Nilesh); T.D. Spector (Timothy); T. Tuomi (Tiinamaija); J. Tuomilehto (Jaakko); M. Uda (Manuela); A.G. Uitterlinden (André); P. Deloukas (Panagiotis); N.J. Wareham (Nick); T.M. Frayling (Timothy); L. Groop (Leif); R.B. Hayes (Richard); D. Hunter (David); K.L. Mohlke (Karen); L. Peltonen (Leena Johanna); D. Schlessinger (David); D.P. Strachan (David); H.E. Wichmann (Erich); M.I. McCarthy (Mark); M. Boehnke (Michael); I. Barroso (Inês); G.R. Abecasis (Gonçalo); J.N. Hirschhorn (Joel)

    2009-01-01

    textabstractCommon variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts

  11. Seven newly identified loci for autoimmune thyroid disease.

    Science.gov (United States)

    Cooper, Jason D; Simmonds, Matthew J; Walker, Neil M; Burren, Oliver; Brand, Oliver J; Guo, Hui; Wallace, Chris; Stevens, Helen; Coleman, Gillian; Franklyn, Jayne A; Todd, John A; Gough, Stephen C L

    2012-12-01

    Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci (P test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases.

  12. Development of microsatellite loci in Artocarpus altilis (Moraceae) and cross-amplification in congeneric species.

    Science.gov (United States)

    Witherup, Colby; Ragone, Diane; Wiesner-Hanks, Tyr; Irish, Brian; Scheffler, Brian; Simpson, Sheron; Zee, Francis; Zuberi, M Iqbal; Zerega, Nyree J C

    2013-07-01

    Microsatellite loci were isolated and characterized from enriched genomic libraries of Artocarpus altilis (breadfruit) and tested in four Artocarpus species and one hybrid. The microsatellite markers provide new tools for further studies in Artocarpus. • A total of 25 microsatellite loci were evaluated across four Artocarpus species and one hybrid. Twenty-one microsatellite loci were evaluated on A. altilis (241), A. camansi (34), A. mariannensis (15), and A. altilis × mariannensis (64) samples. Nine of those loci plus four additional loci were evaluated on A. heterophyllus (jackfruit, 426) samples. All loci are polymorphic for at least one species. The average number of alleles ranges from two to nine within taxa. • These microsatellite primers will facilitate further studies on the genetic structure and evolutionary and domestication history of Artocarpus species. They will aid in cultivar identification and establishing germplasm conservation strategies for breadfruit and jackfruit.

  13. Development of Microsatellite Loci in Artocarpus altilis (Moraceae and Cross-Amplification in Congeneric Species

    Directory of Open Access Journals (Sweden)

    Colby Witherup

    2013-07-01

    Full Text Available Premise of the study: Microsatellite loci were isolated and characterized from enriched genomic libraries of Artocarpus altilis (breadfruit and tested in four Artocarpus species and one hybrid. The microsatellite markers provide new tools for further studies in Artocarpus. Methods and Results: A total of 25 microsatellite loci were evaluated across four Artocarpus species and one hybrid. Twenty-one microsatellite loci were evaluated on A. altilis (241, A. camansi (34, A. mariannensis (15, and A. altilis × mariannensis (64 samples. Nine of those loci plus four additional loci were evaluated on A. heterophyllus (jackfruit, 426 samples. All loci are polymorphic for at least one species. The average number of alleles ranges from two to nine within taxa. Conclusions: These microsatellite primers will facilitate further studies on the genetic structure and evolutionary and domestication history of Artocarpus species. They will aid in cultivar identification and establishing germplasm conservation strategies for breadfruit and jackfruit.

  14. Development of microsatellite loci in Artocarpus altilis (Moraceae) and cross-amplification in congeneric species1

    Science.gov (United States)

    Witherup, Colby; Ragone, Diane; Wiesner-Hanks, Tyr; Irish, Brian; Scheffler, Brian; Simpson, Sheron; Zee, Francis; Zuberi, M. Iqbal; Zerega, Nyree J. C.

    2013-01-01

    • Premise of the study: Microsatellite loci were isolated and characterized from enriched genomic libraries of Artocarpus altilis (breadfruit) and tested in four Artocarpus species and one hybrid. The microsatellite markers provide new tools for further studies in Artocarpus. • Methods and Results: A total of 25 microsatellite loci were evaluated across four Artocarpus species and one hybrid. Twenty-one microsatellite loci were evaluated on A. altilis (241), A. camansi (34), A. mariannensis (15), and A. altilis × mariannensis (64) samples. Nine of those loci plus four additional loci were evaluated on A. heterophyllus (jackfruit, 426) samples. All loci are polymorphic for at least one species. The average number of alleles ranges from two to nine within taxa. • Conclusions: These microsatellite primers will facilitate further studies on the genetic structure and evolutionary and domestication history of Artocarpus species. They will aid in cultivar identification and establishing germplasm conservation strategies for breadfruit and jackfruit. PMID:25202565

  15. Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

    Directory of Open Access Journals (Sweden)

    Jingjing Liang

    2017-05-01

    Full Text Available Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8 for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4 and multiple-trait analyses identified one novel locus (FRMD3 for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

  16. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

    NARCIS (Netherlands)

    Paternoster, Lavinia; Standl, Marie; Waage, Johannes; Baurecht, Hansjoerg; Hotze, Melanie; Strachan, David P.; Curtin, John A.; Bonnelykke, Klaus; Tian, Chao; Takahashi, Atsushi; Esparza-Gordillo, Jorge; Alves, Alexessander Couto; Thyssen, Jacob P.; den Dekker, Herman T.; Ferreira, Manuel A.; Altmaier, Elisabeth; Sleiman, Patrick M. A.; Xiao, Feng Li; Gonzalez, Juan R.; Marenholz, Ingo; Kalb, Birgit; Pino-Yanes, Maria; Xu, Chengjian; Carstensen, Lisbeth; Groen-Blokhuis, Maria M.; Venturini, Cristina; Pennell, Craig E.; Barton, Sheila J.; Levin, Albert M.; Curjuric, Ivan; Bustamante, Mariona; Kreiner-Moller, Eskil; Lockett, Gabrielle A.; Bacelis, Jonas; Bunyavanich, Supinda; Myers, Rachel A.; Matanovic, Anja; Kumar, Ashish; Tung, Joyce Y.; Hirota, Tomomitsu; Kubo, Michiaki; McArdle, Wendy L.; Henderson, A. John; Kemp, John P.; Zheng, Jie; Smith, George Davey; Rueschendorf, Franz; Bauerfeind, Anja; Lee-Kirsch, Min Ae; Arnold, Andreas; Homuth, Georg; Schmidt, Carsten O.; Mangold, Elisabeth; Cichon, Sven; Keil, Thomas; Rodriguez, Elke; Peters, Annette; Franke, Andre; Lieb, Wolfgang; Novak, Natalija; Foelster-Holst, Regina; Horikoshi, Momoko; Pekkanen, Juha; Sebert, Sylvain; Husemoen, Lise L.; Grarup, Niels; De Jongste, Johan C.; Rivadeneira, Fernando; Hofman, Albert; Jaddoe, Vincent W. V.; Pasmans, Suzanne G. M. A.; Elbert, Niels J.; Uitterlinden, Andre G.; Marks, Guy B.; Thompson, Philip J.; Matheson, Melanie C.; Robertson, Colin F.; Ried, Janina S.; Li, Jin; Zuo, Xian Bo; Zheng, Xiao Dong; Yin, Xian Yong; Sun, Liang Dan; McAleer, Maeve A.; O'Regan, Grainne M.; Fahy, Caoimhe M. R.; Campbell, Linda E.; Macek, Milan; Kurek, Michael; Hu, Donglei; Eng, Celeste; Postma, Dirkje S.; Feenstra, Bjarke; Geller, Frank; Hottenga, Jouke Jan; Middeldorp, Christel M.; Hysi, Pirro; Bataille, Veronique; Spector, Tim; Tiesler, Carla M. T.; Thiering, Elisabeth; Pahukasahasram, Badri; Yang, James J.; Imboden, Medea; Huntsman, Scott; Vilor-Tejedor, Natalia; Relton, Caroline L.; Myhre, Ronny; Nystad, Wenche; Custovic, Adnan; Weiss, Scott T.; Meyers, Deborah A.; Soederhaell, Cilla; Melen, Erik; Ober, Carole; Raby, Benjamin A.; Simpson, Angela; Jacobsson, Bo; Holloway, John W.; Bisgaard, Hans; Sunyer, Jordi; Probst-Hensch, Nicole M.; Williams, L. Keoki; Godfrey, Keith M.; Wang, Carol A.; Boomsma, Dorret I.; Melbye, Mads; Koppelman, Gerard H.; Jarvis, Deborah; McLean, W. H. Irwin; Irvine, Alan D.; Zhang, Xue Jun; Hakonarson, Hakon; Gieger-, Christian; Burchard, Esteban G.; Martin, Nicholas G.; Duijts, Liesbeth; Linneberg, Allan; Jarvelin, Marjo-Riitta; Noethen, Markus M.; Lau, Susanne; Huebner, Norbert; Lee, Young-Ae; Tamari, Mayumi; Hinds, David A.; Glass, Daniel; Brown, Sara J.; Heinrich, Joachim; Evans, David M.; Weidinger, Stephan

    2015-01-01

    Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases

  17. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

    DEFF Research Database (Denmark)

    Paternoster, Lavinia; Standl, Marie; Waage, Johannes

    2015-01-01

    Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases...

  18. Quantitative trait loci for resistance to maize streak virus disease in ...

    African Journals Online (AJOL)

    STORAGESEVER

    2008-07-18

    Jul 18, 2008 ... characterized quantitative trait loci affecting resistance to maize streak virus in maize populations of S4 families from the cross of one resistant MAL13 and one susceptible MAL9 recombinant inbred lines. Resistance was evaluated in replicated field trials under artificial inoculation while selecting using.

  19. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

    NARCIS (Netherlands)

    Speliotes, Elizabeth K.; Willer, Cristen J.; Berndt, Sonja I.; Monda, Keri L.; Thorleifsson, Gudmar; Jackson, Anne U.; Allen, Hana Lango; Lindgren, Cecilia M.; Luan, Jian'an; Maegi, Reedik; Randall, Joshua C.; Vedantam, Sailaja; Winkler, Thomas W.; Qi, Lu; Workalemahu, Tsegaselassie; Heid, Iris M.; Steinthorsdottir, Valgerdur; Stringham, Heather M.; Weedon, Michael N.; Wheeler, Eleanor; Wood, Andrew R.; Ferreira, Teresa; Weyant, Robert J.; Segre, Ayellet V.; Estrada, Karol; Liang, Liming; Nemesh, James; Park, Ju-Hyun; Gustafsson, Stefan; Kilpelaenen, Tuomas O.; Yang, Jian; Bouatia-Naji, Nabila; Esko, Tonu; Feitosa, Mary F.; Kutalik, Zoltan; Mangino, Massimo; Raychaudhuri, Soumya; Scherag, Andre; Smith, Albert Vernon; Welch, Ryan; Zhao, Jing Hua; Aben, Katja K.; Absher, Devin M.; Amin, Najaf; Dixon, Anna L.; Fisher, Eva; Glazer, Nicole L.; Goddard, Michael E.; Heard-Costa, Nancy L.; Hoesel, Volker; Hottenga, Jouke-Jan; Johansson, Asa; Johnson, Toby; Ketkar, Shamika; Lamina, Claudia; Li, Shengxu; Moffatt, Miriam F.; Myers, Richard H.; Narisu, Narisu; Perry, John R. B.; Peters, Marjolein J.; Preuss, Michael; Ripatti, Samuli; Rivadeneira, Fernando; Sandholt, Camilla; Scott, Laura J.; Timpson, Nicholas J.; Tyrer, Jonathan P.; van Wingerden, Sophie; Watanabe, Richard M.; White, Charles C.; Wiklund, Fredrik; Barlassina, Christina; Chasman, Daniel I.; Cooper, Matthew N.; Jansson, John-Olov; Lawrence, Robert W.; Pellikka, Niina; Prokopenko, Inga; Shi, Jianxin; Thiering, Elisabeth; Alavere, Helene; Alibrandi, Maria T. S.; Almgren, Peter; Arnold, Alice M.; Aspelund, Thor; Atwood, Larry D.; Balkau, Beverley; Balmforth, Anthony J.; Bennett, Amanda J.; Ben-Shlomo, Yoav; Bergman, Richard N.; Bergmann, Sven; Biebermann, Heike; Blakemore, Alexandra I. F.; Boes, Tanja; Bonnycastle, Lori L.; Bornstein, Stefan R.; Brown, Morris J.; Buchanan, Thomas A.; Busonero, Fabio; Campbell, Harry; Cappuccio, Francesco P.; Cavalcanti-Proenca, Christine; Chen, Yii-Der Ida; Chen, Chih-Mei; Chines, Peter S.; Clarke, Robert; Coin, Lachlan; Connell, John; Day, Ian N. M.; den Heijer, Martin; Duan, Jubao; Ebrahim, Shah; Elliott, Paul; Elosua, Roberto; Eiriksdottir, Gudny; Erdos, Michael R.; Eriksson, Johan G.; Facheris, Maurizio F.; Felix, Stephan B.; Fischer-Posovszky, Pamela; Folsom, Aaron R.; Friedrich, Nele; Freimer, Nelson B.; Fu, Mao; Gaget, Stefan; Gejman, Pablo V.; Geus, Eco J. C.; Gieger, Christian; Gjesing, Anette P.; Goel, Anuj; Goyette, Philippe; Grallert, Harald; Graessler, Juergen; Greenawalt, Danielle M.; Groves, Christopher J.; Gudnason, Vilmundur; Guiducci, Candace; Hartikainen, Anna-Liisa; Hassanali, Neelam; Hall, Alistair S.; Havulinna, Aki S.; Hayward, Caroline; Heath, Andrew C.; Hengstenberg, Christian; Hicks, Andrew A.; Hinney, Anke; Hofman, Albert; Homuth, Georg; Hui, Jennie; Igl, Wilmar; Iribarren, Carlos; Isomaa, Bo; Jacobs, Kevin B.; Jarick, Ivonne; Jewell, Elizabeth; John, Ulrich; Jorgensen, Torben; Jousilahti, Pekka; Jula, Antti; Kaakinen, Marika; Kajantie, Eero; Kaplan, Lee M.; Kathiresan, Sekar; Kettunen, Johannes; Kinnunen, Leena; Knowles, Joshua W.; Kolcic, Ivana; Koenig, Inke R.; Koskinen, Seppo; Kovacs, Peter; Kuusisto, Johanna; Kraft, Peter; Kvaloy, Kirsti; Laitinen, Jaana; Lantieri, Olivier; Lanzani, Chiara; Launer, Lenore J.; Lecoeur, Cecile; Lehtimaeki, Terho; Lettre, Guillaume; Liu, Jianjun; Lokki, Marja-Liisa; Lorentzon, Mattias; Luben, Robert N.; Ludwig, Barbara; Manunta, Paolo; Marek, Diana; Marre, Michel; Martin, Nicholas G.; McArdle, Wendy L.; McCarthy, Anne; McKnight, Barbara; Meitinger, Thomas; Melander, Olle; Meyre, David; Midthjell, Kristian; Montgomery, Grant W.; Morken, Mario A.; Morris, Andrew P.; Mulic, Rosanda; Ngwa, Julius S.; Nelis, Mari; Neville, Matt J.; Nyholt, Dale R.; O'Donnell, Christopher J.; O'Rahilly, Stephen; Ong, Ken K.; Oostra, Ben; Pare, Guillaume; Parker, Alex N.; Perola, Markus; Pichler, Irene; Pietilaeinen, Kirsi H.; Platou, Carl G. P.; Polasek, Ozren; Pouta, Anneli; Rafelt, Suzanne; Raitakari, Olli; Rayner, Nigel W.; Ridderstrale, Martin; Rief, Winfried; Ruokonen, Aimo; Robertson, Neil R.; Rzehak, Peter; Salomaa, Veikko; Sanders, Alan R.; Sandhu, Manjinder S.; Sanna, Serena; Saramies, Jouko; Savolainen, Markku J.; Scherag, Susann; Schipf, Sabine; Schreiber, Stefan; Schunkert, Heribert; Silander, Kaisa; Sinisalo, Juha; Siscovick, David S.; Smit, Jan H.; Soranzo, Nicole; Sovio, Ulla; Stephens, Jonathan; Surakka, Ida; Swift, Amy J.; Tammesoo, Mari-Liis; Tardif, Jean-Claude; Teder-Laving, Maris; Teslovich, Tanya M.; Thompson, John R.; Thomson, Brian; Toenjes, Anke; Tuomi, Tiinamaija; van Meurs, Joyce B. J.; van Ommen, Gert-Jan; Vatin, Vincent; Viikari, Jorma; Visvikis-Siest, Sophie; Vitart, Veronique; Vogel, Carla I. G.; Voight, Benjamin F.; Waite, Lindsay L.; Wallaschofski, Henri; Walters, G. Bragi; Widen, Elisabeth; Wiegand, Susanna; Wild, Sarah H.; Willemsen, Gonneke; Witte, Daniel R.; Witteman, Jacqueline C.; Xu, Jianfeng; Zhang, Qunyuan; Zgaga, Lina; Ziegler, Andreas; Zitting, Paavo; Beilby, John P.; Farooqi, I. Sadaf; Hebebrand, Johannes; Huikuri, Heikki V.; James, Alan L.; Kaehoenen, Mika; Levinson, Douglas F.; Macciardi, Fabio; Nieminen, Markku S.; Ohlsson, Claes; Palmer, Lyle J.; Ridker, Paul M.; Stumvoll, Michael; Beckmann, Jacques S.; Boeing, Heiner; Boerwinkle, Eric; Boomsma, Dorret I.; Caulfield, Mark J.; Chanock, Stephen J.; Collins, Francis S.; Cupples, L. Adrienne; Smith, George Davey; Erdmann, Jeanette; Froguel, Philippe; Greonberg, Henrik; Gyllensten, Ulf; Hall, Per; Hansen, Torben; Harris, Tamara B.; Hattersley, Andrew T.; Hayes, Richard B.; Heinrich, Joachim; Hu, Frank B.; Hveem, Kristian; Illig, Thomas; Jarvelin, Marjo-Riitta; Kaprio, Jaakko; Karpe, Fredrik; Khaw, Kay-Tee; Kiemeney, Lambertus A.; Krude, Heiko; Laakso, Markku; Lawlor, Debbie A.; Metspalu, Andres; Munroe, Patricia B.; Ouwehand, Willem H.; Pedersen, Oluf; Penninx, Brenda W.; Peters, Annette; Pramstaller, Peter P.; Quertermous, Thomas; Reinehr, Thomas; Rissanen, Aila; Rudan, Igor; Samani, Nilesh J.; Schwarz, Peter E. H.; Shuldiner, Alan R.; Spector, Timothy D.; Tuomilehto, Jaakko; Uda, Manuela; Uitterlinden, Andre; Valle, Timo T.; Wabitsch, Martin; Waeber, Gerard; Wareham, Nicholas J.; Watkins, Hugh; Wilson, James F.; Wright, Alan F.; Zillikens, M. Carola; Chatterjee, Nilanjan; McCarroll, Steven A.; Purcell, Shaun; Schadt, Eric E.; Visscher, Peter M.; Assimes, Themistocles L.; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Groop, Leif C.; Haritunians, Talin; Hunter, David J.; Kaplan, Robert C.; Mohlke, Karen L.; O'Connell, Jeffrey R.; Peltonen, Leena; Schlessinger, David; Strachan, David P.; van Duijn, Cornelia M.; Wichmann, H-Erich; Frayling, Timothy M.; Thorsteinsdottir, Unnur; Abecasis, Goncalo R.; Barroso, Ines; Boehnke, Michael; Stefansson, Kari; North, Kari E.; McCarthy, Mark I.; Hirschhorn, Joel N.; Ingelsson, Erik; Loos, Ruth J. F.

    2010-01-01

    Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of

  20. Quantitative trait loci for resistance to maize streak virus disease in ...

    African Journals Online (AJOL)

    Maize streak virus disease is an important disease of maize in Kenya. In this study, we mapped and characterized quantitative trait loci affecting resistance to maize streak virus in maize populations of S4 families from the cross of one resistant MAL13 and one susceptible MAL9 recombinant inbred lines. Resistance was ...

  1. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

    DEFF Research Database (Denmark)

    Speliotes, Elizabeth K; Willer, Cristen J; Berndt, Sonja I

    2010-01-01

    Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SN...

  2. Large-scale genotyping identifies 41 new loci associated with breast cancer risk

    NARCIS (Netherlands)

    Michailidou, Kyriaki; Hall, Per; Gonzalez-Neira, Anna; Ghoussaini, Maya; Dennis, Joe; Milne, Roger L.; Schmidt, Marjanka K.; Chang-Claude, Jenny; Bojesen, Stig E.; Bolla, Manjeet K.; Wang, Qin; Dicks, Ed; Lee, Andrew; Turnbull, Clare; Rahman, Nazneen; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; dos Santos Silva, Isabel; Nevanlinna, Heli; Muranen, Taru A.; Aittomäki, Kristiina; Blomqvist, Carl; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel; van der Luijt, Rob B.; Hein, Rebecca; Dahmen, Norbert; Beckman, Lars; Meindl, Alfons; Schmutzler, Rita K.; Müller-Myhsok, Bertram; Lichtner, Peter; Hopper, John L.; Southey, Melissa C.; Makalic, Enes; Schmidt, Daniel F.; Uitterlinden, Andre G.; Hofman, Albert; Hunter, David J.; Chanock, Stephen J.; Vincent, Daniel; Bacot, François; Tessier, Daniel C.; Canisius, Sander; Wessels, Lodewyk F. A.; Haiman, Christopher A.; Shah, Mitul; Luben, Robert; Brown, Judith; Luccarini, Craig; Schoof, Nils; Humphreys, Keith; Li, Jingmei; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Couch, Fergus J.; Wang, Xianshu; Vachon, Celine; Stevens, Kristen N.; Lambrechts, Diether; Moisse, Matthieu; Paridaens, Robert; Christiaens, Marie-Rose; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Johnson, Nichola; Aitken, Zoe; Aaltonen, Kirsimari; Heikkinen, Tuomas; Broeks, Annegien; van 't Veer, Laura J.; van der Schoot, C. Ellen; Guénel, Pascal; Truong, Thérèse; Laurent-Puig, Pierre; Menegaux, Florence; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Burwinkel, Barbara; Zamora, M. Pilar; Perez, Jose Ignacio Arias; Pita, Guillermo; Alonso, M. Rosario; Cox, Angela; Brock, Ian W.; Cross, Simon S.; Reed, Malcolm W. R.; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Lindblom, Annika; Margolin, Sara; Hooning, Maartje J.; Hollestelle, Antoinette; van den Ouweland, Ans M. W.; Jager, Agnes; Bui, Quang M.; Stone, Jennifer; Dite, Gillian S.; Apicella, Carmel; Tsimiklis, Helen; Giles, Graham G.; Severi, Gianluca; Baglietto, Laura; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Swerdlow, Anthony; Ashworth, Alan; Orr, Nick; Jones, Michael; Figueroa, Jonine; Lissowska, Jolanta; Brinton, Louise; Goldberg, Mark S.; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Brüning, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bonanni, Bernardo; Devilee, Peter; Tollenaar, Rob A. E. M.; Seynaeve, Caroline; van Asperen, Christi J.; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Durda, Katarzyna; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M.; Bogdanova, Natalia V.; Antonenkova, Natalia N.; Dörk, Thilo; Kristensen, Vessela N.; Anton-Culver, Hoda; Slager, Susan; Toland, Amanda E.; Edge, Stephen; Fostira, Florentia; Kang, Daehee; Yoo, Keun-Young; Noh, Dong-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Sueta, Aiko; Wu, Anna H.; Tseng, Chiu-Chen; van den Berg, David; Stram, Daniel O.; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; teo, Soo Hwang; Yip, Cheng Har; Phuah, Sze Yee; Cornes, Belinda K.; Hartman, Mikael; Miao, Hui; Lim, Wei Yen; Sng, Jen-Hwei; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Ding, Shian-Ling; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Blot, William J.; Signorello, Lisa B.; Cai, Qiuyin; Zheng, Wei; Deming-Halverson, Sandra; Shrubsole, Martha; Long, Jirong; Simard, Jacques; Garcia-Closas, Montse; Pharoah, Paul D. P.; Chenevix-Trench, Georgia; Dunning, Alison M.; Benitez, Javier; Easton, Douglas F.

    2013-01-01

    Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including

  3. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

    NARCIS (Netherlands)

    Berndt, Sonja I; Camp, Nicola J; Skibola, Christine F; Vijai, Joseph; Wang, Zhaoming; Gu, Jian; Nieters, Alexandra; Kelly, Rachel S; Smedby, Karin E; Monnereau, Alain; Cozen, Wendy; Cox, Angela; Wang, Sophia S; Lan, Qing; Teras, Lauren R; Machado, Moara; Yeager, Meredith; Brooks-Wilson, Angela R; Hartge, Patricia; Purdue, Mark P; Birmann, Brenda M; Vajdic, Claire M; Cocco, Pierluigi; Zhang, Yawei; Giles, Graham G; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Montalvan, Rebecca; Burdett, Laurie; Hutchinson, Amy; Ye, Yuanqing; Call, Timothy G; Shanafelt, Tait D; Novak, Anne J; Kay, Neil E; Liebow, Mark; Cunningham, Julie M; Allmer, Cristine; Hjalgrim, Henrik; Adami, Hans-Olov; Melbye, Mads; Glimelius, Bengt; Chang, Ellen T; Glenn, Martha; Curtin, Karen; Cannon-Albright, Lisa A; Diver, W Ryan; Link, Brian K; Weiner, George J; Conde, Lucia; Bracci, Paige M; Riby, Jacques; Arnett, Donna K; Zhi, Degui; Leach, Justin M; Holly, Elizabeth A; Jackson, Rebecca D; Tinker, Lesley F; Benavente, Yolanda; Sala, Núria; Casabonne, Delphine; Becker, Nikolaus; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; McKay, James; Staines, Anthony; Chaffee, Kari G; Achenbach, Sara J; Vachon, Celine M; Goldin, Lynn R; Strom, Sara S; Leis, Jose F; Weinberg, J Brice; Caporaso, Neil E; Norman, Aaron D; De Roos, Anneclaire J; Morton, Lindsay M; Severson, Richard K; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Masala, Giovanna; Weiderpass, Elisabete; Chirlaque, María-Dolores; Vermeulen, Roel C H; Travis, Ruth C; Southey, Melissa C; Milne, Roger L; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Clavel, Jacqueline; Zheng, Tongzhang; Holford, Theodore R; Villano, Danylo J; Maria, Ann; Spinelli, John J; Gascoyne, Randy D; Connors, Joseph M; Bertrand, Kimberly A; Giovannucci, Edward; Kraft, Peter; Kricker, Anne; Turner, Jenny; Ennas, Maria Grazia; Ferri, Giovanni M; Miligi, Lucia; Liang, Liming; Ma, Baoshan; Huang, Jinyan; Crouch, Simon; Park, Ju-Hyun; Chatterjee, Nilanjan; North, Kari E; Snowden, John A; Wright, Josh; Fraumeni, Joseph F; Offit, Kenneth; Wu, Xifeng; de Sanjose, Silvia; Cerhan, James R; Chanock, Stephen J; Rothman, Nathaniel; Slager, Susan L

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and

  4. Gene-network analysis identifies susceptibility genes related to glycobiology in autism.

    Directory of Open Access Journals (Sweden)

    Bert van der Zwaag

    Full Text Available The recent identification of copy-number variation in the human genome has opened up new avenues for the discovery of positional candidate genes underlying complex genetic disorders, especially in the field of psychiatric disease. One major challenge that remains is pinpointing the susceptibility genes in the multitude of disease-associated loci. This challenge may be tackled by reconstruction of functional gene-networks from the genes residing in these loci. We applied this approach to autism spectrum disorder (ASD, and identified the copy-number changes in the DNA of 105 ASD patients and 267 healthy individuals with Illumina Humanhap300 Beadchips. Subsequently, we used a human reconstructed gene-network, Prioritizer, to rank candidate genes in the segmental gains and losses in our autism cohort. This analysis highlighted several candidate genes already known to be mutated in cognitive and neuropsychiatric disorders, including RAI1, BRD1, and LARGE. In addition, the LARGE gene was part of a sub-network of seven genes functioning in glycobiology, present in seven copy-number changes specifically identified in autism patients with limited co-morbidity. Three of these seven copy-number changes were de novo in the patients. In autism patients with a complex phenotype and healthy controls no such sub-network was identified. An independent systematic analysis of 13 published autism susceptibility loci supports the involvement of genes related to glycobiology as we also identified the same or similar genes from those loci. Our findings suggest that the occurrence of genomic gains and losses of genes associated with glycobiology are important contributors to the development of ASD.

  5. Epigenomic elements enriched in the promoters of autoimmunity susceptibility genes.

    Science.gov (United States)

    Dozmorov, Mikhail G; Wren, Jonathan D; Alarcón-Riquelme, Marta E

    2014-02-01

    Genome-wide association studies have identified a number of autoimmune disease-susceptibility genes. Whether or not these loci share any regulatory or functional elements, however, is an open question. Finding such common regulators is of considerable research interest in order to define systemic therapeutic targets. The growing amount of experimental genomic annotations, particularly those from the ENCODE project, provide a wealth of opportunities to search for such commonalities. We hypothesized that regulatory commonalities might not only delineate a regulatory landscape predisposing to autoimmune diseases, but also define functional elements distinguishing specific diseases. We further investigated if, and how, disease-specific epigenomic elements can identify novel genes yet to be associated with the diseases. We evaluated transcription factors, histone modifications, and chromatin state data obtained from the ENCODE project for statistically significant over- or under-representation in the promoters of genes associated with Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Systemic Sclerosis (SSc). We identified BATF, BCL11A, IRF4, NFkB, PAX5, and PU.1 as transcription factors over-represented in SLE- and RA-susceptibility gene promoters. H3K4me1 and H3K4me2 epigenomic marks were associated with SLE susceptibility genes, and H3K9me3 was common to both SLE and RA. In contrast to a transcriptionally active signature in SLE and RA, SSc-susceptibility genes were depleted in activating epigenomic elements. Using epigenomic elements enriched in SLE and RA, we identified additional immune and B cell signaling-related genes with the same elements in their promoters. Our analysis suggests common and disease-specific epigenomic elements that may define novel therapeutic targets for controlling aberrant activation of autoimmune susceptibility genes.

  6. Blood Pressure Loci Identified with a Gene-Centric Array

    NARCIS (Netherlands)

    Johnson, Toby; Gaunt, Tom R.; Newhouse, Stephen J.; Padmanabhan, Sandosh; Tomaszewski, Maciej; Kumari, Meena; Morris, Richard W.; Tzoulaki, Ioanna; O'Brien, Eoin T.; Poulter, Neil R.; Sever, Peter; Shields, Denis C.; Thom, Simon; Wannamethee, Sasiwarang G.; Whincup, Peter H.; Brown, Morris J.; Connell, John M.; Dobson, Richard J.; Howard, Philip J.; Mein, Charles A.; Onipinla, Abiodun; Shaw-Hawkins, Sue; Zhang, Yun; Smith, George Davey; Day, Ian N. M.; Lawlor, Debbie A.; Goodall, Alison H.; Fowkes, F. Gerald; Abecasis, Goncalo R.; Elliott, Paul; Gateva, Vesela; Braund, Peter S.; Burton, Paul R.; Nelson, Christopher P.; Tobin, Martin D.; van der Harst, Pim; Glorioso, Nicola; Neuvrith, Hani; Salvi, Erika; Staessen, Jan A.; Stucchi, Andrea; Devos, Nabila; Jeunemaitre, Xavier; Plouin, Pierre-Francois; Tichet, Jean; Juhanson, Peeter; Org, Elin; Putku, Margus; Sober, Siim; Veldre, Gudrun; Viigimaa, Margus; Levinsson, Anna; Rosengren, Annika; Thelle, Dag S.; Hastie, Claire E.; Hedner, Thomas; Lee, Wai K.; Melander, Olle; Wahlstrand, Bjoern; Hardy, Rebecca; Wong, Andrew; Cooper, Jackie A.; Palmen, Jutta; Chen, Li; Stewart, Alexandre F. R.; Wells, George A.; Westra, Harm-Jan; Wolfs, Marcel G. M.; Clarke, Robert; Franzosi, Maria Grazia; Goel, Anuj; Hamsten, Anders; Lathrop, Mark; Peden, John F.; Seedorf, Udo; Watkins, Hugh; Ouwehand, Willem H.; Sambrook, Jennifer; Stephens, Jonathan; Casas, Juan-Pablo; Drenos, Fotios; Holmes, Michael V.; Kivimaki, Mika; Shah, Sonia; Shah, Tina; Talmud, Philippa J.; Whittaker, John; Wallace, Chris; Delles, Christian; Laan, Mans; Kuh, Diana; Humphries, Steve E.; Nyberg, Fredrik; Cusi, Daniele; Roberts, Robert; Newton-Cheh, Christopher; Franke, Lude; Stanton, Alice V.; Dominiczak, Anna F.; Farrall, Martin; Hingorani, Aroon D.; Samani, Nilesh J.; Caulfield, Mark J.; Munroe, Patricia B.

    2011-01-01

    Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a

  7. Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management

    National Research Council Canada - National Science Library

    Vishnubhotla Venkata Ravi Kanth Mitnala Sasikala Mithun Sharma Padaki Nagaraja Rao Duvvuru Nageshwar Reddy

    2016-01-01

    .... While various genotyping approaches such as whole exome sequencing using next generation sequencers and genome wide association studies have identified susceptibility loci for non-alcoholic fatty liver disease(NAFLD...

  8. Mapping of Gene Expression Reveals CYP27A1 as a Susceptibility Gene for Sporadic ALS

    NARCIS (Netherlands)

    Diekstra, Frank P.; Saris, Christiaan G. J.; van Rheenen, Wouter; Franke, Lude; Jansen, Ritsert C.; van Es, Michael A.; van Vught, Paul W. J.; Blauw, Hylke M.; Groen, Ewout J. N.; Horvath, Steve; Estrada, Karol; Rivadeneira, Fernando; Hofman, Albert; Uitterlinden, Andre G.; Robberecht, Wim; Andersen, Peter M.; Melki, Judith; Meininger, Vincent; Hardiman, Orla; Landers, John E.; Brown, Robert H.; Shatunov, Aleksey; Shaw, Christopher E.; Leigh, P. Nigel; Al-Chalabi, Ammar; Ophoff, Roel A.; van den Berg, Leonard H.; Veldink, Jan H.; Brown Jr., Robert H.; Brug, Marcel P. van der

    2012-01-01

    Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain

  9. 11q13 is a Susceptibility Locus for Hormone Receptor Positive Breast Cancer

    DEFF Research Database (Denmark)

    Lambrechts, Diether; Truong, Therese; Justenhoven, Christina

    2012-01-01

    A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10 and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we ge...

  10. 'MN1606SP' by 'Spencer' filial soybean population reveals novel quantitative trait loci and interactions among loci conditioning SDS resistance.

    Science.gov (United States)

    Luckew, Alexander S; Swaminathan, Sivakumar; Leandro, Leonor F; Orf, James H; Cianzio, Silvia R

    2017-10-01

    Four novel QTL and interactions among QTL were identified in this research, using as a parent line the most SDS-resistant genotype within soybean cultivars of the US early maturity groups. Soybean sudden death syndrome (SDS) reduces soybean yield in most of the growing areas of the world. The causal agent of SDS, soilborne fungus Fusarium virguliforme (Fv), releases phytotoxins taken up by the plant to produce chlorosis and necrosis in the leaves. Planting resistant cultivars is the most successful management practice to control the disease. The objective of this study was to identify quantitative trait loci (QTL) associated with the resistance response of MN1606SP to SDS. A mapping population of F 2:3 lines created by crossing the highly resistant cultivar 'MN1606SP' and the susceptible cultivar 'Spencer' was phenotyped in the greenhouse at three different planting times, each with three replications. Plants were artificially inoculated using SDS infested sorghum homogeneously mixed with the soil. Data were collected on three disease criteria, foliar disease incidence (DI), foliar leaf scorch disease severity (DS), and root rot severity. Disease index (DX) was calculated as DI × DS. Ten QTL were identified for the different disease assessment criteria, three for DI, four for DX, and three for root rot severity. Three QTL identified for root rot severity and one QTL for disease incidence are considered novel, since no previous reports related to these QTL are available. Among QTL, two interactions were detected between four different QTL. The interactions suggest that resistance to SDS is not only dependent on additive gene effects. The novel QTL and the interactions observed in this study will be useful to soybean breeders for improvement of SDS resistance in soybean germplasm.

  11. A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23

    Science.gov (United States)

    Wu, Xifeng; Scelo, Ghislaine; Purdue, Mark P.; Rothman, Nathaniel; Johansson, Mattias; Ye, Yuanqing; Wang, Zhaoming; Zelenika, Diana; Moore, Lee E.; Wood, Christopher G.; Prokhortchouk, Egor; Gaborieau, Valerie; Jacobs, Kevin B.; Chow, Wong-Ho; Toro, Jorge R.; Zaridze, David; Lin, Jie; Lubinski, Jan; Trubicka, Joanna; Szeszenia-Dabrowska, Neonilia; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Mates, Dana; Jinga, Viorel; Bencko, Vladimir; Slamova, Alena; Holcatova, Ivana; Navratilova, Marie; Janout, Vladimir; Boffetta, Paolo; Colt, Joanne S.; Davis, Faith G.; Schwartz, Kendra L.; Banks, Rosamonde E.; Selby, Peter J.; Harnden, Patricia; Berg, Christine D.; Hsing, Ann W.; Grubb, Robert L.; Boeing, Heiner; Vineis, Paolo; Clavel-Chapelon, Françoise; Palli, Domenico; Tumino, Rosario; Krogh, Vittorio; Panico, Salvatore; Duell, Eric J.; Quirós, José Ramón; Sanchez, Maria-José; Navarro, Carmen; Ardanaz, Eva; Dorronsoro, Miren; Khaw, Kay-Tee; Allen, Naomi E.; Bueno-de-Mesquita, H. Bas; Peeters, Petra H.M.; Trichopoulos, Dimitrios; Linseisen, Jakob; Ljungberg, Börje; Overvad, Kim; Tjønneland, Anne; Romieu, Isabelle; Riboli, Elio; Stevens, Victoria L; Thun, Michael J; Diver, W. Ryan; Gapstur, Susan M.; Pharoah, Paul D.; Easton, Douglas F.; Albanes, Demetrius; Virtamo, Jarmo; Vatten, Lars; Hveem, Kristian; Fletcher, Tony; Koppova, Kvetoslava; Cussenot, Olivier; Cancel-Tassin, Geraldine; Benhamou, Simone; Hildebrandt, Michelle A.; Pu, Xia; Foglio, Mario; Lechner, Doris; Hutchinson, Amy; Yeager, Meredith; Fraumeni, Joseph F.; Lathrop, Mark; Skryabin, Konstantin G.; McKay, James D.; Gu, Jian; Brennan, Paul; Chanock, Stephen J.

    2012-01-01

    Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome-wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r2 = 0.64, D ′ = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 × 10−10 and P = 6.07 × 10−9, respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13–1.26] for rs718314 and 1.18 (95% CI: 1.12–1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist–hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR. PMID:22010048

  12. Association analysis identifies 65 new breast cancer risk loci.

    Science.gov (United States)

    Michailidou, Kyriaki; Lindström, Sara; Dennis, Joe; Beesley, Jonathan; Hui, Shirley; Kar, Siddhartha; Lemaçon, Audrey; Soucy, Penny; Glubb, Dylan; Rostamianfar, Asha; Bolla, Manjeet K; Wang, Qin; Tyrer, Jonathan; Dicks, Ed; Lee, Andrew; Wang, Zhaoming; Allen, Jamie; Keeman, Renske; Eilber, Ursula; French, Juliet D; Qing Chen, Xiao; Fachal, Laura; McCue, Karen; McCart Reed, Amy E; Ghoussaini, Maya; Carroll, Jason S; Jiang, Xia; Finucane, Hilary; Adams, Marcia; Adank, Muriel A; Ahsan, Habibul; Aittomäki, Kristiina; Anton-Culver, Hoda; Antonenkova, Natalia N; Arndt, Volker; Aronson, Kristan J; Arun, Banu; Auer, Paul L; Bacot, François; Barrdahl, Myrto; Baynes, Caroline; Beckmann, Matthias W; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brand, Judith S; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Brinton, Louise; Broberg, Per; Brock, Ian W; Broeks, Annegien; Brooks-Wilson, Angela; Brucker, Sara Y; Brüning, Thomas; Burwinkel, Barbara; Butterbach, Katja; Cai, Qiuyin; Cai, Hui; Caldés, Trinidad; Canzian, Federico; Carracedo, Angel; Carter, Brian D; Castelao, Jose E; Chan, Tsun L; David Cheng, Ting-Yuan; Seng Chia, Kee; Choi, Ji-Yeob; Christiansen, Hans; Clarke, Christine L; Collée, Margriet; Conroy, Don M; Cordina-Duverger, Emilie; Cornelissen, Sten; Cox, David G; Cox, Angela; Cross, Simon S; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Devilee, Peter; Doheny, Kimberly F; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dumont, Martine; Durcan, Lorraine; Dwek, Miriam; Eccles, Diana M; Ekici, Arif B; Eliassen, A Heather; Ellberg, Carolina; Elvira, Mingajeva; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fritschi, Lin; Gaborieau, Valerie; Gabrielson, Marike; Gago-Dominguez, Manuela; Gao, Yu-Tang; Gapstur, Susan M; García-Sáenz, José A; Gaudet, Mia M; Georgoulias, Vassilios; Giles, Graham G; Glendon, Gord; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Grenaker Alnæs, Grethe I; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Guénel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Harrington, Patricia; Hart, Steven N; Hartikainen, Jaana M; Hartman, Mikael; Hein, Alexander; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Ho, Dona N; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Robert N; Hopper, John L; Hou, Ming-Feng; Hsiung, Chia-Ni; Huang, Guanmengqian; Humphreys, Keith; Ishiguro, Junko; Ito, Hidemi; Iwasaki, Motoki; Iwata, Hiroji; Jakubowska, Anna; Janni, Wolfgang; John, Esther M; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kasuga, Yoshio; Kerin, Michael J; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I; Kim, Sung-Won; Knight, Julia A; Kosma, Veli-Matti; Kristensen, Vessela N; Krüger, Ute; Kwong, Ava; Lambrechts, Diether; Le Marchand, Loic; Lee, Eunjung; Lee, Min Hyuk; Lee, Jong Won; Neng Lee, Chuen; Lejbkowicz, Flavio; Li, Jingmei; Lilyquist, Jenna; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Lophatananon, Artitaya; Lubinski, Jan; Luccarini, Craig; Lux, Michael P; Ma, Edmond S K; MacInnis, Robert J; Maishman, Tom; Makalic, Enes; Malone, Kathleen E; Kostovska, Ivana Maleva; Mannermaa, Arto; Manoukian, Siranoush; Manson, JoAnn E; Margolin, Sara; Mariapun, Shivaani; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; McKay, James; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Menéndez, Primitiva; Menon, Usha; Meyer, Jeffery; Miao, Hui; Miller, Nicola; Taib, Nur Aishah Mohd; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Nielsen, Sune F; Noh, Dong-Young; Nordestgaard, Børge G; Norman, Aaron; Olopade, Olufunmilayo I; Olson, Janet E; Olsson, Håkan; Olswold, Curtis; Orr, Nick; Pankratz, V Shane; Park, Sue K; Park-Simon, Tjoung-Won; Lloyd, Rachel; Perez, Jose I A; Peterlongo, Paolo; Peto, Julian; Phillips, Kelly-Anne; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Prentice, Ross; Presneau, Nadege; Prokofyeva, Darya; Pugh, Elizabeth; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rennert, Gadi; Rennert, Hedy S; Rhenius, Valerie; Romero, Atocha; Romm, Jane; Ruddy, Kathryn J; Rüdiger, Thomas; Rudolph, Anja; Ruebner, Matthias; Rutgers, Emiel J T; Saloustros, Emmanouil; Sandler, Dale P; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Daniel F; Schmutzler, Rita K; Schneeweiss, Andreas; Schoemaker, Minouk J; Schumacher, Fredrick; Schürmann, Peter; Scott, Rodney J; Scott, Christopher; Seal, Sheila; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Grace; Sherman, Mark E; Shrubsole, Martha J; Shu, Xiao-Ou; Smeets, Ann; Sohn, Christof; Southey, Melissa C; Spinelli, John J; Stegmaier, Christa; Stewart-Brown, Sarah; Stone, Jennifer; Stram, Daniel O; Surowy, Harald; Swerdlow, Anthony; Tamimi, Rulla; Taylor, Jack A; Tengström, Maria; Teo, Soo H; Beth Terry, Mary; Tessier, Daniel C; Thanasitthichai, Somchai; Thöne, Kathrin; Tollenaar, Rob A E M; Tomlinson, Ian; Tong, Ling; Torres, Diana; Truong, Thérèse; Tseng, Chiu-Chen; Tsugane, Shoichiro; Ulmer, Hans-Ulrich; Ursin, Giske; Untch, Michael; Vachon, Celine; van Asperen, Christi J; Van Den Berg, David; van den Ouweland, Ans M W; van der Kolk, Lizet; van der Luijt, Rob B; Vincent, Daniel; Vollenweider, Jason; Waisfisz, Quinten; Wang-Gohrke, Shan; Weinberg, Clarice R; Wendt, Camilla; Whittemore, Alice S; Wildiers, Hans; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H; Xia, Lucy; Yamaji, Taiki; Yang, Xiaohong R; Har Yip, Cheng; Yoo, Keun-Young; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Lakhani, Sunil R; Antoniou, Antonis C; Droit, Arnaud; Andrulis, Irene L; Amos, Christopher I; Couch, Fergus J; Pharoah, Paul D P; Chang-Claude, Jenny; Hall, Per; Hunter, David J; Milne, Roger L; García-Closas, Montserrat; Schmidt, Marjanka K; Chanock, Stephen J; Dunning, Alison M; Edwards, Stacey L; Bader, Gary D; Chenevix-Trench, Georgia; Simard, Jacques; Kraft, Peter; Easton, Douglas F

    2017-11-02

    Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

  13. Cross-amplification and characterization of microsatellite loci for the Neotropical orchid genus Epidendrum.

    Science.gov (United States)

    Pinheiro, Fábio; Palma-Silva, Clarisse; de Barros, Fábio; Cozzolino, Salvatore

    2009-04-01

    In this study we tested the cross-amplification of 33 microsatellite loci previously developed for two closely related Neotropical orchid genera (Epidendrum and Laelia). A set of ten loci were polymorphic across five examined species (20 individuals each) with 2 to 15 alleles per locus. The mean expected and observed heterozygosity (average across species) ranged from 0.34 to 0.82 and from 0.27 to 0.85, respectively. In addition we tested all loci in 35 species representative of the genus Epidendrum. Of these, 26 loci showed successful amplification. Cross-application of these loci represent a potential source of co-dominant markers for evolutionary, ecological and conservation studies in this important orchid genus.

  14. Cross-amplification and characterization of microsatellite loci for the Neotropical orchid genus Epidendrum

    Directory of Open Access Journals (Sweden)

    Fábio Pinheiro

    2009-01-01

    Full Text Available In this study we tested the cross-amplification of 33 microsatellite loci previously developed for two closely related Neotropical orchid genera (Epidendrum and Laelia. A set of ten loci were polymorphic across five examined species (20 individuals each with 2 to 15 alleles per locus. The mean expected and observed heterozygosity (average across species ranged from 0.34 to 0.82 and from 0.27 to 0.85, respectively. In addition we tested all loci in 35 species representative of the genus Epidendrum. Of these, 26 loci showed successful amplification. Cross-application of these loci represent a potential source of co-dominant markers for evolutionary, ecological and conservation studies in this important orchid genus.

  15. Pathway analysis supports association of nonsyndromic cryptorchidism with genetic loci linked to cytoskeleton-dependent functions.

    Science.gov (United States)

    Barthold, Julia Spencer; Wang, Yanping; Kolon, Thomas F; Kollin, Claude; Nordenskjöld, Agneta; Olivant Fisher, Alicia; Figueroa, T Ernesto; BaniHani, Ahmad H; Hagerty, Jennifer A; Gonzaléz, Ricardo; Noh, Paul H; Chiavacci, Rosetta M; Harden, Kisha R; Abrams, Debra J; Kim, Cecilia E; Li, Jin; Hakonarson, Hakon; Devoto, Marcella

    2015-10-01

    in normal and cryptorchid rat gubernaculum, were also significantly overrepresented. No tested marker showed significant replication in an independent population. The results suggest heterogeneous, multilocus and potentially multifactorial susceptibility to nonsyndromic cryptorchidism. The present study failed to identify genome-wide significant markers associated with cryptorchidism that could be replicated in an independent population, so further studies are required to define true positive signals among suggestive loci. As the only GWAS to date of nonsyndromic cryptorchidism, these data will provide a basis for future efforts to understand genetic susceptibility to this common reproductive anomaly and the potential for additive risk from environmental exposures. This work was supported by R01HD060769 (the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD)), P20RR20173 (the National Center for Research Resources (NCRR), currently P20GM103464 from the National Institute of General Medical Sciences (NIGMS)), an Institute Development Fund to the Center for Applied Genomics at The Children's Hospital of Philadelphia, and Nemours Biomedical Research. The authors have no competing interests to declare. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. An X chromosome association scan of the Norfolk Island genetic isolate provides evidence for a novel migraine susceptibility locus at Xq12.

    Directory of Open Access Journals (Sweden)

    Bridget H Maher

    Full Text Available Migraine is a common and debilitating neurovascular disorder with a complex envirogenomic aetiology. Numerous studies have demonstrated a preponderance of women affected with migraine and previous pedigree linkage studies in our laboratory have identified susceptibility loci on chromosome Xq24-Xq28. In this study we have used the genetic isolate of Norfolk Island to further analyse the X chromosome for migraine susceptibility loci.An association approach was employed to analyse 14,124 SNPs spanning the entire X chromosome. Genotype data from 288 individuals comprising a large core-pedigree, of which 76 were affected with migraine, were analysed. Although no SNP reached chromosome-wide significance (empirical α = 1 × 10(-5 ranking by P-value revealed two primary clusters of SNPs in the top 25. A 10 SNP cluster represents a novel migraine susceptibility locus at Xq12 whilst a 11 SNP cluster represents a previously identified migraine susceptibility locus at Xq27. The strongest association at Xq12 was seen for rs599958 (OR = 1.75, P = 8.92 × 10(-4, whilst at Xq27 the strongest association was for rs6525667 (OR = 1.53, P = 1.65 × 10(-4. Further analysis of SNPs at these loci was performed in 5,122 migraineurs from the Women's Genome Health Study and provided additional evidence for association at the novel Xq12 locus (P<0.05.Overall, this study provides evidence for a novel migraine susceptibility locus on Xq12. The strongest effect SNP (rs102834, joint P = 1.63 × 10(-5 is located within the 5'UTR of the HEPH gene, which is involved in iron homeostasis in the brain and may represent a novel pathway for involvement in migraine pathogenesis.

  17. Polymorphic microsatellite loci identified through development and cross-species amplification within shorebirds

    Science.gov (United States)

    Williams, I.; Guzzetti, B.M.; Gust, Judy R.; Sage, G.K.; Gill, R.E.; Tibbitts, T.L.; Sonsthagen, S.A.; Talbot, S.L.

    2012-01-01

    We developed microsatellite loci for demographic assessments of shorebirds, a group with limited markers. First, we isolated five dinucleotide repeat microsatellite loci from the Black Oystercatcher (Haematopodidae: Haematopus bachmani), and three from the Bristle-thighed Curlew (Scolopacidae: Numenius tahitiensis); both species are of conservation concern. All eight loci were polymorphic in their respective target species. Hbaμ loci were characterized by two to three alleles with observed heterozygosity ranging from 0.07 to 0.33, and two to nine alleles were detected for Nut loci with observed heterozygosity ranging from 0.08 to 0.72. No linkage disequilibrium or departures from Hardy–Weinberg equilibrium were observed. The eight loci were also tested for cross-species amplification in 12 other species within Charadriidae and Scolopacidae, and the results demonstrated transferability across several genera. We further tested all 14 species at 12 additional microsatellite markers developed for other shorebirds: Dunlin (Calidris alpina; four loci) and Ruff (Philomachus pugnax; eight loci). Two markers (Hbaμ4 and Ruff6) were polymorphic in 13 species, while two (Calp6 and Ruff9) were monomorphic. The remaining eight markers revealed polymorphism in one to nine species each. Our results provide further evidence that locus Ruff10 is sex-linked, contrary to the initial description. These markers can be used to enhance our understanding of shorebird biology by, for example, helping to determine migratory connectivity among breeding and wintering populations and detecting relatedness among individuals.

  18. Evidence for linkage of migraine in Rolandic epilepsy to known 1q23 FHM2 and novel 17q22 genetic loci.

    Science.gov (United States)

    Addis, L; Chiang, T; Clarke, T; Hardison, H; Kugler, S; Mandelbaum, D E; Novotny, E; Wolf, S; Strug, L J; Pal, D K

    2014-03-01

    Migraine headaches are a common comorbidity in Rolandic epilepsy (RE) and familial aggregation of migraine in RE families suggests a genetic basis not mediated by seizures. We performed a genome-wide linkage analysis of the migraine phenotype in 38 families with RE to localize potential genetic contribution, with a follow-up in an additional 21 families at linked loci. We used two-point and multipoint LOD (logarithm of the odds) score methods for linkage, maximized over genetic models. We found evidence of linkage to migraine at chromosome 17q12-22 [multipoint HLOD (heterogeneity LOD) 4.40, recessive, 99% penetrance], replicated in the second dataset (HLOD 2.61), and suggestive evidence at 1q23.1-23.2, centering over the FHM2 locus (two-point LOD 3.00 and MP HLOD 2.52). Sanger sequencing in 14 migraine-affected individuals found no coding mutations in the FHM2 gene ATP1A2. There was no evidence of pleiotropy for migraine and either reading or speech disorder, or the electroencephalographic endophenotype of RE when the affected definition was redefined as those with migraine or the comorbid phenotype, and pedigrees were reanalyzed for linkage. In summary, we report a novel migraine susceptibility locus at 17q12-22, and a second locus that may contribute to migraine in the general population at 1q23.1-23.2. Comorbid migraine in RE appears genetically influenced, but we did not obtain evidence that the identified susceptibility loci are consistent with pleiotropic effects on other comorbidities in RE. Loci identified here should be fine-mapped in individuals from RE families with migraine, and prioritized for analysis in other types of epilepsy-associated migraine. © 2013 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

  19. Integration of Murine and Human Studies for Mapping Periodontitis Susceptibility.

    Science.gov (United States)

    Nashef, A; Qabaja, R; Salaymeh, Y; Botzman, M; Munz, M; Dommisch, H; Krone, B; Hoffmann, P; Wellmann, J; Laudes, M; Berger, K; Kocher, T; Loos, B; van der Velde, N; Uitterlinden, A G; de Groot, L C P G M; Franke, A; Offenbacher, S; Lieb, W; Divaris, K; Mott, R; Gat-Viks, I; Wiess, E; Schaefer, A; Iraqi, F A; Haddad, Y H

    2017-12-01

    Periodontitis is one of the most common inflammatory human diseases with a strong genetic component. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWASs) of chronic periodontitis (CP) have largely been unsuccessful in identifying common susceptibility factors. A combination of quantitative trait loci (QTL) mapping in mice with association studies in humans has the potential to discover novel risk loci. To this end, we assessed alveolar bone loss in response to experimental periodontal infection in 25 lines (286 mice) from the Collaborative Cross (CC) mouse population using micro-computed tomography (µCT) analysis. The orthologous human chromosomal regions of the significant QTL were analyzed for association using imputed genotype data (OmniExpress BeadChip arrays) derived from case-control samples of aggressive periodontitis (AgP; 896 cases, 7,104 controls) and chronic periodontitis (CP; 2,746 cases, 1,864 controls) of northwest European and European American descent, respectively. In the mouse genome, QTL mapping revealed 2 significant loci (-log P = 5.3; false discovery rate = 0.06) on chromosomes 1 ( Perio3) and 14 ( Perio4). The mapping resolution ranged from ~1.5 to 3 Mb. Perio3 overlaps with a previously reported QTL associated with residual bone volume in F2 cross and includes the murine gene Ccdc121. Its human orthologue showed previously a nominal significant association with CP in humans. Use of variation data from the genomes of the CC founder strains further refined the QTL and suggested 7 candidate genes ( CAPN8, DUSP23, PCDH17, SNORA17, PCDH9, LECT1, and LECT2). We found no evidence of association of these candidates with the human orthologues. In conclusion, the CC populations enabled mapping of confined QTL that confer susceptibility to alveolar bone loss in mice and larger human phenotype-genotype samples and additional expression data from gingival

  20. Genome-wide Association Study Identifies New Loci for Resistance to Leptosphaeria maculans in Canola

    Science.gov (United States)

    Raman, Harsh; Raman, Rosy; Coombes, Neil; Song, Jie; Diffey, Simon; Kilian, Andrzej; Lindbeck, Kurt; Barbulescu, Denise M.; Batley, Jacqueline; Edwards, David; Salisbury, Phil A.; Marcroft, Steve

    2016-01-01

    Key message “We identified both quantitative and quantitative resistance loci to Leptosphaeria maculans, a fungal pathogen, causing blackleg disease in canola. Several genome-wide significant associations were detected at known and new loci for blackleg resistance. We further validated statistically significant associations in four genetic mapping populations, demonstrating that GWAS marker loci are indeed associated with resistance to L. maculans. One of the novel loci identified for the first time, Rlm12, conveys adult plant resistance in canola.” Blackleg, caused by Leptosphaeria maculans, is a significant disease which affects the sustainable production of canola (Brassica napus). This study reports a genome-wide association study based on 18,804 polymorphic SNPs to identify loci associated with qualitative and quantitative resistance to L. maculans. Genomic regions delimited with 694 significant SNP markers, that are associated with resistance evaluated using 12 single spore isolates and pathotypes from four canola stubble were identified. Several significant associations were detected at known disease resistance loci including in the vicinity of recently cloned Rlm2/LepR3 genes, and at new loci on chromosomes A01/C01, A02/C02, A03/C03, A05/C05, A06, A08, and A09. In addition, we validated statistically significant associations on A01, A07, and A10 in four genetic mapping populations, demonstrating that GWAS marker loci are indeed associated with resistance to L. maculans. One of the novel loci identified for the first time, Rlm12, conveys adult plant resistance and mapped within 13.2 kb from Arabidopsis R gene of TIR-NBS class. We showed that resistance loci are located in the vicinity of R genes of Arabidopsis thaliana and Brassica napus on the sequenced genome of B. napus cv. Darmor-bzh. Significantly associated SNP markers provide a valuable tool to enrich germplasm for favorable alleles in order to improve the level of resistance to L. maculans in

  1. Genome-wide analysis identifies 12 loci influencing human reproductive behavior

    DEFF Research Database (Denmark)

    Barban, Nicola; Jansen, Rick; de Vlaming, Ronald

    2016-01-01

    The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified......-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits....

  2. Type 2 Diabetes Risk Allele Loci in the Qatari Population.

    Directory of Open Access Journals (Sweden)

    Sarah L O'Beirne

    Full Text Available The prevalence of type 2 diabetes (T2D is increasing in the Middle East. However, the genetic risk factors for T2D in the Middle Eastern populations are not known, as the majority of studies of genetic risk for T2D are in Europeans and Asians.All subjects were ≥3 generation Qataris. Cases with T2D (n = 1,124 and controls (n = 590 were randomly recruited and assigned to the 3 known Qatari genetic subpopulations [Bedouin (Q1, Persian/South Asian (Q2 and African (Q3]. Subjects underwent genotyping for 37 single nucleotide polymorphisms (SNPs in 29 genes known to be associated with T2D in Europeans and/or Asian populations, and an additional 27 tag SNPs related to these susceptibility loci. Pre-study power analysis suggested that with the known incidence of T2D in adult Qataris (22%, the study population size would be sufficient to detect significant differences if the SNPs were risk factors among Qataris, assuming that the odds ratio (OR for T2D SNPs in Qatari's is greater than or equal to the SNP with highest known OR in other populations.Haplotype analysis demonstrated that Qatari haplotypes in the region of known T2D risk alleles in Q1 and Q2 genetic subpopulations were similar to European haplotypes. After Benjamini-Hochberg adjustment for multiple testing, only two SNPs (rs7903146 and rs4506565, both associated with transcription factor 7-like 2 (TCF7L2, achieved statistical significance in the whole study population. When T2D subjects and control subjects were assigned to the known 3 Qatari subpopulations, and analyzed individually and with the Q1 and Q2 genetic subpopulations combined, one of these SNPs (rs4506565 was also significant in the admixed group. No other SNPs associated with T2D in all Qataris or individual genetic subpopulations.With the caveats of the power analysis, the European/Asian T2D SNPs do not contribute significantly to the high prevalence of T2D in the Qatari population, suggesting that the genetic risks for T2D are

  3. Hundreds of variants clustered in genomic loci and biological pathways affect human height

    Science.gov (United States)

    Lango Allen, Hana; Estrada, Karol; Lettre, Guillaume; Berndt, Sonja I.; Weedon, Michael N.; Rivadeneira, Fernando; Willer, Cristen J.; Jackson, Anne U.; Vedantam, Sailaja; Raychaudhuri, Soumya; Ferreira, Teresa; Wood, Andrew R.; Weyant, Robert J.; Segrè, Ayellet V.; Speliotes, Elizabeth K.; Wheeler, Eleanor; Soranzo, Nicole; Park, Ju-Hyun; Yang, Jian; Gudbjartsson, Daniel; Heard-Costa, Nancy L.; Randall, Joshua C.; Qi, Lu; Smith, Albert Vernon; Mägi, Reedik; Pastinen, Tomi; Liang, Liming; Heid, Iris M.; Luan, Jian'an; Thorleifsson, Gudmar; Winkler, Thomas W.; Goddard, Michael E.; Lo, Ken Sin; Palmer, Cameron; Workalemahu, Tsegaselassie; Aulchenko, Yurii S.; Johansson, Åsa; Zillikens, M.Carola; Feitosa, Mary F.; Esko, Tõnu; Johnson, Toby; Ketkar, Shamika; Kraft, Peter; Mangino, Massimo; Prokopenko, Inga; Absher, Devin; Albrecht, Eva; Ernst, Florian; Glazer, Nicole L.; Hayward, Caroline; Hottenga, Jouke-Jan; Jacobs, Kevin B.; Knowles, Joshua W.; Kutalik, Zoltán; Monda, Keri L.; Polasek, Ozren; Preuss, Michael; Rayner, Nigel W.; Robertson, Neil R.; Steinthorsdottir, Valgerdur; Tyrer, Jonathan P.; Voight, Benjamin F.; Wiklund, Fredrik; Xu, Jianfeng; Zhao, Jing Hua; Nyholt, Dale R.; Pellikka, Niina; Perola, Markus; Perry, John R.B.; Surakka, Ida; Tammesoo, Mari-Liis; Altmaier, Elizabeth L.; Amin, Najaf; Aspelund, Thor; Bhangale, Tushar; Boucher, Gabrielle; Chasman, Daniel I.; Chen, Constance; Coin, Lachlan; Cooper, Matthew N.; Dixon, Anna L.; Gibson, Quince; Grundberg, Elin; Hao, Ke; Junttila, M. Juhani; Kaplan, Lee M.; Kettunen, Johannes; König, Inke R.; Kwan, Tony; Lawrence, Robert W.; Levinson, Douglas F.; Lorentzon, Mattias; McKnight, Barbara; Morris, Andrew P.; Müller, Martina; Ngwa, Julius Suh; Purcell, Shaun; Rafelt, Suzanne; Salem, Rany M.; Salvi, Erika; Sanna, Serena; Shi, Jianxin; Sovio, Ulla; Thompson, John R.; Turchin, Michael C.; Vandenput, Liesbeth; Verlaan, Dominique J.; Vitart, Veronique; White, Charles C.; Ziegler, Andreas; Almgren, Peter; Balmforth, Anthony J.; Campbell, Harry; Citterio, Lorena; De Grandi, Alessandro; Dominiczak, Anna; Duan, Jubao; Elliott, Paul; Elosua, Roberto; Eriksson, Johan G.; Freimer, Nelson B.; Geus, Eco J.C.; Glorioso, Nicola; Haiqing, Shen; Hartikainen, Anna-Liisa; Havulinna, Aki S.; Hicks, Andrew A.; Hui, Jennie; Igl, Wilmar; Illig, Thomas; Jula, Antti; Kajantie, Eero; Kilpeläinen, Tuomas O.; Koiranen, Markku; Kolcic, Ivana; Koskinen, Seppo; Kovacs, Peter; Laitinen, Jaana; Liu, Jianjun; Lokki, Marja-Liisa; Marusic, Ana; Maschio, Andrea; Meitinger, Thomas; Mulas, Antonella; Paré, Guillaume; Parker, Alex N.; Peden, John F.; Petersmann, Astrid; Pichler, Irene; Pietiläinen, Kirsi H.; Pouta, Anneli; Ridderstråle, Martin; Rotter, Jerome I.; Sambrook, Jennifer G.; Sanders, Alan R.; Schmidt, Carsten Oliver; Sinisalo, Juha; Smit, Jan H.; Stringham, Heather M.; Walters, G.Bragi; Widen, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Zagato, Laura; Zgaga, Lina; Zitting, Paavo; Alavere, Helene; Farrall, Martin; McArdle, Wendy L.; Nelis, Mari; Peters, Marjolein J.; Ripatti, Samuli; van Meurs, Joyce B.J.; Aben, Katja K.; Ardlie, Kristin G; Beckmann, Jacques S.; Beilby, John P.; Bergman, Richard N.; Bergmann, Sven; Collins, Francis S.; Cusi, Daniele; den Heijer, Martin; Eiriksdottir, Gudny; Gejman, Pablo V.; Hall, Alistair S.; Hamsten, Anders; Huikuri, Heikki V.; Iribarren, Carlos; Kähönen, Mika; Kaprio, Jaakko; Kathiresan, Sekar; Kiemeney, Lambertus; Kocher, Thomas; Launer, Lenore J.; Lehtimäki, Terho; Melander, Olle; Mosley, Tom H.; Musk, Arthur W.; Nieminen, Markku S.; O'Donnell, Christopher J.; Ohlsson, Claes; Oostra, Ben; Palmer, Lyle J.; Raitakari, Olli; Ridker, Paul M.; Rioux, John D.; Rissanen, Aila; Rivolta, Carlo; Schunkert, Heribert; Shuldiner, Alan R.; Siscovick, David S.; Stumvoll, Michael; Tönjes, Anke; Tuomilehto, Jaakko; van Ommen, Gert-Jan; Viikari, Jorma; Heath, Andrew C.; Martin, Nicholas G.; Montgomery, Grant W.; Province, Michael A.; Kayser, Manfred; Arnold, Alice M.; Atwood, Larry D.; Boerwinkle, Eric; Chanock, Stephen J.; Deloukas, Panos; Gieger, Christian; Grönberg, Henrik; Hall, Per; Hattersley, Andrew T.; Hengstenberg, Christian; Hoffman, Wolfgang; Lathrop, G.Mark; Salomaa, Veikko; Schreiber, Stefan; Uda, Manuela; Waterworth, Dawn; Wright, Alan F.; Assimes, Themistocles L.; Barroso, Inês; Hofman, Albert; Mohlke, Karen L.; Boomsma, Dorret I.; Caulfield, Mark J.; Cupples, L.Adrienne; Erdmann, Jeanette; Fox, Caroline S.; Gudnason, Vilmundur; Gyllensten, Ulf; Harris, Tamara B.; Hayes, Richard B.; Jarvelin, Marjo-Riitta; Mooser, Vincent; Munroe, Patricia B.; Ouwehand, Willem H.; Penninx, Brenda W.; Pramstaller, Peter P.; Quertermous, Thomas; Rudan, Igor; Samani, Nilesh J.; Spector, Timothy D.; Völzke, Henry; Watkins, Hugh; Wilson, James F.; Groop, Leif C.; Haritunians, Talin; Hu, Frank B.; Kaplan, Robert C.; Metspalu, Andres; North, Kari E.; Schlessinger, David; Wareham, Nicholas J.; Hunter, David J.; O'Connell, Jeffrey R.; Strachan, David P.; Wichmann, H.-Erich; Borecki, Ingrid B.; van Duijn, Cornelia M.; Schadt, Eric E.; Thorsteinsdottir, Unnur; Peltonen, Leena; Uitterlinden, André; Visscher, Peter M.; Chatterjee, Nilanjan; Loos, Ruth J.F.; Boehnke, Michael; McCarthy, Mark I.; Ingelsson, Erik; Lindgren, Cecilia M.; Abecasis, Gonçalo R.; Stefansson, Kari; Frayling, Timothy M.; Hirschhorn, Joel N

    2010-01-01

    Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence phenotype. Genome-wide association (GWA) studies have identified >600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the utility of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait2,3. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P=0.016), and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants, and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented amongst variants that alter amino acid structure of proteins and expression levels of nearby genes. Our data explain ∼10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to ∼16% of phenotypic variation (∼20% of heritable variation). Although additional approaches are needed to fully dissect the genetic architecture of polygenic human traits, our findings indicate that GWA studies can identify large numbers of loci that

  4. Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor

    NARCIS (Netherlands)

    Wang, Z.; McGlynn, K.A.; Rajpert- de Meyts, E.; Bishop, D.T.; Chung, C.C.; Dalgaard, M.D.; Greene, M.H.; Gupta, R; Grotmol, T.; Haugen, T.B.; Karlsson, R.; Litchfield, K.; Mitra, N.; Nielsen, K.; Pyle, L.C.; Schwartz, S.M.; Thorsson, V.; Vardhanabhuti, S.; Wiklund, F.; Turnbull, C.; Chanock, S.J.; Kanetsky, P.A.; Nathanson, K.L.; Kiemeney, B.; Skotheim, R.I.; Zheng, T.

    2017-01-01

    The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the first

  5. Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes

    DEFF Research Database (Denmark)

    Imamura, Minako; Takahashi, Atsushi; Yamauchi, Toshimasa

    2016-01-01

    Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and ...

  6. Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor

    DEFF Research Database (Denmark)

    Wang, Zhaoming; McGlynn, Katherine A.; Rajpert-De Meyts, Ewa

    2017-01-01

    The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the fi...

  7. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

    NARCIS (Netherlands)

    Nalls, Mike A.; Pankratz, Nathan; Lill, Christina M.; Do, Chuong B.; Hernandez, Dena G.; Saad, Mohamad; DeStefano, Anita L.; Kara, Eleanna; Bras, Jose; Sharma, Manu; Schulte, Claudia; Keller, Margaux F.; Arepalli, Sampath; Letson, Christopher; Edsall, Connor; Stefansson, Hreinn; Liu, Xinmin; Pliner, Hannah; Lee, Joseph H.; Cheng, Rong; Ikram, M. Arfan; Ioannidis, John P. A.; Hadjigeorgiou, Georgios M.; Bis, Joshua C.; Martinez, Maria; Perlmutter, Joel S.; Goate, Alison; Marder, Karen; Fiske, Brian; Sutherland, Margaret; Xiromerisiou, Georgia; Myers, Richard H.; Clark, Lorraine N.; Stefansson, Kari; Hardy, John A.; Heutink, Peter; Chen, Honglei; Wood, Nicholas W.; Houlden, Henry; Payami, Haydeh; Brice, Alexis; Scott, William K.; Gasser, Thomas; Bertram, Lars; Eriksson, Nicholas; Foroud, Tatiana; Singleton, Andrew B.; Plagnol, Vincent; Sheerin, Una-Marie; Simón-Sánchez, Javier; Lesage, Suzanne; Sveinbjörnsdóttir, Sigurlaug; Barker, Roger; Ben-Shlomo, Yoav; Berendse, Henk W.; Berg, Daniela; Bhatia, Kailash; de Bie, Rob M. A.; Biffi, Alessandro; Bloem, Bas; Bochdanovits, Zoltan; Bonin, Michael; Bras, Jose M.; Brockmann, Kathrin; Brooks, Janet; Burn, David J.; Charlesworth, Gavin; Chinnery, Patrick F.; Chong, Sean; Clarke, Carl E.; Cookson, Mark R.; Cooper, J. Mark; Corvol, Jean Christophe; Counsell, Carl; Damier, Philippe; Dartigues, Jean-François; Deloukas, Panos; Deuschl, Günther; Dexter, David T.; van Dijk, Karin D.; Dillman, Allissa; Durif, Frank; Dürr, Alexandra; Edkins, Sarah; Evans, Jonathan R.; Foltynie, Thomas; Dong, Jing; Gardner, Michelle; Gibbs, J. Raphael; Gray, Emma; Guerreiro, Rita; Harris, Clare; van Hilten, Jacobus J.; Hofman, Albert; Hollenbeck, Albert; Holton, Janice; Hu, Michele; Huang, Xuemei; Wurster, Isabel; Mätzler, Walter; Hudson, Gavin; Hunt, Sarah E.; Huttenlocher, Johanna; Illig, Thomas; Jónsson, Pálmi V.; Lambert, Jean-Charles; Langford, Cordelia; Lees, Andrew; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; McNeill, Alisdair; Moorby, Catriona; Moore, Matthew; Morris, Huw R.; Morrison, Karen E.; Mudanohwo, Ese; O'Sullivan, Sean S.; Pearson, Justin; Pétursson, Hjörvar; Pollak, Pierre; Post, Bart; Potter, Simon; Ravina, Bernard; Revesz, Tamas; Riess, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Sawcer, Stephen; Schapira, Anthony; Scheffer, Hans; Shaw, Karen; Shoulson, Ira; Sidransky, Ellen; Smith, Colin; Spencer, Chris C. A.; Stefánsson, Hreinn; Bettella, Francesco; Stockton, Joanna D.; Strange, Amy; Talbot, Kevin; Tanner, Carlie M.; Tashakkori-Ghanbaria, Avazeh; Tison, François; Trabzuni, Daniah; Traynor, Bryan J.; Uitterlinden, André G.; Velseboer, Daan; Vidailhet, Marie; Walker, Robert; van de Warrenburg, Bart; Wickremaratchi, Mirdhu; Williams, Nigel; Williams-Gray, Caroline H.; Winder-Rhodes, Sophie; Stefánsson, Kári; Hardy, John; Factor, S.; Higgins, D.; Evans, S.; Shill, H.; Stacy, M.; Danielson, J.; Marlor, L.; Williamson, K.; Jankovic, J.; Hunter, C.; Simon, D.; Ryan, P.; Scollins, L.; Saunders-Pullman, R.; Boyar, K.; Costan-Toth, C.; Ohmann, E.; Sudarsky, L.; Joubert, C.; Friedman, J.; Chou, K.; Fernandez, H.; Lannon, M.; Galvez-Jimenez, N.; Podichetty, A.; Thompson, K.; Lewitt, P.; Deangelis, M.; O'Brien, C.; Seeberger, L.; Dingmann, C.; Judd, D.; Marder, K.; Fraser, J.; Harris, J.; Bertoni, J.; Peterson, C.; Rezak, M.; Medalle, G.; Chouinard, S.; Panisset, M.; Hall, J.; Poiffaut, H.; Calabrese, V.; Roberge, P.; Wojcieszek, J.; Belden, J.; Jennings, D.; Marek, K.; Mendick, S.; Reich, S.; Dunlop, B.; Jog, M.; Horn, C.; Uitti, R.; Turk, M.; Ajax, T.; Mannetter, J.; Sethi, K.; Carpenter, J.; Dill, B.; Hatch, L.; Ligon, K.; Narayan, S.; Blindauer, K.; Abou-Samra, K.; Petit, J.; Elmer, L.; Aiken, E.; Davis, K.; Schell, C.; Wilson, S.; Velickovic, M.; Koller, W.; Phipps, S.; Feigin, A.; Gordon, M.; Hamann, J.; Licari, E.; Marotta-Kollarus, M.; Shannon, B.; Winnick, R.; Simuni, T.; Videnovic, A.; Kaczmarek, A.; Williams, K.; Wolff, M.; Rao, J.; Cook, M.; Fernandez, M.; Kostyk, S.; Hubble, J.; Campbell, A.; Reider, C.; Seward, A.; Camicioli, R.; Carter, J.; Nutt, J.; Andrews, P.; Morehouse, S.; Stone, C.; Mendis, T.; Grimes, D.; Alcorn-Costa, C.; Gray, P.; Haas, K.; Vendette, J.; Sutton, J.; Hutchinson, B.; Young, J.; Rajput, A.; Klassen, L.; Shirley, T.; Manyam, B.; Simpson, P.; Whetteckey, J.; Wulbrecht, B.; Truong, D.; Pathak, M.; Frei, K.; Luong, N.; Tra, T.; Tran, A.; Vo, J.; Lang, A.; Kleiner- Fisman, G.; Nieves, A.; Johnston, L.; So, J.; Podskalny, G.; Giffin, L.; Atchison, P.; Allen, C.; Martin, W.; Wieler, M.; Suchowersky, O.; Furtado, S.; Klimek, M.; Hermanowicz, N.; Niswonger, S.; Shults, C.; Fontaine, D.; Aminoff, M.; Christine, C.; Diminno, M.; Hevezi, J.; Dalvi, A.; Kang, U.; Richman, J.; Uy, S.; Sahay, A.; Gartner, M.; Schwieterman, D.; Hall, D.; Leehey, M.; Culver, S.; Derian, T.; Demarcaida, T.; Thurlow, S.; Rodnitzky, R.; Dobson, J.; Lyons, K.; Pahwa, R.; Gales, T.; Thomas, S.; Shulman, L.; Weiner, W.; Dustin, K.; Singer, C.; Zelaya, L.; Tuite, P.; Hagen, V.; Rolandelli, S.; Schacherer, R.; Kosowicz, J.; Gordon, P.; Werner, J.; Serrano, C.; Roque, S.; Kurlan, R.; Berry, D.; Gardiner, I.; Hauser, R.; Sanchez-Ramos, J.; Zesiewicz, T.; Delgado, H.; Price, K.; Rodriguez, P.; Wolfrath, S.; Pfeiffer, R.; Davis, L.; Pfeiffer, B.; Dewey, R.; Hayward, B.; Johnson, A.; Meacham, M.; Estes, B.; Walker, F.; Hunt, V.; O'Neill, C.; Racette, B.; Swisher, L.; Dijamco, Cheri; Conley, Emily Drabant; Dorfman, Elizabeth; Tung, Joyce Y.; Hinds, David A.; Mountain, Joanna L.; Wojcicki, Anne; Lew, M.; Klein, C.; Golbe, L.; Growdon, J.; Wooten, G. F.; Watts, R.; Guttman, M.; Goldwurm, S.; Saint-Hilaire, M. H.; Baker, K.; Litvan, I.; Nicholson, G.; Nance, M.; Drasby, E.; Isaacson, S.; Burn, D.; Pramstaller, P.; Al-hinti, J.; Moller, A.; Sherman, S.; Roxburgh, R.; Slevin, J.; Perlmutter, J.; Mark, M. H.; Huggins, N.; Pezzoli, G.; Massood, T.; Itin, I.; Corbett, A.; Chinnery, P.; Ostergaard, K.; Snow, B.; Cambi, F.; Kay, D.; Samii, A.; Agarwal, P.; Roberts, J. W.; Higgins, D. S.; Molho, Eric; Rosen, Ami; Montimurro, J.; Martinez, E.; Griffith, A.; Kusel, V.; Yearout, D.; Zabetian, C.; Clark, L. N.; Liu, X.; Lee, J. H.; Taub, R. Cheng; Louis, E. D.; Cote, L. J.; Waters, C.; Ford, B.; Fahn, S.; Vance, Jeffery M.; Beecham, Gary W.; Martin, Eden R.; Nuytemans, Karen; Pericak-Vance, Margaret A.; Haines, Jonathan L.; DeStefano, Anita; Seshadri, Sudha; Choi, Seung Hoan; Frank, Samuel; Psaty, Bruce M.; Rice, Kenneth; Longstreth, W. T.; Ton, Thanh G. N.; Jain, Samay; van Duijn, Cornelia M.; Verlinden, Vincent J.; Koudstaal, Peter J.; Singleton, Andrew; Cookson, Mark; Hernandez, Dena; Nalls, Michael; Zonderman, Alan; Ferrucci, Luigi; Johnson, Robert; Longo, Dan; O'Brien, Richard; Traynor, Bryan; Troncoso, Juan; van der Brug, Marcel; Zielke, Ronald; Weale, Michael; Ramasamy, Adaikalavan; Dardiotis, Efthimios; Tsimourtou, Vana; Spanaki, Cleanthe; Plaitakis, Andreas; Bozi, Maria; Stefanis, Leonidas; Vassilatis, Dimitris; Koutsis, Georgios; Panas, Marios; Lunnon, Katie; Lupton, Michelle; Powell, John; Parkkinen, Laura; Ansorge, Olaf

    2014-01-01

    We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were

  8. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

    NARCIS (Netherlands)

    E.K. Speliotes (Elizabeth); C.J. Willer (Cristen); S.I. Berndt (Sonja); K.L. Monda (Keri); G. Thorleifsson (Gudmar); A.U. Jackson (Anne); H.L. Allen; C.M. Lindgren (Cecilia); J. Luan; R. Mägi (Reedik); J.C. Randall (Joshua); S. Vedantam (Sailaja); T.W. Winkler (Thomas); L. Qi (Lu); T. Workalemahu (Tsegaselassie); I.M. Heid (Iris); V. Steinthorsdottir (Valgerdur); H.M. Stringham (Heather); E. Wheeler (Eleanor); A.R. Wood (Andrew); T. Ferreira (Teresa); R.J. Weyant (Robert); A.V. Segrè (Ayellet); K. Eestrada (Karol); L. Liang (Liming); J. Nemesh (James); J.H. Park; S. Gustafsson (Stefan); T.O. Kilpeläinen (Tuomas); J. Yang (Joanna); N. Bouatia-Naji (Nabila); T. Eesko (Tõnu); M.F. Feitosa (Mary Furlan); Z. Kutalik (Zoltán); M. Mangino (Massimo); S. Raychaudhuri (Soumya); A. Scherag (Andre); A.V. Smith (Albert Vernon); R.P. Welch (Ryan); J.H. Zhao (Jing Hua); K.K.H. Aben (Katja); D. Absher (Devin); N. Amin (Najaf); A.L. Dixon (Anna); E. Fisher (Eeva); N.L. Glazer (Nicole); M.E. Goddard (Michael); N.L. Heard-Costa (Nancy); V. Hoesel (Volker); J.J. Hottenga (Jouke Jan); A. Johansson (Åsa); T. Johnson (Toby); S. Ketkar (Shamika); C. Lamina (Claudia); S. Li (Shengxu); M.F. Moffatt (Miriam); R.H. Myers (Richard); N. Narisu (Narisu); J.R.B. Perry (John); M.J. Peters (Marjolein); M. Preuss (Michael); S. Ripatti (Samuli); F. Rivadeneira Ramirez (Fernando); C. Sandholt (Camilla); L.J. Scott (Laura); N.J. Timpson (Nicholas); J.P. Tyrer (Jonathan); S. van Wingerden (Sophie); C.C. White (Charles); F. Wiklund (Fredrik); C. Barlassina (Christina); D.I. Chasman (Daniel); M.N. Cooper (Matthew); J.O. Jansson; R.W. Lawrence (Robert); N. Pellikka (Niina); I. Prokopenko (Inga); J. Shi (Jianxin); E. Thiering (Eelisabeth); H. Alavere (Helene); M.T.S. Alibrandi (Maria); P. Almgren (Peter); A.M. Arnold (Alice); T. Aspelund (Thor); L.D. Atwood (Larry); B. Balkau (Beverley); A.J. Balmforth (Anthony); A.J. Bennett (Amanda); Y. Ben-Shlomo; R.N. Bergman (Richard); S.M. Bergmann (Sven); H. Biebermann (Heike); A.I.F. Blakemore (Alexandra); T. Boes (Tanja); L.L. Bonnycastle (Lori); S.R. Bornstein (Stefan); M.J. Brown (Morris); T.A. Buchanan (Thomas); F. Busonero; H. Campbell (Harry); F.P. Cappuccio (Francesco); C. Cavalcanti-Proença (Christine); Y.D.I. Chen (Yii-Der Ida); C.-M. Chen (Chih-Mei); P.S. Chines (Peter); R. Clarke; L. Coin (Lachlan); J. Connell (John); I.N.M. Day (Ian); M. den Heijer (Martin); J. Duan (Jubao); S. Eebrahim (Shah); P. Eelliott (Paul); R. Eelosua (Roberto); G. Eeiriksdottir (Gudny); M.R. Eerdos (Micheal); J.G. Eeriksson (Johan); M.F. Facheris (Maurizio); S.B. Felix (Stephan); P. Fischer-Posovszky (Pamela); A.R. Folsom (Aaron); N. Friedrich (Nele); N.B. Freimer (Nelson); M. Fu (Mao); S. Gaget (Stefan); P.V. Gejman (Pablo); E.J. Geus (Eeco); C. Gieger (Christian); A.P. Gjesing (Anette); A. Goel (Anuj); P. Goyette (Philippe); H. Grallert (Harald); J. Gräßler (Jürgen); D. Greenawalt (Danielle); C.J. Groves (Christopher); V. Gudnason (Vilmundur); C. Guiducci (Candace); A.L. Hartikainen; N. Hassanali (Neelam); A.S. Hall (Alistair); A.S. Havulinna (Aki); C. Hayward (Caroline); A.C. Heath (Andrew); C. Hengstenberg (Christian); A.A. Hicks (Andrew); A. Hinney (Anke); A. Hofman (Albert); G. Homuth (Georg); J. Hui (Jennie); W. Igl (Wilmar); C. Iribarren (Carlos); B. Isomaa (Bo); K.B. Jacobs (Kevin); I. Jarick (Ivonne); E. Jewell (Eelizabeth); U. John (Ulrich); T. Jørgensen (Torben); P. Jousilahti (Pekka); A. Jula (Antti); M. Kaakinen (Marika); E. Kajantie (Eero); R.C. Kaplan (Robert); S. Kathiresan (Sekar); J. Kettunen (Johannes); L. Kinnunen (Leena); J.W. Knowles (Joshua); I. Kolcic (Ivana); I.R. König (Inke); S. Koskinen (Seppo); P. Kovacs (Peter); J. Kusisto (Johanna); P. Kraft (Peter); K. Kvaløy (Kirsti); J. Laitinen (Jaana); O. Lantieri (Olivier); C. Lanzani (Chiara); L.J. Launer (Lenore); C. Lecoeur (Cécile); T. Lehtimäki (Terho); G. Lettre (Guillaume); J. Liu (Jianjun); M.L. Lokki; M. Lorentzon (Mattias); R.N. Luben (Robert); B. Ludwig (Barbara); P. Manunta (Paolo); D. Marek (Diana); M. Marre (Michel); N.G. Martin (Nicholas); W.L. McArdle (Wendy); M.I. McCarthy (Mark); B. McKnight (Barbara); T. Meitinger (Thomas); O. Melander (Olle); D. Meyre (David); K. Midthjell (Kristian); G.W. Montgomery (Grant); M.A. Morken (Mario); A.D. Morris (Andrew); R. Mulic (Rosanda); J.S. Ngwa; M. Nelis (Mari); M.J. Neville (Matthew); D.R. Nyholt (Dale); C.J. O'Ddonnell (Christopher); S. O'Rahilly (Stephen); K. Ong (Ken); B.A. Oostra (Ben); G. Paré (Guillaume); A.N. Parker (Alex); M. Perola (Markus); I. Pichler (Irene); K.H. Pietilainen (Kirsi Hannele); C.P. Platou (Carl); O. Polasek (Ozren); A. Pouta (Anneli); S. Rafelt (Suzanne); O. Raitakari (Olli); N.W. Rayner (Nigel William); M. Ridderstråle (Martin); W. Rief (Winfried); A. Ruokonen (Aimo); N.R. Robertson (Neil); P. Rzehak (Peter); V. Salomaa (Veikko); A.R. Sanders (Alan); M.S. Sandhu (Manjinder); S. Sanna (Serena); J. Saramies (Jouko); M.J. Savolainen (Markku); S. Schipf (Sabine); S. Schreiber (Stefan); H. Schunkert (Heribert); K. Silander (Kaisa); J. Sinisalo (Juha); D.S. Siscovick (David); J.H. Smit (Jan); N. Soranzo (Nicole); U. Sovio (Ulla); J. Stephens (Jonathan); I. Surakka (Ida); A.J. Swift (Amy); M.L. Tammesoo; J.-C. Tardif (Jean-Claude); M. Teder-Laving (Maris); T.M. Teslovich (Tanya); J.R. Thompson (John); B. Thomson (Brian); A. Tönjes (Anke); T. Tuomi (Tiinamaija); J.B.J. van Meurs (Joyce); G.J. van OMen; V. Vatin (Vincent); J. Viikari (Jorma); S. Visvikis-Siest (Sophie); V. Vitart (Veronique); C.I. Vogel (Carla); B.F. Voight (Benjamin); L. Waite (Lindsay); H. Wallaschofski (Henri); G.B. Walters (Bragi); E. Widen (Elisabeth); S. Wiegand (Susanna); S.H. Wild (Sarah); G.A.H.M. Willemsen (Gonneke); D.R. Witte (Deniel); J.C.M. Witteman (Jacqueline); J. Xu (Jianfeng); Q. Zhang (Qunyuan); L. Zgaga (Lina); A. Ziegler (Andreas); P. Zitting (Paavo); J.P. Beilby (John); I.S. FarOqi (Ssadaf); J. Hebebrand (Johannes); H.V. Huikuri (Heikki); A. James (Alan); M. Kähönen (Mika); D.F. Levinson (Douglas); F. MacCiardi (Fabio); M.S. Nieminen (Markku); C. Ohlsson (Claes); C. Palmer (Cameron); P.M. Ridker (Paul); M. Stumvoll (Michael); J.S. Beckmann (Jacques); H. Boeing (Heiner); E.A. Boerwinkle (Eric); D.I. Boomsma (Dorret); M. Caulfield (Mark); S.J. Chanock (Stephen); F.S. Collins (Francis); L.A. Cupples (Adrienne); J. Eerdmann (Jeanette); P. Frogue (Philippe); H. Grönberg (Henrik); U. Gyllensten (Ulf); T. Hansen (Torben); T.B. Harris (Tamara); A.T. Hattersley (Andrew); R.B. Hayes (Richard); J. Heinrich (Joachim); F.B. Hu (Frank); K. Hveem (Kristian); T. Illig (Thomas); M.R. Järvelin; J. Kaprio (Jaakko); F. Karpe (Fredrik); K-T. Khaw (Kay-Tee); L.A.L.M. Kiemeney (Bart); H. Krude; M. Laakso (Markku); D.A. Lawlor (Debbie); A. Metspalu (Andres); P. Munroe (Patricia); W.H. Ouwehand (Willem); O. Pedersen (Oluf); B.W.J.H. Penninx (Brenda); P.P. Pramstaller (Peter Paul); T. Quertermous (Thomas); T. Reinehr (Thomas); A. Rissanen (Aila); I. Rudan (Igor); N.J. Samani (Nilesh); P.E.H. Schwarz (Peter); A.R. Shuldiner (Alan); T.D. Spector (Timothy); J. Tuomilehto (Jaakko); M. Uda (Manuela); A.G. Uitterlinden (André); T.T. Valle (Timo); M. Wabitsch (Martin); G. Waeber (Gérard); N.J. Wareham (Nick); H. Watkins (Hugh); J.F. Wilson (James); A.F. Wright (Alan); M.C. Zillikens (Carola); N. ChatterjE (Nilanjan); S.A. McCarroll (Steve); S. Purcell (Shaun); E.E. Schadt (Eric); P.M. Visscher (Peter); T.L. Assimes (Themistocles); I.B. Borecki (Ingrid); P. Deloukas (Panagiotis); C.S. Fox (Caroline); L. Groop (Leif); T. Haritunians (Talin); D.J. Hunter (David); K.L. Mohlke (Karen); J.R. O'ConneL (Jeffrey); L. Peltonen (Leena Johanna); D. SchleSinger (David); D.P. Strachan (David); R.M. Watanabe (Richard); C.M. van Duijn (Cornelia); H.E. Wichmann (Heinz Erich); T.M. Frayling (Timothy); U. Thorsteinsdottir (Unnur); G.R. Abecasis (Gonçalo); M. Boehnke (Michael); K. StefanSon (Kari); K.E. North (Kari); M.I. McArthy (Mark); J.N. Hirschhorn (Joel); E. IngelSon (Erik); R.J.F. Loos (Ruth); M.N. Weedon (Michael)

    2010-01-01

    textabstractObesity is globaLy prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined aSociations betwEn body maS index and ĝ̂1/42.8 miLion SNPs in up to 123,865 individuals with targeted foLow up of

  9. Genome-Wide Association Identifies Regulatory Loci Associated with Distinct Local Histogram Emphysema Patterns

    Science.gov (United States)

    Cho, Michael H.; San José Estépar, Raúl; McDonald, Merry-Lynn N.; Laird, Nan; Beaty, Terri H.; Washko, George; Crapo, James D.; Silverman, Edwin K.

    2014-01-01

    Rationale: Emphysema is a heritable trait that occurs in smokers with and without chronic obstructive pulmonary disease. Emphysema occurs in distinct pathologic patterns, but the genetic determinants of these patterns are unknown. Objectives: To identify genetic loci associated with distinct patterns of emphysema in smokers and investigate the regulatory function of these loci. Methods: Quantitative measures of distinct emphysema patterns were generated from computed tomography scans from smokers in the COPDGene Study using the local histogram emphysema quantification method. Genome-wide association studies (GWAS) were performed in 9,614 subjects for five emphysema patterns, and the results were referenced against enhancer and DNase I hypersensitive regions from ENCODE and Roadmap Epigenomics cell lines. Measurements and Main Results: Genome-wide significant associations were identified for seven loci. Two are novel associations (top single-nucleotide polymorphism rs379123 in MYO1D and rs9590614 in VMA8) located within genes that function in cell-cell signaling and cell migration, and five are in loci previously associated with chronic obstructive pulmonary disease susceptibility (HHIP, IREB2/CHRNA3, CYP2A6/ADCK, TGFB2, and MMP12). Five of these seven loci lay within enhancer or DNase I hypersensitivity regions in lung fibroblasts or small airway epithelial cells, respectively. Enhancer enrichment analysis for top GWAS associations (single-nucleotide polymorphisms associated at P emphysema quantified by computed tomography scan. Enhancer regions are significantly enriched among these GWAS results, with pulmonary fibroblasts among the cell types showing the strongest enrichment. PMID:25006744

  10. Identification of risk loci for necrotizing meningoencephalitis in Pug dogs.

    Science.gov (United States)

    Barber, Renee M; Schatzberg, Scott J; Corneveaux, Jason J; Allen, April N; Porter, Brian F; Pruzin, Jeremy J; Platt, Simon R; Kent, Marc; Huentelman, Matthew J

    2011-01-01

    Due to their unique population structure, purebred dogs have emerged as a key model for the study of complex genetic disorders. To evaluate the utility of a newly available high-density canine whole-genome array with >170,000 single nucleotide polymorphisms (SNPs), genome-wide association was performed on a small number of case and control dogs to determine disease susceptibility loci in canine necrotizing meningoencephalitis (NME), a disorder with known non-Mendelian inheritance that shares clinical similarities with atypical variants of multiple sclerosis in humans. Genotyping of 30 NME-affected Pug dogs and 68 healthy control Pugs identified 2 loci associated with NME, including a region within dog leukocyte antigen class II on chromosome 12 that remained significant after Bonferroni correction. Our results support the utility of this high-density SNP array, confirm that dogs are a powerful model for mapping complex genetic disorders and provide important preliminary data to support in depth genetic analysis of NME in numerous affected breeds.

  11. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

    Science.gov (United States)

    Dupuis, Josée; Langenberg, Claudia; Prokopenko, Inga; Saxena, Richa; Soranzo, Nicole; Jackson, Anne U; Wheeler, Eleanor; Glazer, Nicole L; Bouatia-Naji, Nabila; Gloyn, Anna L; Lindgren, Cecilia M; Mägi, Reedik; Morris, Andrew P; Randall, Joshua; Johnson, Toby; Elliott, Paul; Rybin, Denis; Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Henneman, Peter; Grallert, Harald; Dehghan, Abbas; Hottenga, Jouke Jan; Franklin, Christopher S; Navarro, Pau; Song, Kijoung; Goel, Anuj; Perry, John R B; Egan, Josephine M; Lajunen, Taina; Grarup, Niels; Sparsø, Thomas; Doney, Alex; Voight, Benjamin F; Stringham, Heather M; Li, Man; Kanoni, Stavroula; Shrader, Peter; Cavalcanti-Proença, Christine; Kumari, Meena; Qi, Lu; Timpson, Nicholas J; Gieger, Christian; Zabena, Carina; Rocheleau, Ghislain; Ingelsson, Erik; An, Ping; O’Connell, Jeffrey; Luan, Jian'an; Elliott, Amanda; McCarroll, Steven A; Payne, Felicity; Roccasecca, Rosa Maria; Pattou, François; Sethupathy, Praveen; Ardlie, Kristin; Ariyurek, Yavuz; Balkau, Beverley; Barter, Philip; Beilby, John P; Ben-Shlomo, Yoav; Benediktsson, Rafn; Bennett, Amanda J; Bergmann, Sven; Bochud, Murielle; Boerwinkle, Eric; Bonnefond, Amélie; Bonnycastle, Lori L; Borch-Johnsen, Knut; Böttcher, Yvonne; Brunner, Eric; Bumpstead, Suzannah J; Charpentier, Guillaume; Chen, Yii-Der Ida; Chines, Peter; Clarke, Robert; Coin, Lachlan J M; Cooper, Matthew N; Cornelis, Marilyn; Crawford, Gabe; Crisponi, Laura; Day, Ian N M; de Geus, Eco; Delplanque, Jerome; Dina, Christian; Erdos, Michael R; Fedson, Annette C; Fischer-Rosinsky, Antje; Forouhi, Nita G; Fox, Caroline S; Frants, Rune; Franzosi, Maria Grazia; Galan, Pilar; Goodarzi, Mark O; Graessler, Jürgen; Groves, Christopher J; Grundy, Scott; Gwilliam, Rhian; Gyllensten, Ulf; Hadjadj, Samy; Hallmans, Göran; Hammond, Naomi; Han, Xijing; Hartikainen, Anna-Liisa; Hassanali, Neelam; Hayward, Caroline; Heath, Simon C; Hercberg, Serge; Herder, Christian; Hicks, Andrew A; Hillman, David R; Hingorani, Aroon D; Hofman, Albert; Hui, Jennie; Hung, Joe; Isomaa, Bo; Johnson, Paul R V; Jørgensen, Torben; Jula, Antti; Kaakinen, Marika; Kaprio, Jaakko; Kesaniemi, Y Antero; Kivimaki, Mika; Knight, Beatrice; Koskinen, Seppo; Kovacs, Peter; Kyvik, Kirsten Ohm; Lathrop, G Mark; Lawlor, Debbie A; Le Bacquer, Olivier; Lecoeur, Cécile; Li, Yun; Lyssenko, Valeriya; Mahley, Robert; Mangino, Massimo; Manning, Alisa K; Martínez-Larrad, María Teresa; McAteer, Jarred B; McCulloch, Laura J; McPherson, Ruth; Meisinger, Christa; Melzer, David; Meyre, David; Mitchell, Braxton D; Morken, Mario A; Mukherjee, Sutapa; Naitza, Silvia; Narisu, Narisu; Neville, Matthew J; Oostra, Ben A; Orrù, Marco; Pakyz, Ruth; Palmer, Colin N A; Paolisso, Giuseppe; Pattaro, Cristian; Pearson, Daniel; Peden, John F; Pedersen, Nancy L.; Perola, Markus; Pfeiffer, Andreas F H; Pichler, Irene; Polasek, Ozren; Posthuma, Danielle; Potter, Simon C; Pouta, Anneli; Province, Michael A; Psaty, Bruce M; Rathmann, Wolfgang; Rayner, Nigel W; Rice, Kenneth; Ripatti, Samuli; Rivadeneira, Fernando; Roden, Michael; Rolandsson, Olov; Sandbaek, Annelli; Sandhu, Manjinder; Sanna, Serena; Sayer, Avan Aihie; Scheet, Paul; Scott, Laura J; Seedorf, Udo; Sharp, Stephen J; Shields, Beverley; Sigurðsson, Gunnar; Sijbrands, Erik J G; Silveira, Angela; Simpson, Laila; Singleton, Andrew; Smith, Nicholas L; Sovio, Ulla; Swift, Amy; Syddall, Holly; Syvänen, Ann-Christine; Tanaka, Toshiko; Thorand, Barbara; Tichet, Jean; Tönjes, Anke; Tuomi, Tiinamaija; Uitterlinden, André G; van Dijk, Ko Willems; van Hoek, Mandy; Varma, Dhiraj; Visvikis-Siest, Sophie; Vitart, Veronique; Vogelzangs, Nicole; Waeber, Gérard; Wagner, Peter J; Walley, Andrew; Walters, G Bragi; Ward, Kim L; Watkins, Hugh; Weedon, Michael N; Wild, Sarah H; Willemsen, Gonneke; Witteman, Jaqueline C M; Yarnell, John W G; Zeggini, Eleftheria; Zelenika, Diana; Zethelius, Björn; Zhai, Guangju; Zhao, Jing Hua; Zillikens, M Carola; Borecki, Ingrid B; Loos, Ruth J F; Meneton, Pierre; Magnusson, Patrik K E; Nathan, David M; Williams, Gordon H; Hattersley, Andrew T; Silander, Kaisa; Salomaa, Veikko; Smith, George Davey; Bornstein, Stefan R; Schwarz, Peter; Spranger, Joachim; Karpe, Fredrik; Shuldiner, Alan R; Cooper, Cyrus; Dedoussis, George V; Serrano-Ríos, Manuel; Morris, Andrew D; Lind, Lars; Palmer, Lyle J; Hu, Frank B.; Franks, Paul W; Ebrahim, Shah; Marmot, Michael; Kao, W H Linda; Pankow, James S; Sampson, Michael J; Kuusisto, Johanna; Laakso, Markku; Hansen, Torben

    2010-01-01

    Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes. PMID:20081858

  12. Differential pre-amplification of STR loci for fragmented forensic DNA profiling.

    Science.gov (United States)

    Ham, Seon-Kyu; Kim, Se-Yong; Seo, Bo Young; Woo, Kwang-Man; Lee, Seung-Hwan; Choi, Cheol Yong

    2016-11-01

    DNA profiling of short tandem repeats (STR) has been successfully used for the identification of individuals in forensic samples, accidents and natural disasters. However, STR profiling of DNA isolated from old crime scenes and damaged biological samples is difficult due to DNA degradation and fragmentation. Here, we show that pre-amplification of STR loci using biotinylated primers for the STR loci is an efficient strategy to obtain STR profiling results from fragmented forensic samples. Analysis of STR loci with longer amplicon sizes is generally hampered, since these relatively long loci are vulnerable to DNA fragmentation. This problem was overcome by using reduced or increased primer concentrations for loci with shorter or longer amplicon sizes, respectively, in our pre-amplification strategy. In addition, pre-amplification of STR loci into two groups of short or long amplicon size increases the efficiency of STR profiling from highly fragmented forensic DNA samples. Therefore, differential pre-amplification of STR loci is an effective way to obtain DNA profiling results from fragmented forensic samples. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Genetic loci for retinal arteriolar microcirculation.

    Directory of Open Access Journals (Sweden)

    Xueling Sim

    Full Text Available Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5×10(-8. This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11×10(-12 in combined meta-analysis of discovery and replication cohorts. In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

  14. Spare PRELI gene loci: failsafe chromosome insurance?

    Directory of Open Access Journals (Sweden)

    Wenbin Ma

    Full Text Available LEA (late embryogenesis abundant proteins encode conserved N-terminal mitochondrial signal domains and C-terminal (A/TAEKAK motif repeats, long-presumed to confer cell resistance to stress and death cues. This prompted the hypothesis that LEA proteins are central to mitochondria mechanisms that connect bioenergetics with cell responses to stress and death signaling. In support of this hypothesis, recent studies have demonstrated that mammalian LEA protein PRELI can act as a biochemical hub, which upholds mitochondria energy metabolism, while concomitantly promoting B cell resistance to stress and induced death. Hence, it is important to define in vivo the physiological relevance of PRELI expression.Given the ubiquitous PRELI expression during mouse development, embryo lethality could be anticipated. Thus, conditional gene targeting was engineered by insertion of flanking loxP (flox/Cre recognition sites on PRELI chromosome 13 (Chr 13 locus to abort its expression in a tissue-specific manner. After obtaining mouse lines with homozygous PRELI floxed alleles (PRELI(f/f, the animals were crossed with CD19-driven Cre-recombinase transgenic mice to investigate whether PRELI inactivation could affect B-lymphocyte physiology and survival. Mice with homozygous B cell-specific PRELI deletion (CD19-Cre/Chr13 PRELI(-/- bred normally and did not show any signs of morbidity. Histopathology and flow cytometry analyses revealed that cell lineage identity, morphology, and viability were indistinguishable between wild type CD19-Cre/Chr13 PRELI(+/+ and CD19-Cre/Chr13 PRELI(-/- deficient mice. Furthermore, B cell PRELI gene expression seemed unaffected by Chr13 PRELI gene targeting. However, identification of additional PRELI loci in mouse Chr1 and Chr5 provided an explanation for the paradox between LEA-dependent cytoprotection and the seemingly futile consequences of Chr 13 PRELI gene inactivation. Importantly, PRELI expression from spare gene loci appeared ample

  15. Complex loci in human and mouse genomes

    OpenAIRE

    Engstroem, P.G.; Suzuki, H.; Ninomiya, N.; Akalin, A.; Sessa, L.; Lavorgna, G.; Brozzi, A.; Luzi, L.; Tan, S.L.; Yang, L.; Kunarso, G.; Ng, E.L.C.; Batalov, S.; Wahlestedt, C.; Kai, C.

    2006-01-01

    Mammalian genomes harbor a larger than expected number of complex loci, in which multiple genes are coupled by shared transcribed regions in antisense orientation and/or by bidirectional core promoters. To determine the incidence, functional significance, and evolutionary context of mammalian complex loci, we identified and characterized 5,248 cis–antisense pairs, 1,638 bidirectional promoters, and 1,153 chains of multiple cis–antisense and/or bidirectionally promoted pairs from 36,606 mouse ...

  16. OS046. Genome-wide association scans identify novel maternalsusceptibility loci for preeclampsia.

    Science.gov (United States)

    Johnson, M; Brennecke, S; Iversen, A-C; East, C; Olsen, G; Kent, J; Dyer, T; Said, J; Roten, L; Abraham, L; Zwart, J-A; Winsvold, B; Håberg, A; Huentelman, M; Krokan, H; Gabrielsen, M; Austgulen, R; Blangero, J; Moses, E

    2012-07-01

    We have successfully utilized a family-based study design to localize several positional candidate preeclampsia susceptibility genes to chromosomes 2q22(ACVR2A,LCT,LRP1B,RND3,GCA),5q (ERAP2) and 13q(TNFSF13B). We now report on our continued positional cloning efforts using an alternative genome-wide association (GWA) mapping strategy in large Caucasian case-control cohorts from Australia and Norway. To identify maternal genetic risk loci for preeclampsia. The unrelated Australian samples (545 cases,547 controls) were genotyped using Illumina BeadChip technology (700K loci) and have been analyzed using PLINK. All unrelated Norwegian samples were genotyped across several Illumina BeadChip substrates and consist of 847 cases (700K loci) and 638 controls. The Norwegian control samples originate from other HUNT studies pertaining to migraine (n=95,700K loci), lung cancer (n=89,370K loci) and normal brain pathology (n=454,2.5M loci). To analyze a concordant set of 2.5-3 million genotypes across all Norwegian samples we are currently using MaCH to impute those loci not directly genotyped. The Norwegian GWA data will be analyzed in SOLAR utilizing empirical kinship estimates to account for any distant relatedness. 1078 Australian samples (538 cases,540 controls) and 648, 175 SNPs passed our quality control metrics. Two SNP associations (rs7579169,p=3.6×10(-7); rs12711941,p=4.3×10(-7)) satisfied our genome-wide significant threshold (p1.56) and are in strong linkage disequilibrium with each other (r(2)>0.9) but not with any other genotyped SNP ±200kb. The analysis of the Norwegian GWAS is underway. The Australian GWAS has identified a novel preeclampsia risk locus on chromosome 2q. The INHBB gene closest to our SNP associations is a plausible positional candidate susceptibility gene. There is a substantive body of evidence implicating inhibins, activins and other members of the TGF-βsuperfamily to have a role in the development of preeclampsia. The biological connection

  17. Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS.

    Directory of Open Access Journals (Sweden)

    Frank P Diekstra

    Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls. These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls. Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 × 10(-51 withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible

  18. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci

    Science.gov (United States)

    Cortes, Adrian; Hadler, Johanna; Pointon, Jenny P; Robinson, Philip C; Karaderi, Tugce; Leo, Paul; Cremin, Katie; Pryce, Karena; Harris, Jessica; lee, Seunghun; Joo, Kyung Bin; Shim, Seung-Cheol; Weisman, Michael; Ward, Michael; Zhou, Xiaodong; Garchon, Henri-Jean; Chiocchia, Gilles; Nossent, Johannes; Lie, Benedicte A; Førre, Øystein; Tuomilehto, Jaakko; Laiho, Kari; Jiang, Lei; Liu, Yu; Wu, Xin; Bradbury, Linda A; Elewaut, Dirk; Burgos-Vargas, Ruben; Stebbings, Simon; Appleton, Louise; Farrah, Claire; Lau, Jonathan; Kenna, Tony J; Haroon, Nigil; Ferreira, Manuel A; Yang, Jian; Mulero, Juan; Fernandez-Sueiro, Jose Luis; Gonzalez-Gay, Miguel A; lopez-Larrea, Carlos; Deloukas, Panos; Donnelly, Peter; Bowness, Paul; Gafney, Karl; Gaston, Hill; Gladman, Dafna D; Rahman, Proton; Maksymowych, Walter P; Xu, Huji; Crusius, J Bart A; van der Horst-Bruinsma, Irene E; Chou, Chung-Tei; Valle-Oñate, Raphael; Romero-Sánchez, Consuelo; Hansen, Inger Myrnes; Pimentel-Santos, Fernando M; Inman, Robert D; Videm, Vibeke; Martin, Javier; Breban, Maxime; Reveille, John D; Evans, David M; Kim, Tae-Hwan; Wordsworth, Bryan Paul; Brown, Matthew A

    2013-01-01

    Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis–associated haplotypes at 11 loci. Two ankylosing spondylitis–associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression. PMID:23749187

  19. X Chromosome-wide Association Study Identifies a Susceptibility Locus for Inflammatory Bowel Disease in Koreans.

    Science.gov (United States)

    Lee, Ho-Su; Oh, Hyunjung; Yang, Suk-Kyun; Baek, Jiwon; Jung, Seulgi; Hong, Myunghee; Kim, Kyung Mo; Shin, Hyoung Doo; Kim, Kyung-Jo; Park, Sang Hyoung; Ye, Byong Duk; Han, Buhm; Song, Kyuyoung

    2017-07-01

    Genome-wide association studies of inflammatory bowel disease identified > 200 susceptibility loci only in autosomes. This study aimed to identify inflammatory bowel disease susceptibility loci on the X chromosome. We performed an X chromosome-wide association study in Korean patients with inflammatory bowel disease. We analysed X chromosome data from our recent genome-wide association studies, including 1505 cases [922 Crohn's disease and 583 ulcerative colitis] and 4041 controls during the discovery phase, followed by replication in additional 1989 cases [993 Crohn's disease, 996 ulcerative colitis] and 3491 controls. Sex-related differential effects of single nucleotide polymorphisms on disease were also evaluated. We confirmed a significant association of a previously reported inflammatory bowel disease susceptibility locus at chromosome Xq26.3 [CD40LG-ARHGEF6; odds ratio, 1.22; 95% confidence interval, 1.16-1.28; combined p = 3.79 × 10-15]. This locus accounted for 0.18% and 0.12% of genetic variance in Crohn's disease and ulcerative colitis, respectively, and increased the total autosomal chromosome genetic variance from 6.65% to 6.83% and from 5.47% to 5.59% for Crohn's disease and ulcerative colitis risk, respectively, in the Korean population. Sex-stratified analyses did not reveal sex-related differences in effect sizes. We confirmed the association of rs2427870 at the CD40LG-ARHGEF6 locus with an inflammatory bowel disease through an X chromosome-wide association study in a Korean population. Our data suggest that the CD40LG-ARHGEF6 locus on the X chromosome might play a role in inflammatory bowel disease pathogenesis in the Korean population.

  20. Multi-ethnic genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

    Science.gov (United States)

    Waage, Johannes; Baurecht, Hansjörg; Hotze, Melanie; Strachan, David P; Curtin, John A; Bønnelykke, Klaus; Tian, Chao; Takahashi, Atsushi; Esparza-Gordillo, Jorge; Alves, Alexessander Couto; Thyssen, Jacob P; den Dekker, Herman T; Ferreira, Manuel A; Altmaier, Elisabeth; Sleiman, Patrick MA; Xiao, Feng Li; Gonzalez, Juan R; Marenholz, Ingo; Kalb, Birgit; Yanes, Maria Pino; Xu, Cheng-Jian; Carstensen, Lisbeth; Groen-Blokhuis, Maria M; Venturini, Cristina; Pennell, Craig E; Barton, Sheila J; Levin, Albert M; Curjuric, Ivan; Bustamante, Mariona; Kreiner-Møller, Eskil; Lockett, Gabrielle A; Bacelis, Jonas; Bunyavanich, Supinda; Myers, Rachel A; Matanovic, Anja; Kumar, Ashish; Tung, Joyce Y; Hirota, Tomomitsu; Kubo, Michiaki; McArdle, Wendy L; Henderson, A J; Kemp, John P; Zheng, Jie; Smith, George Davey; Rüschendorf, Franz; Bauerfeind, Anja; Lee-Kirsch, Min Ae; Arnold, Andreas; Homuth, Georg; Schmidt, Carsten O; Mangold, Elisabeth; Cichon, Sven; Keil, Thomas; Rodríguez, Elke; Peters, Annette; Franke, Andre; Lieb, Wolfgang; Novak, Natalija; Fölster-Holst, Regina; Horikoshi, Momoko; Pekkanen, Juha; Sebert, Sylvain; Husemoen, Lise L; Grarup, Niels; de Jongste, Johan C; Rivadeneira, Fernando; Hofman, Albert; Jaddoe, Vincent WV; Pasmans, Suzanne GMA; Elbert, Niels J; Uitterlinden, André G; Marks, Guy B; Thompson, Philip J; Matheson, Melanie C; Robertson, Colin F; Ried, Janina S; Li, Jin; Zuo, Xian Bo; Zheng, Xiao Dong; Yin, Xian Yong; Sun, Liang Dan; McAleer, Maeve A; O'Regan, Grainne M; Fahy, Caoimhe MR; Campbell, Linda E; Macek, Milan; Kurek, Michael; Hu, Donglei; Eng, Celeste; Postma, Dirkje S; Feenstra, Bjarke; Geller, Frank; Hottenga, Jouke Jan; Middeldorp, Christel M; Hysi, Pirro; Bataille, Veronique; Spector, Tim; Tiesler, Carla MT; Thiering, Elisabeth; Pahukasahasram, Badri; Yang, James J; Imboden, Medea; Huntsman, Scott; Vilor-Tejedor, Natàlia; Relton, Caroline L; Myhre, Ronny; Nystad, Wenche; Custovic, Adnan; Weiss, Scott T; Meyers, Deborah A; Söderhäll, Cilla; Melén, Erik; Ober, Carole; Raby, Benjamin A; Simpson, Angela; Jacobsson, Bo; Holloway, John W; Bisgaard, Hans; Sunyer, Jordi; Hensch, Nicole M Probst; Williams, L Keoki; Godfrey, Keith M; Wang, Carol A; Boomsma, Dorret I; Melbye, Mads; Koppelman, Gerard H; Jarvis, Deborah; McLean, WH Irwin; Irvine, Alan D; Zhang, Xue Jun; Hakonarson, Hakon; Gieger, Christian; Burchard, Esteban G; Martin, Nicholas G; Duijts, Liesbeth; Linneberg, Allan; Jarvelin, Marjo-Riitta; Noethen, Markus M; Lau, Susanne; Hübner, Norbert; Lee, Young-Ae; Tamari, Mayumi; Hinds, David A; Glass, Daniel; Brown, Sara J; Heinrich, Joachim; Evans, David M; Weidinger, Stephan

    2015-01-01

    Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified 10 novel risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with novel secondary signals at 4 of these). Notably, the new loci include candidate genes with roles in regulation of innate host defenses and T-cell function, underscoring the important contribution of (auto-)immune mechanisms to atopic dermatitis pathogenesis. PMID:26482879

  1. Genome-wide analysis identifies 12 loci influencing human reproductive behavior

    Science.gov (United States)

    Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J.; Tropf, Felix C.; Shen, Xia; Wilson, James F.; Chasman, Daniel I.; Nolte, Ilja M.; Tragante, Vinicius; van der Laan, Sander W.; Perry, John R. B.; Kong, Augustine; Ahluwalia, Tarunveer; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F.; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J.; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F.; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J.; Gieger, Christian; Gunderson, Erica P.; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K.; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A.; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F.; McMahon, George; Meddens, S. Fleur W.; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A.; Monnereau, Claire; van der Most, Peter J.; Myhre, Ronny; Nalls, Mike A.; Nutile, Teresa; Panagiota, Kalafati Ioanna; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B.; Rich-Edwards, Janet; Rietveld, Cornelius A.; Robino, Antonietta; Rose, Lynda M.; Rueedi, Rico; Ryan, Kathy; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A.; Stolk, Lisette; Streeten, Elizabeth; Tonjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V.; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I.; Buring, Julie E.; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R.; Cucca, Francesco; Daniela, Toniolo; Davey-Smith, George; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M.; de Geus, Eco JC.; Eriksson, Johan G.; Evans, Denis A.; Faul, Jessica D.; Felicita, Sala Cinzia; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J.F.; de Haan, Hugoline G.; Haerting, Johannes; Harris, Tamara B.; Heath, Andrew C.; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G; Hopper, John; Hypponen, Elina; Jacobsson, Bo; Jaddoe, Vincent W. V.; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L.R.; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William; Lai, Sandra; Lehtimäki, Terho; Liewald, David C; Lindgren, Cecilia; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; McQuillan, Ruth; Medland, Sarah E.; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Michela, Traglia; Milani, Lili; Mitchell, Paul; Montgomery, Grant W.; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K.; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda WJH; Perola, Markus; Peyser, Patricia A.; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J.; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M.; Ring, Susan M.; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D.; Starr, John M.; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A.; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tönjes, Anke; Tung, Joyce Y.; Uitterlinden, André G.; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G.; Wang, Jie Jin; Wareham, Nicholas J.; Weir, David R.; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F.; Zondervan, Krina T.; Stefansson, Kari; Krueger, Robert F.; Lee, James J.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C.

    2017-01-01

    The genetic architecture of human reproductive behavior – age at first birth (AFB) and number of children ever born (NEB) – has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified and the underlying mechanisms of AFB and NEB are poorly understood. We report the largest genome-wide association study to date of both sexes including 251,151 individuals for AFB and 343,072 for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study, and four additional loci in a gene-based effort. These loci harbor genes that are likely to play a role – either directly or by affecting non-local gene expression – in human reproduction and infertility, thereby increasing our understanding of these complex traits. PMID:27798627

  2. Modeling susceptibility to periodontitis

    NARCIS (Netherlands)

    Laine, M.L.; Moustakis, V.; Koumakis, L.; Potamias, G.; Loos, B.G.

    2013-01-01

    Chronic inflammatory diseases like periodontitis have a complex pathogenesis and a multifactorial etiology, involving complex interactions between multiple genetic loci and infectious agents. We aimed to investigate the influence of genetic polymorphisms and bacteria on chronic periodontitis risk.

  3. Genetic linkage of endogenous viral loci with the B (MHC) and C histocompatibility loci in chickens.

    Science.gov (United States)

    Plachý, J; Korec, E; Hlozánek, I; Zdĕnková, E

    1985-01-01

    Genetic linkage of endogenous viral loci and histocompatibility loci B (MHC) and C has been demonstrated serologically in backcross progeny of inbred lines of chickens. The endogenous viral locus linked to the B complex is the first case of the localization of an endogenous viral gene to the microchromosomes in chickens.

  4. Genetic evidence of multiple loci in dystocia - difficult labour

    Directory of Open Access Journals (Sweden)

    Westgren Magnus

    2010-06-01

    Full Text Available Abstract Background Dystocia, difficult labour, is a common but also complex problem during childbirth. It can be attributed to either weak contractions of the uterus, a large infant, reduced capacity of the pelvis or combinations of these. Previous studies have indicated that there is a genetic component in the susceptibility of experiencing dystocia. The purpose of this study was to identify susceptibility genes in dystocia. Methods A total of 104 women in 47 families were included where at least two sisters had undergone caesarean section at a gestational length of 286 days or more at their first delivery. Study of medical records and a telephone interview was performed to identify subjects with dystocia. Whole-genome scanning using Affymetrix genotyping-arrays and non-parametric linkage (NPL analysis was made in 39 women exhibiting the phenotype of dystocia from 19 families. In 68 women re-sequencing was performed of candidate genes showing suggestive linkage: oxytocin (OXT on chromosome 20 and oxytocin-receptor (OXTR on chromosome 3. Results We found a trend towards linkage with suggestive NPL-score (3.15 on chromosome 12p12. Suggestive linkage peaks were observed on chromosomes 3, 4, 6, 10, 20. Re-sequencing of OXT and OXTR did not reveal any causal variants. Conclusions Dystocia is likely to have a genetic component with variations in multiple genes affecting the patient outcome. We found 6 loci that could be re-evaluated in larger patient cohorts.

  5. Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease.

    Science.gov (United States)

    Meddens, Claartje A; Harakalova, Magdalena; van den Dungen, Noortje A M; Foroughi Asl, Hassan; Hijma, Hemme J; Cuppen, Edwin P J G; Björkegren, Johan L M; Asselbergs, Folkert W; Nieuwenhuis, Edward E S; Mokry, Michal

    2016-11-30

    Genome-wide association studies (GWAS) have revealed many susceptibility loci for complex genetic diseases. For most loci, the causal genes have not been identified. Currently, the identification of candidate genes is predominantly based on genes that localize close to or within identified loci. We have recently shown that 92 of the 163 inflammatory bowel disease (IBD)-loci co-localize with non-coding DNA regulatory elements (DREs). Mutations in DREs can contribute to IBD pathogenesis through dysregulation of gene expression. Consequently, genes that are regulated by these 92 DREs are to be considered as candidate genes. This study uses circular chromosome conformation capture-sequencing (4C-seq) to systematically analyze chromatin-interactions at IBD susceptibility loci that localize to regulatory DNA. Using 4C-seq, we identify genomic regions that physically interact with the 92 DRE that were found at IBD susceptibility loci. Since the activity of regulatory elements is cell-type specific, 4C-seq was performed in monocytes, lymphocytes, and intestinal epithelial cells. Altogether, we identified 902 novel IBD candidate genes. These include genes specific for IBD-subtypes and many noteworthy genes including ATG9A and IL10RA. We show that expression of many novel candidate genes is genotype-dependent and that these genes are upregulated during intestinal inflammation in IBD. Furthermore, we identify HNF4α as a potential key upstream regulator of IBD candidate genes. We reveal many novel and relevant IBD candidate genes, pathways, and regulators. Our approach complements classical candidate gene identification, links novel genes to IBD and can be applied to any existing GWAS data.

  6. A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13

    DEFF Research Database (Denmark)

    Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R

    2016-01-01

    factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases...

  7. Identification of the tyrosine-protein phosphatase non-receptor type 2 as a rheumatoid arthritis susceptibility locus in europeans

    DEFF Research Database (Denmark)

    Cobb, Joanna E; Plant, Darren; Flynn, Edward

    2013-01-01

    Genome-wide association studies have facilitated the identification of over 30 susceptibility loci for rheumatoid arthritis (RA). However, evidence for a number of potential susceptibility genes have not so far reached genome-wide significance in studies of Caucasian RA....

  8. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation.

    Science.gov (United States)

    Willer, Cristen J; Speliotes, Elizabeth K; Loos, Ruth J F; Li, Shengxu; Lindgren, Cecilia M; Heid, Iris M; Berndt, Sonja I; Elliott, Amanda L; Jackson, Anne U; Lamina, Claudia; Lettre, Guillaume; Lim, Noha; Lyon, Helen N; McCarroll, Steven A; Papadakis, Konstantinos; Qi, Lu; Randall, Joshua C; Roccasecca, Rosa Maria; Sanna, Serena; Scheet, Paul; Weedon, Michael N; Wheeler, Eleanor; Zhao, Jing Hua; Jacobs, Leonie C; Prokopenko, Inga; Soranzo, Nicole; Tanaka, Toshiko; Timpson, Nicholas J; Almgren, Peter; Bennett, Amanda; Bergman, Richard N; Bingham, Sheila A; Bonnycastle, Lori L; Brown, Morris; Burtt, Noël P; Chines, Peter; Coin, Lachlan; Collins, Francis S; Connell, John M; Cooper, Cyrus; Smith, George Davey; Dennison, Elaine M; Deodhar, Parimal; Elliott, Paul; Erdos, Michael R; Estrada, Karol; Evans, David M; Gianniny, Lauren; Gieger, Christian; Gillson, Christopher J; Guiducci, Candace; Hackett, Rachel; Hadley, David; Hall, Alistair S; Havulinna, Aki S; Hebebrand, Johannes; Hofman, Albert; Isomaa, Bo; Jacobs, Kevin B; Johnson, Toby; Jousilahti, Pekka; Jovanovic, Zorica; Khaw, Kay-Tee; Kraft, Peter; Kuokkanen, Mikko; Kuusisto, Johanna; Laitinen, Jaana; Lakatta, Edward G; Luan, Jian'an; Luben, Robert N; Mangino, Massimo; McArdle, Wendy L; Meitinger, Thomas; Mulas, Antonella; Munroe, Patricia B; Narisu, Narisu; Ness, Andrew R; Northstone, Kate; O'Rahilly, Stephen; Purmann, Carolin; Rees, Matthew G; Ridderstråle, Martin; Ring, Susan M; Rivadeneira, Fernando; Ruokonen, Aimo; Sandhu, Manjinder S; Saramies, Jouko; Scott, Laura J; Scuteri, Angelo; Silander, Kaisa; Sims, Matthew A; Song, Kijoung; Stephens, Jonathan; Stevens, Suzanne; Stringham, Heather M; Tung, Y C Loraine; Valle, Timo T; Van Duijn, Cornelia M; Vimaleswaran, Karani S; Vollenweider, Peter; Waeber, Gerard; Wallace, Chris; Watanabe, Richard M; Waterworth, Dawn M; Watkins, Nicholas; Witteman, Jacqueline C M; Zeggini, Eleftheria; Zhai, Guangju; Zillikens, M Carola; Altshuler, David; Caulfield, Mark J; Chanock, Stephen J; Farooqi, I Sadaf; Ferrucci, Luigi; Guralnik, Jack M; Hattersley, Andrew T; Hu, Frank B; Jarvelin, Marjo-Riitta; Laakso, Markku; Mooser, Vincent; Ong, Ken K; Ouwehand, Willem H; Salomaa, Veikko; Samani, Nilesh J; Spector, Timothy D; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Uda, Manuela; Uitterlinden, André G; Wareham, Nicholas J; Deloukas, Panagiotis; Frayling, Timothy M; Groop, Leif C; Hayes, Richard B; Hunter, David J; Mohlke, Karen L; Peltonen, Leena; Schlessinger, David; Strachan, David P; Wichmann, H-Erich; McCarthy, Mark I; Boehnke, Michael; Barroso, Inês; Abecasis, Gonçalo R; Hirschhorn, Joel N

    2009-01-01

    Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

  9. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

    Science.gov (United States)

    Willer, Cristen J; Speliotes, Elizabeth K; Loos, Ruth J F; Li, Shengxu; Lindgren, Cecilia M; Heid, Iris M; Berndt, Sonja I; Elliott, Amanda L; Jackson, Anne U; Lamina, Claudia; Lettre, Guillaume; Lim, Noha; Lyon, Helen N; McCarroll, Steven A; Papadakis, Konstantinos; Qi, Lu; Randall, Joshua C; Roccasecca, Rosa Maria; Sanna, Serena; Scheet, Paul; Weedon, Michael N; Wheeler, Eleanor; Zhao, Jing Hua; Jacobs, Leonie C; Prokopenko, Inga; Soranzo, Nicole; Tanaka, Toshiko; Timpson, Nicholas J; Almgren, Peter; Bennett, Amanda; Bergman, Richard N; Bingham, Sheila A; Bonnycastle, Lori L; Brown, Morris; Burtt, Noël P; Chines, Peter; Coin, Lachlan; Collins, Francis S; Connell, John M; Cooper, Cyrus; Smith, George Davey; Dennison, Elaine M; Deodhar, Parimal; Elliott, Paul; Erdos, Michael R; Estrada, Karol; Evans, David M; Gianniny, Lauren; Gieger, Christian; Gillson, Christopher J; Guiducci, Candace; Hackett, Rachel; Hadley, David; Hall, Alistair S; Havulinna, Aki S; Hebebrand, Johannes; Hofman, Albert; Isomaa, Bo; Jacobs, Kevin B; Johnson, Toby; Jousilahti, Pekka; Jovanovic, Zorica; Khaw, Kay-Tee; Kraft, Peter; Kuokkanen, Mikko; Kuusisto, Johanna; Laitinen, Jaana; Lakatta, Edward G; Luan, Jian'an; Luben, Robert N; Mangino, Massimo; McArdle, Wendy L; Meitinger, Thomas; Mulas, Antonella; Munroe, Patricia B; Narisu, Narisu; Ness, Andrew R; Northstone, Kate; O'Rahilly, Stephen; Purmann, Carolin; Rees, Matthew G; Ridderstråle, Martin; Ring, Susan M; Rivadeneira, Fernando; Ruokonen, Aimo; Sandhu, Manjinder S; Saramies, Jouko; Scott, Laura J; Scuteri, Angelo; Silander, Kaisa; Sims, Matthew A; Song, Kijoung; Stephens, Jonathan; Stevens, Suzanne; Stringham, Heather M; Tung, Y C Loraine; Valle, Timo T; Van Duijn, Cornelia M; Vimaleswaran, Karani S; Vollenweider, Peter; Waeber, Gerard; Wallace, Chris; Watanabe, Richard M; Waterworth, Dawn M; Watkins, Nicholas; Witteman, Jacqueline C M; Zeggini, Eleftheria; Zhai, Guangju; Zillikens, M Carola; Altshuler, David; Caulfield, Mark J; Chanock, Stephen J; Farooqi, I Sadaf; Ferrucci, Luigi; Guralnik, Jack M; Hattersley, Andrew T; Hu, Frank B; Jarvelin, Marjo-Riitta; Laakso, Markku; Mooser, Vincent; Ong, Ken K; Ouwehand, Willem H; Salomaa, Veikko; Samani, Nilesh J; Spector, Timothy D; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Uda, Manuela; Uitterlinden, André G; Wareham, Nicholas J; Deloukas, Panagiotis; Frayling, Timothy M; Groop, Leif C; Hayes, Richard B; Hunter, David J; Mohlke, Karen L; Peltonen, Leena; Schlessinger, David; Strachan, David P; Wichmann, H-Erich; McCarthy, Mark I; Boehnke, Michael; Barroso, Inês; Abecasis, Gonçalo R; Hirschhorn, Joel N

    2009-01-01

    Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10−8): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity. PMID:19079261

  10. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

    Science.gov (United States)

    Scott, Robert A; Lagou, Vasiliki; Welch, Ryan P; Wheeler, Eleanor; Montasser, May E; Luan, Jian’an; Mägi, Reedik; Strawbridge, Rona J; Rehnberg, Emil; Gustafsson, Stefan; Kanoni, Stavroula; Rasmussen-Torvik, Laura J; Yengo, Loïc; Lecoeur, Cecile; Shungin, Dmitry; Sanna, Serena; Sidore, Carlo; Johnson, Paul C D; Jukema, J Wouter; Johnson, Toby; Mahajan, Anubha; Verweij, Niek; Thorleifsson, Gudmar; Hottenga, Jouke-Jan; Shah, Sonia; Smith, Albert V; Sennblad, Bengt; Gieger, Christian; Salo, Perttu; Perola, Markus; Timpson, Nicholas J; Evans, David M; Pourcain, Beate St; Wu, Ying; Andrews, Jeanette S; Hui, Jennie; Bielak, Lawrence F; Zhao, Wei; Horikoshi, Momoko; Navarro, Pau; Isaacs, Aaron; O’Connell, Jeffrey R; Stirrups, Kathleen; Vitart, Veronique; Hayward, Caroline; Esko, Tönu; Mihailov, Evelin; Fraser, Ross M; Fall, Tove; Voight, Benjamin F; Raychaudhuri, Soumya; Chen, Han; Lindgren, Cecilia M; Morris, Andrew P; Rayner, Nigel W; Robertson, Neil; Rybin, Denis; Liu, Ching-Ti; Beckmann, Jacques S; Willems, Sara M; Chines, Peter S; Jackson, Anne U; Kang, Hyun Min; Stringham, Heather M; Song, Kijoung; Tanaka, Toshiko; Peden, John F; Goel, Anuj; Hicks, Andrew A; An, Ping; Müller-Nurasyid, Martina; Franco-Cereceda, Anders; Folkersen, Lasse; Marullo, Letizia; Jansen, Hanneke; Oldehinkel, Albertine J; Bruinenberg, Marcel; Pankow, James S; North, Kari E; Forouhi, Nita G; Loos, Ruth J F; Edkins, Sarah; Varga, Tibor V; Hallmans, Göran; Oksa, Heikki; Antonella, Mulas; Nagaraja, Ramaiah; Trompet, Stella; Ford, Ian; Bakker, Stephan J L; Kong, Augustine; Kumari, Meena; Gigante, Bruna; Herder, Christian; Munroe, Patricia B; Caulfield, Mark; Antti, Jula; Mangino, Massimo; Small, Kerrin; Miljkovic, Iva; Liu, Yongmei; Atalay, Mustafa; Kiess, Wieland; James, Alan L; Rivadeneira, Fernando; Uitterlinden, Andre G; Palmer, Colin N A; Doney, Alex S F; Willemsen, Gonneke; Smit, Johannes H; Campbell, Susan; Polasek, Ozren; Bonnycastle, Lori L; Hercberg, Serge; Dimitriou, Maria; Bolton, Jennifer L; Fowkes, Gerard R; Kovacs, Peter; Lindström, Jaana; Zemunik, Tatijana; Bandinelli, Stefania; Wild, Sarah H; Basart, Hanneke V; Rathmann, Wolfgang; Grallert, Harald; Maerz, Winfried; Kleber, Marcus E; Boehm, Bernhard O; Peters, Annette; Pramstaller, Peter P; Province, Michael A; Borecki, Ingrid B; Hastie, Nicholas D; Rudan, Igor; Campbell, Harry; Watkins, Hugh; Farrall, Martin; Stumvoll, Michael; Ferrucci, Luigi; Waterworth, Dawn M; Bergman, Richard N; Collins, Francis S; Tuomilehto, Jaakko; Watanabe, Richard M; de Geus, Eco J C; Penninx, Brenda W; Hofman, Albert; Oostra, Ben A; Psaty, Bruce M; Vollenweider, Peter; Wilson, James F; Wright, Alan F; Hovingh, G Kees; Metspalu, Andres; Uusitupa, Matti; Magnusson, Patrik K E; Kyvik, Kirsten O; Kaprio, Jaakko; Price, Jackie F; Dedoussis, George V; Deloukas, Panos; Meneton, Pierre; Lind, Lars; Boehnke, Michael; Shuldiner, Alan R; van Duijn, Cornelia M; Morris, Andrew D; Toenjes, Anke; Peyser, Patricia A; Beilby, John P; Körner, Antje; Kuusisto, Johanna; Laakso, Markku; Bornstein, Stefan R; Schwarz, Peter E H; Lakka, Timo A; Rauramaa, Rainer; Adair, Linda S; Smith, George Davey; Spector, Tim D; Illig, Thomas; de Faire, Ulf; Hamsten, Anders; Gudnason, Vilmundur; Kivimaki, Mika; Hingorani, Aroon; Keinanen-Kiukaanniemi, Sirkka M; Saaristo, Timo E; Boomsma, Dorret I; Stefansson, Kari; van der Harst, Pim; Dupuis, Josée; Pedersen, Nancy L; Sattar, Naveed; Harris, Tamara B; Cucca, Francesco; Ripatti, Samuli; Salomaa, Veikko; Mohlke, Karen L; Balkau, Beverley; Froguel, Philippe; Pouta, Anneli; Jarvelin, Marjo-Riitta; Wareham, Nicholas J; Bouatia-Naji, Nabila; McCarthy, Mark I; Franks, Paul W; Meigs, James B; Teslovich, Tanya M; Florez, Jose C; Langenberg, Claudia; Ingelsson, Erik; Prokopenko, Inga; Barroso, Inês

    2012-01-01

    Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have raised the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional follow-up of these newly discovered loci will further improve our understanding of glycemic control. PMID:22885924

  11. Genome-wide Association Study Identifies New Loci for Resistance to Leptosphaeria maculans in Canola

    Directory of Open Access Journals (Sweden)

    Harsh Raman

    2016-10-01

    Full Text Available Blackleg, caused by Leptosphaeria maculans, is a significant disease which affects the sustainable production of canola. This study reports a genome-wide association study based on 18,804 polymorphic SNPs to identify loci associated with qualitative and quantitative resistance to L. maculans. Genomic regions delimited with 503 significant SNP markers, that are associated with resistance evaluated using 12 single spore isolates and pathotypes from four canola stubble were identified. Several significant associations were detected at known disease resistance loci including in the vicinity of recently cloned Rlm2/LepR3 genes, and at new loci on chromosomes A01/C01, A02/C02, A03/C03, A05/C05, A06, A08, and A09. In addition, we validated statistically significant associations on A01, A07 and A10 in four genetic mapping populations, demonstrating that GWAS marker loci are indeed associated with resistance to L. maculans. One of the novel loci identified for the first time, Rlm12, conveys adult plant resistance and mapped within 13.2 kb from Arabidopsis R gene of TIR-NBS class. We showed that resistance loci are located in the vicinity of R genes of A. thaliana and B. napus on the sequenced genome of B. napus cv. Darmor-bzh. Significantly associated SNP markers provide a valuable tool to enrich germplasm for favorable alleles in order to improve the level of resistance to L. maculans in canola.

  12. Incorporation of covariates in simultaneous localization of two linked loci using affected relative pairs

    Directory of Open Access Journals (Sweden)

    Liang Kung-Yee

    2010-07-01

    Full Text Available Abstract Background Many dichotomous traits for complex diseases are often involved more than one locus and/or associated with quantitative biomarkers or environmental factors. Incorporating these quantitative variables into linkage analysis as well as localizing two linked disease loci simultaneously could therefore improve the efficiency in mapping genes. We extended the robust multipoint Identity-by-Descent (IBD approach with incorporation of covariates developed previously to simultaneously estimate two linked loci using different types of affected relative pairs (ARPs. Results We showed that the efficiency was enhanced by incorporating a quantitative covariate parametrically or non-parametrically while localizing two disease loci using ARPs. In addition to its help in identifying factors associated with the disease and in improving the efficiency in estimating disease loci, this extension also allows investigators to account for heterogeneity in risk-ratios for different ARPs. Data released from the collaborative study on the genetics of alcoholism (COGA for Genetic Analysis Workshop 14 (GAW 14 were used to illustrate the application of this extended method. Conclusions The simulation studies and example illustrated that the efficiency in estimating disease loci was demonstratively enhanced by incorporating a quantitative covariate and by using all relative pairs while mapping two linked loci simultaneously.

  13. radEq Add-On Module for CFD Solver Loci-CHEM

    Science.gov (United States)

    McCloud, Peter

    2013-01-01

    Loci-CHEM to be applied to flow velocities where surface radiation due to heating from compression and friction becomes significant. The module adds a radiation equilibrium boundary condition to the computational fluid dynamics (CFD) code to produce accurate results. The module expanded the upper limit for accurate CFD solutions of Loci-CHEM from Mach 4 to Mach 10 based on Space Shuttle Orbiter Re-Entry trajectories. Loci-CHEM already has a very promising architecture and performance, but absence of radiation equilibrium boundary condition limited the application of Loci-CHEM to below Mach 4. The immediate advantage of the add-on module is that it allows Loci-CHEM to work with supersonic flows up to Mach 10. This transformed Loci-CHEM from a rocket engine- heritage CFD code with general subsonic and low-supersonic applications, to an aeroheating code with hypersonic applications. The follow-on advantage of the module is that it is a building block for additional add-on modules that will solve for the heating generated at Mach numbers higher than 10.

  14. Further evidence for the existence of major susceptibility of nasopharyngeal carcinoma in the region near HLA-A locus in Southern Chinese

    National Research Council Canada - National Science Library

    Zhao, Manli; Cai, Hongbing; Li, Xin; Zheng, Hang; Yang, Xuexi; Fang, Weiyi; Zhang, Longcheng; Wei, Ganguan; Li, Ming; Yao, Kaitai

    2012-01-01

    .... Human leukocyte antigen (HLA) complex, specially the region near HLA-A locus, was regarded as a major candidate region bearing NPC genetic susceptibility loci in many previous studies including two recent genome-wide association (GWA) studies...

  15. Meta-analysis identifies four new loci associated with testicular germ cell tumor.

    Science.gov (United States)

    Chung, Charles C; Kanetsky, Peter A; Wang, Zhaoming; Hildebrandt, Michelle A T; Koster, Roelof; Skotheim, Rolf I; Kratz, Christian P; Turnbull, Clare; Cortessis, Victoria K; Bakken, Anne C; Bishop, D Timothy; Cook, Michael B; Erickson, R Loren; Fosså, Sophie D; Jacobs, Kevin B; Korde, Larissa A; Kraggerud, Sigrid M; Lothe, Ragnhild A; Loud, Jennifer T; Rahman, Nazneen; Skinner, Eila C; Thomas, Duncan C; Wu, Xifeng; Yeager, Meredith; Schumacher, Fredrick R; Greene, Mark H; Schwartz, Stephen M; McGlynn, Katherine A; Chanock, Stephen J; Nathanson, Katherine L

    2013-06-01

    We conducted a meta-analysis to identify new susceptibility loci for testicular germ cell tumor (TGCT). In the discovery phase, we analyzed 931 affected individuals and 1,975 controls from 3 genome-wide association studies (GWAS). We conducted replication in 6 independent sample sets comprising 3,211 affected individuals and 7,591 controls. In the combined analysis, risk of TGCT was significantly associated with markers at four previously unreported loci: 4q22.2 in HPGDS (per-allele odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.12-1.26; P = 1.11 × 10(-8)), 7p22.3 in MAD1L1 (OR = 1.21, 95% CI = 1.14-1.29; P = 5.59 × 10(-9)), 16q22.3 in RFWD3 (OR = 1.26, 95% CI = 1.18-1.34; P = 5.15 × 10(-12)) and 17q22 (rs9905704: OR = 1.27, 95% CI = 1.18-1.33; P = 4.32 × 10(-13) and rs7221274: OR = 1.20, 95% CI = 1.12-1.28; P = 4.04 × 10(-9)), a locus that includes TEX14, RAD51C and PPM1E. These new TGCT susceptibility loci contain biologically plausible genes encoding proteins important for male germ cell development, chromosomal segregation and the DNA damage response.

  16. Interval Mapping of Multiple Quantitative Trait Loci

    NARCIS (Netherlands)

    Jansen, Ritsert C.

    1993-01-01

    The interval mapping method is widely used for the mapping of quantitative trait loci (QTLs) in segregating generations derived from crosses between inbred lines. The efficiency of detecting and the accuracy of mapping multiple QTLs by using genetic markers are much increased by employing multiple

  17. Development and characterization of microsatellite loci for ...

    African Journals Online (AJOL)

    Eight novel microsatellite loci from the genome of Fenneropenaeus penicillatus Alcock were developed using the protocol of fast isolation by amplified fragment length polymorphism of sequences containing repeats (FIASCO). Thirty (30) wild individuals were used to analyze the polymorphism of these eight microsatellite ...

  18. Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci.

    Science.gov (United States)

    Fernández-Rhodes, Lindsay; Gong, Jian; Haessler, Jeffrey; Franceschini, Nora; Graff, Mariaelisa; Nishimura, Katherine K; Wang, Yujie; Highland, Heather M; Yoneyama, Sachiko; Bush, William S; Goodloe, Robert; Ritchie, Marylyn D; Crawford, Dana; Gross, Myron; Fornage, Myriam; Buzkova, Petra; Tao, Ran; Isasi, Carmen; Avilés-Santa, Larissa; Daviglus, Martha; Mackey, Rachel H; Houston, Denise; Gu, C Charles; Ehret, Georg; Nguyen, Khanh-Dung H; Lewis, Cora E; Leppert, Mark; Irvin, Marguerite R; Lim, Unhee; Haiman, Christopher A; Le Marchand, Loic; Schumacher, Fredrick; Wilkens, Lynne; Lu, Yingchang; Bottinger, Erwin P; Loos, Ruth J L; Sheu, Wayne H-H; Guo, Xiuqing; Lee, Wen-Jane; Hai, Yang; Hung, Yi-Jen; Absher, Devin; Wu, I-Chien; Taylor, Kent D; Lee, I-Te; Liu, Yeheng; Wang, Tzung-Dau; Quertermous, Thomas; Juang, Jyh-Ming J; Rotter, Jerome I; Assimes, Themistocles; Hsiung, Chao A; Chen, Yii-Der Ida; Prentice, Ross; Kuller, Lewis H; Manson, JoAnn E; Kooperberg, Charles; Smokowski, Paul; Robinson, Whitney R; Gordon-Larsen, Penny; Li, Rongling; Hindorff, Lucia; Buyske, Steven; Matise, Tara C; Peters, Ulrike; North, Kari E

    2017-06-01

    Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m2) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

  19. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

    Science.gov (United States)

    Estrada, Karol; Styrkarsdottir, Unnur; Evangelou, Evangelos; Hsu, Yi-Hsiang; Duncan, Emma L; Ntzani, Evangelia E; Oei, Ling; Albagha, Omar M E; Amin, Najaf; Kemp, John P; Koller, Daniel L; Li, Guo; Liu, Ching-Ti; Minster, Ryan L; Moayyeri, Alireza; Vandenput, Liesbeth; Willner, Dana; Xiao, Su-Mei; Yerges-Armstrong, Laura M; Zheng, Hou-Feng; Alonso, Nerea; Eriksson, Joel; Kammerer, Candace M; Kaptoge, Stephen K; Leo, Paul J; Thorleifsson, Gudmar; Wilson, Scott G; Wilson, James F; Aalto, Ville; Alen, Markku; Aragaki, Aaron K; Aspelund, Thor; Center, Jacqueline R; Dailiana, Zoe; Duggan, David J; Garcia, Melissa; Garcia-Giralt, Natàlia; Giroux, Sylvie; Hallmans, Göran; Hocking, Lynne J; Husted, Lise Bjerre; Jameson, Karen A; Khusainova, Rita; Kim, Ghi Su; Kooperberg, Charles; Koromila, Theodora; Kruk, Marcin; Laaksonen, Marika; Lacroix, Andrea Z; Lee, Seung Hun; Leung, Ping C; Lewis, Joshua R; Masi, Laura; Mencej-Bedrac, Simona; Nguyen, Tuan V; Nogues, Xavier; Patel, Millan S; Prezelj, Janez; Rose, Lynda M; Scollen, Serena; Siggeirsdottir, Kristin; Smith, Albert V; Svensson, Olle; Trompet, Stella; Trummer, Olivia; van Schoor, Natasja M; Woo, Jean; Zhu, Kun; Balcells, Susana; Brandi, Maria Luisa; Buckley, Brendan M; Cheng, Sulin; Christiansen, Claus; Cooper, Cyrus; Dedoussis, George; Ford, Ian; Frost, Morten; Goltzman, David; González-Macías, Jesús; Kähönen, Mika; Karlsson, Magnus; Khusnutdinova, Elza; Koh, Jung-Min; Kollia, Panagoula; Langdahl, Bente Lomholt; Leslie, William D; Lips, Paul; Ljunggren, Östen; Lorenc, Roman S; Marc, Janja; Mellström, Dan; Obermayer-Pietsch, Barbara; Olmos, José M; Pettersson-Kymmer, Ulrika; Reid, David M; Riancho, José A; Ridker, Paul M; Rousseau, François; Slagboom, P Eline; Tang, Nelson LS; Urreizti, Roser; Van Hul, Wim; Viikari, Jorma; Zarrabeitia, María T; Aulchenko, Yurii S; Castano-Betancourt, Martha; Grundberg, Elin; Herrera, Lizbeth; Ingvarsson, Thorvaldur; Johannsdottir, Hrefna; Kwan, Tony; Li, Rui; Luben, Robert; Medina-Gómez, Carolina; Palsson, Stefan Th; Reppe, Sjur; Rotter, Jerome I; Sigurdsson, Gunnar; van Meurs, Joyce B J; Verlaan, Dominique; Williams, Frances MK; Wood, Andrew R; Zhou, Yanhua; Gautvik, Kaare M; Pastinen, Tomi; Raychaudhuri, Soumya; Cauley, Jane A; Chasman, Daniel I; Clark, Graeme R; Cummings, Steven R; Danoy, Patrick; Dennison, Elaine M; Eastell, Richard; Eisman, John A; Gudnason, Vilmundur; Hofman, Albert; Jackson, Rebecca D; Jones, Graeme; Jukema, J Wouter; Khaw, Kay-Tee; Lehtimäki, Terho; Liu, Yongmei; Lorentzon, Mattias; McCloskey, Eugene; Mitchell, Braxton D; Nandakumar, Kannabiran; Nicholson, Geoffrey C; Oostra, Ben A; Peacock, Munro; Pols, Huibert A P; Prince, Richard L; Raitakari, Olli; Reid, Ian R; Robbins, John; Sambrook, Philip N; Sham, Pak Chung; Shuldiner, Alan R; Tylavsky, Frances A; van Duijn, Cornelia M; Wareham, Nick J; Cupples, L Adrienne; Econs, Michael J; Evans, David M; Harris, Tamara B; Kung, Annie Wai Chee; Psaty, Bruce M; Reeve, Jonathan; Spector, Timothy D; Streeten, Elizabeth A; Zillikens, M Carola; Thorsteinsdottir, Unnur; Ohlsson, Claes; Karasik, David; Richards, J Brent; Brown, Matthew A; Stefansson, Kari; Uitterlinden, André G; Ralston, Stuart H; Ioannidis, John P A; Kiel, Douglas P; Rivadeneira, Fernando

    2012-01-01

    Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10−4, Bonferroni corrected), of which six reached P<5×10−8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. PMID:22504420

  20. Microsatellite loci for population and parentage analysis in the Amazon River dolphin (Inia geoffrensis de Blainville, 1817).

    Science.gov (United States)

    Gravena, Waleska; Hrbek, Tomas; DA Silva, Vera M S; Astolfi-Filho, Spartaco; Farias, Izeni P

    2009-03-01

    We developed specific primers for microsatellite DNA regions for the Amazon River dolphin or boto Inia geoffrensis, for use in population and conservation genetic studies. We also tested their transferability for two other species, Pontoporia blainvillei (sister taxon of I. geoffrensis) and Sotalia guianensis. A total of 12 microsatellite loci were polymorphic for the boto. An additional 25 microsatellite loci previously isolated from other cetacean species were also tested in the boto. The 26 polymorphic microsatellite loci indicate they will be excellent markers for studies of population structure and kinship relations of the boto. © 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Ltd.

  1. Identification of Susceptibility Genes of Adult Asthma in French Canadian Women

    Directory of Open Access Journals (Sweden)

    Jean-Christophe Bérubé

    2016-01-01

    Full Text Available Susceptibility genes of asthma may be more successfully identified by studying subgroups of phenotypically similar asthma patients. This study aims to identify single nucleotide polymorphisms (SNPs associated with asthma in French Canadian adult women. A pooling-based genome-wide association study was performed in 240 allergic asthmatic and 120 allergic nonasthmatic women. The top associated SNPs were selected for individual genotyping in an extended cohort of 349 asthmatic and 261 nonasthmatic women. The functional impact of asthma-associated SNPs was investigated in a lung expression quantitative trait loci (eQTL mapping study (n=1035. Twenty-one of the 38 SNPs tested by individual genotyping showed P values lower than 0.05 for association with asthma. Cis-eQTL analyses supported the functional contribution of rs17801353 associated with C3AR1 (P=7.90E-10. The asthma risk allele for rs17801353 is associated with higher mRNA expression levels of C3AR1 in lung tissue. In silico functional characterization of the asthma-associated SNPs also supported the contribution of C3AR1 and additional genes including SYNE1, LINGO2, and IFNG-AS1. This pooling-based GWAS in French Canadian adult women followed by lung eQTL mapping suggested C3AR1 as a functional locus associated with asthma. Additional susceptibility genes were suggested in this homogenous subgroup of asthma patients.

  2. Detection of the introgression loci in Triticum aestivum transferred ...

    African Journals Online (AJOL)

    ... of A. tauschii SQ-214 introgression loci in the two derived populations. The result shows that 82.35% loci of A. tauschii SQ-214 were detected in BC1F2 population, while the frequency of introgression loci was 51.47% in the advanced lines of BC1F2-F7 after artificial selection for stripe rust resistance and agronomic traits.

  3. Involvement of ANXA5 and ILKAP in susceptibility to malignant melanoma.

    Directory of Open Access Journals (Sweden)

    Yoana Arroyo-Berdugo

    Full Text Available Single nucleotide-polymorphisms (SNPs are a source of diversity among human population, which may be responsible for the different individual susceptibility to diseases and/or response to drugs, among other phenotypic traits. Several low penetrance susceptibility genes associated with malignant melanoma (MM have been described, including genes related to pigmentation, DNA damage repair and oxidative stress pathways. In the present work, we conducted a candidate gene association study based on proteins and genes whose expression we had detected altered in melanoma cell lines as compared to normal melanocytes. The result was the selection of 88 loci and 384 SNPs, of which 314 fulfilled our quality criteria for a case-control association study. The SNP rs6854854 in ANXA5 was statistically significant after conservative Bonferroni correction when 464 melanoma patients and 400 controls were analyzed in a discovery Phase I. However, this finding could not be replicated in the validation phase, perhaps because the minor allele frequency of SNP rs6854854 varies depending on the geographical region considered. Additionally, a second SNP (rs6431588 located on ILKAP was found to be associated with melanoma after considering a combined set of 1,883 MM cases and 1,358 disease-free controls. The OR was 1.29 (95% CI 1.12-1.48; p-value = 4×10-4. Both SNPs, rs6854854 in ANXA5 and rs6431588 in ILKAP, show population structure, which, assuming that the Spanish population is not significantly structured, suggests a role of these loci on a specific genetic adaptation to different environmental conditions. Furthermore, the biological relevance of these genes in MM is supported by in vitro experiments, which show a decrease in the transcription levels of ANXA5 and ILKAP in melanoma cells compared to normal melanocytes.

  4. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease

    OpenAIRE

    Escott-Price, Valentina; Bellenguez, Céline; Wang, Li-San; Choi, Seung-Hoan; Harold, Denise; Jones, Lesley; Holmans, Peter; Gerrish, Amy; Vedernikov, Alexey; Richards, Alexander; DeStefano, Anita L.; Lambert, Jean-Charles; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca

    2014-01-01

    PUBLISHED BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over...

  5. Identifying breast cancer risk loci by global differential allele-specific expression (DASE analysis in mammary epithelial transcriptome

    Directory of Open Access Journals (Sweden)

    Gao Chuan

    2012-10-01

    Full Text Available Abstract Background The significant mortality associated with breast cancer (BCa suggests a need to improve current research strategies to identify new genes that predispose women to breast cancer. Differential allele-specific expression (DASE has been shown to contribute to phenotypic variables in humans and recently to the pathogenesis of cancer. We previously reported that nonsense-mediated mRNA decay (NMD could lead to DASE of BRCA1/2, which is associated with elevated susceptibility to breast cancer. In addition to truncation mutations, multiple genetic and epigenetic factors can contribute to DASE, and we propose that DASE is a functional index for cis-acting regulatory variants and pathogenic mutations, and that global analysis of DASE in breast cancer precursor tissues can be used to identify novel causative alleles for breast cancer susceptibility. Results To test our hypothesis, we employed the Illumina® Omni1-Quad BeadChip in paired genomic DNA (gDNA and double-stranded cDNA (ds-cDNA samples prepared from eight BCa patient-derived normal mammary epithelial lines (HMEC. We filtered original array data according to heterozygous genotype calls and calculated DASE values using the Log ratio of cDNA allele intensity, which was normalized to the corresponding gDNA. We developed two statistical methods, SNP- and gene-based approaches, which allowed us to identify a list of 60 candidate DASE loci (DASE ≥ 2.00, P ≤ 0.01, FDR ≤ 0.05 by both methods. Ingenuity Pathway Analysis of DASE loci revealed one major breast cancer-relevant interaction network, which includes two known cancer causative genes, ZNF331 (DASE = 2.31, P = 0.0018, FDR = 0.040 and USP6 (DASE = 4.80, P = 0.0013, FDR = 0.013, and a breast cancer causative gene, DMBT1 (DASE=2.03, P = 0.0017, FDR = 0.014. Sequence analysis of a 5′ RACE product of DMBT1 demonstrated that rs2981745, a putative breast cancer risk locus, appears to be one of the causal variants leading to DASE

  6. The Differences in the Involvements of Loci of Promoter Region and Ile50Val in Interleukin-4 Receptor α Chain Gene between Atopic Dermatitis and Japanese Cedar Pollinosis

    Directory of Open Access Journals (Sweden)

    Takeshi Tanaka

    2012-01-01

    Conclusions: Our data suggest that -3223 T and the -3223 T/Ile50 haplotype were risk factors for AD. Ile50 allele seems to be involved in both JCP and AD. Interactions of the IL-4RA loci may play a role both conferring susceptibility and modulating severity of AD.

  7. Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

    NARCIS (Netherlands)

    Jones, Gregory T; Tromp, Gerard; Kuivaniemi, Helena; Gretarsdottir, Solveig; Baas, Annette F|info:eu-repo/dai/nl/26922517X; Giusti, Betti; Strauss, Ewa; Van't Hof, Femke N G; Webb, Thomas R; Erdman, Robert; Ritchie, Marylyn D; Elmore, James R; Verma, Anurag; Pendergrass, Sarah; Kullo, Iftikhar J; Ye, Zi; Peissig, Peggy L; Gottesman, Omri; Verma, Shefali S; Malinowski, Jennifer; Rasmussen-Torvik, Laura J; Borthwick, Kenneth M; Smelser, Diane T; Crosslin, David R; de Andrade, Mariza; Ryer, Evan J; McCarty, Catherine A; Böttinger, Erwin P; Pacheco, Jennifer A; Crawford, Dana C; Carrell, David S; Gerhard, Glenn S; Franklin, David P; Carey, David J; Phillips, Victoria L; Williams, Michael J A; Wei, Wenhua; Blair, Ross; Hill, Andrew A; Vasudevan, Thodor M; Lewis, David R; Thomson, Ian A; Krysa, Jo; Hill, Geraldine B; Roake, Justin; Merriman, Tony R; Oszkinis, Grzegorz; Galora, Silvia; Saracini, Claudia; Abbate, Rosanna; Pulli, Raffaele; Pratesi, Carlo; Saratzis, Athanasios; Verissimo, Ana R; Bumpstead, Suzannah; Badger, Stephen A; Clough, Rachel E; Cockerill, Gillian; Hafez, Hany; Scott, D Julian A; Futers, T Simon; Romaine, Simon P R; Bridge, Katherine; Griffin, Kathryn J; Bailey, Marc A; Smith, Alberto; Thompson, Matthew M; van Bockxmeer, Frank M; Matthiasson, Stefan E; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Blankensteijn, Jan D; Teijink, Joep A W; Wijmenga, Cisca; de Graaf, Jacqueline; Kiemeney, Lambertus A; Lindholt, Jes S; Hughes, Anne; Bradley, Declan T; Stirrups, Kathleen; Golledge, Jonathan; Norman, Paul E; Powell, Janet T; Humphries, Steve E; Hamby, Stephen E; Goodall, Alison H; Nelson, Christopher P; Sakalihasan, Natzi; Courtois, Audrey; Ferrell, Robert E; Eriksson, Per; Folkersen, Lasse; Franco-Cereceda, Anders; Eicher, John D; Johnson, Andrew D; Betsholtz, Christer; Ruusalepp, Arno; Franzén, Oscar; Schadt, Eric E; Björkegren, Johan L M; Lipovich, Leonard; Drolet, Anne M; Verhoeven, Eric L; Zeebregts, Clark J; Geelkerken, Robert H; van Sambeek, Marc R; van Sterkenburg, Steven M; de Vries, Jean-Paul; Stefansson, Kari; Thompson, John R; de Bakker, Paul I W|info:eu-repo/dai/nl/342957082; Deloukas, Panos; Sayers, Robert D; Harrison, Seamus C; van Rij, Andre M; Samani, Nilesh J; Bown, Matthew J

    2017-01-01

    RATIONALE: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. OBJECTIVE: To identify additional AAA risk loci using data from all available

  8. Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

    NARCIS (Netherlands)

    Jones, Gregory T.; Tromp, Gerard; Kuivaniemi, Helena; Gretarsdottir, Solveig; Baas, Annette F.; Giusti, Betti; Strauss, Ewa; van't Hof, Femke N. G.; Webb, Thomas R.; Erdman, Robert; Ritchie, Marylyn D.; Elmore, James R.; Verma, Anurag; Pendergrass, Sarah A; Kullo, Iftikhar J.; Zy, Zi Ye; Peissig, Peggy L.; Gottesman, Omri; Verma, Shefali S.; Malinowski, Jennifer; Rasmussen-Torvik, Laura J.; Borthwick, Kenneth M.; Smelser, Diane T.; Crosslin, David R; de Andrade, Mariza; Ryer, Evan J.; McCarty, Catherine A.; Bottinger, Erwin P.; Pacheco, Jennifer A.; Crawford, Dana C.; Carrell, David S; Gerhard, Glenn S.; Franklin, David P.; Carey, David J.; Phillips, Victoria L.; Williams, Michael J. A.; Wei, Wenhua; Blair, Ross; Hill, Andrew A.; Vasudevan, Thodor M.; Lewis, David R.; Thomson, Ian A.; Krysa, Jo; Hill, Geraldine B.; Roake, Justin; Merriman, Tony R.; Oszkinis, Grzegorz; Galora, Silvia; Saracini, Claudia; Abbate, Rosanna; Pulli, Raffaele; Pratesi, Carlo; Saratzis, Athanasios; Verissimo, Ana R.; Bumpstead, Suzannah; Badger, Stephen A.; Clough, Rachel E.; Cockerill, Gillian; Hafez, Hany; Scott, D. Julian A.; Futers, T. Simon; Romaine, Simon P. R.; Bridge, Katherine; Griffin, Kathryn J.; Bailey, Marc A.; Smith, Alberto; Thompson, Matthew; van Bockxmeer, Frank M.; Matthiasson, Stefan E.; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Blankensteijn, Jan D.; Teijink, Joep A. W.; Wijmenga, Cisca; de Graaf, Jacqueline; Kiemeney, Lambertus A.; Lindholt, Jes S.; Hughes, Anne E.; Bradley, Declan T.; Stirrups, Kathleen; Golledge, Jonathan; Norman, Paul E.; Powell, Janet T.; Humphries, Steve E.; Hamby, Stephen E.; Goodall, Alison H.; Nelson, Christopher P.; Sakalihasan, Natzi; Courtois, Audrey; Ferrell, Robert E.; Eriksson, Per; Folkersen, Lasse; Franco-Cereceda, Anders; Eicher, John D.; Johnson, Andrew D.; Betsholtz, Christer; Ruusalepp, Arno; Franzen, Oscar; Schadt, Eric; Bjorkegren, Johan L. M.; Lipovich, Leonard; Drolet, Anne M.; Verhoeven, Eric L.; Zeebregts, Clark J.; Geelkerken, Robert H.; Sambeek, Marc R.; van Sterkenburg, Steven M.; De Vries, Jean-Paul; Stefansson, Kari; Thompson, John R.; de Bakker, Paul I. W.; Deloukas, Panos; Sayers, Robert D.; Harrison, Seamus C.; van Rij, Andre M.; Samani, Nilesh J.; Bown, Matthew J.

    2017-01-01

    Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available

  9. Identification of Four Novel Loci in Asthma in European American and African American Populations.

    Science.gov (United States)

    Almoguera, Berta; Vazquez, Lyam; Mentch, Frank; Connolly, John; Pacheco, Jennifer A; Sundaresan, Agnes S; Peissig, Peggy L; Linneman, James G; McCarty, Catherine A; Crosslin, David; Carrell, David S; Lingren, Todd; Namjou-Khales, Bahram; Harley, John B; Larson, Eric; Jarvik, Gail P; Brilliant, Murray; Williams, Marc S; Kullo, Iftikhar J; Hysinger, Erik B; Sleiman, Patrick M A; Hakonarson, Hakon

    2017-02-15

    Despite significant advances in knowledge of the genetic architecture of asthma, specific contributors to the variability in the burden between populations remain uncovered. To identify additional genetic susceptibility factors of asthma in European American and African American populations. A phenotyping algorithm mining electronic medical records was developed and validated to recruit cases with asthma and control subjects from the Electronic Medical Records and Genomics network. Genome-wide association analyses were performed in pediatric and adult asthma cases and control subjects with European American and African American ancestry followed by metaanalysis. Nominally significant results were reanalyzed conditioning on allergy status. The validation of the algorithm yielded an average of 95.8% positive predictive values for both cases and control subjects. The algorithm accrued 21,644 subjects (65.83% European American and 34.17% African American). We identified four novel population-specific associations with asthma after metaanalyses: loci 6p21.31, 9p21.2, and 10q21.3 in the European American population, and the PTGES gene in African Americans. TEK at 9p21.2, which encodes TIE2, has been shown to be involved in remodeling the airway wall in asthma, and the association remained significant after conditioning by allergy. PTGES, which encodes the prostaglandin E synthase, has also been linked to asthma, where deficient prostaglandin E2 synthesis has been associated with airway remodeling. This study adds to understanding of the genetic architecture of asthma in European Americans and African Americans and reinforces the need to study populations of diverse ethnic backgrounds to identify shared and unique genetic predictors of asthma.

  10. Novel genetic loci associated with hippocampal volume.

    OpenAIRE

    Hibar, Derrek P.; Adams, Hieab H.H.; Jahanshad, Neda; Chauhan, Ganesh; Stein, Jason L.; Hofer, Edith; Renteria, Miguel E.; Bis, Joshua C; Arias-Vasquez, Alejandro; Ikram, M. Kamran; Desrivières, Sylvane; Vernooij, Meike W; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf

    2017-01-01

    International audience; The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal ...

  11. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies

    NARCIS (Netherlands)

    C.E. Elks (Cathy); J.R.B. Perry (John); P. Sulem (Patrick); D.I. Chasman (Daniel); N. Franceschini (Nora); C. He (Chunyan); K.L. Lunetta (Kathryn); J.A. Visser (Jenny); E.M. Byrne (Enda); D.L. Cousminer (Diana); D.F. Gudbjartsson (Daniel); T. Esko (Tõnu); B. Feenstra (Bjarke); J.J. Hottenga (Jouke Jan); D.L. Koller (Daniel); Z. Kutalik (Zoltán); P. Lin (Peng); M. Mangino (Massimo); M. Marongiu (Mara); P.F. McArdle (Patrick); A.V. Smith (Albert Vernon); L. Stolk (Lisette); S. van Wingerden (Sophie); J.H. Zhao (Jing Hua); E. Albrecht (Eva); T. Corre (Tanguy); E. Ingelsson (Erik); C. Hayward (Caroline); P.K. Magnusson (Patrik); S. Ulivi (Shelia); N.M. Warrington (Nicole); L. Zgaga (Lina); H. Alavere (Helene); N. Amin (Najaf); T. Aspelund (Thor); S. Bandinelli (Stefania); I. Barroso (Inês); G. Berenson (Gerald); S.M. Bergmann (Sven); H. Blackburn (Hannah); E.A. Boerwinkle (Eric); J.E. Buring (Julie); F. Busonero; H. Campbell (Harry); S.J. Chanock (Stephen); W. Chen (Wei); M. Cornelis (Marilyn); D.J. Couper (David); A.D. Coviello (Andrea); P. d' Adamo (Pio); U. de Faire (Ulf); E.J.C. de Geus (Eco); P. Deloukas (Panagiotis); A. Döring (Angela); D.F. Easton (Douglas); G. Eiriksdottir (Gudny); V. Emilsson (Valur); J.G. Eriksson (Johan); L. Ferrucci (Luigi); A.R. Folsom (Aaron); T. Foroud (Tatiana); M. Garcia (Melissa); P. Gasparini (Paolo); F. Geller (Frank); C. Gieger (Christian); V. Gudnason (Vilmundur); A.S. Hall (Alistair); S.E. Hankinson (Susan); L. Ferreli (Liana); A.C. Heath (Andrew); D.G. Hernandez (Dena); A. Hofman (Albert); F.B. Hu (Frank); T. Illig (Thomas); M.R. Järvelin; A.D. Johnson (Andrew); D. Karasik (David); K-T. Khaw (Kay-Tee); D.P. Kiel (Douglas); T.O. Kilpelänen (Tuomas); I. Kolcic (Ivana); P. Kraft (Peter); L.J. Launer (Lenore); J.S.E. Laven (Joop); S. Li (Shengxu); J. Liu (Jianjun); D. Levy (Daniel); N.G. Martin (Nicholas); M. Melbye (Mads); V. Mooser (Vincent); J.C. Murray (Jeffrey); M.A. Nalls (Michael); P. Navarro (Pau); M. Nelis (Mari); A.R. Ness (Andrew); K. Northstone (Kate); B.A. Oostra (Ben); M. Peacock (Munro); C. Palmer (Cameron); A. Palotie (Aarno); G. Paré (Guillaume); A.N. Parker (Alex); N.L. Pedersen (Nancy); L. Peltonen (Leena Johanna); C.E. Pennell (Craig); P.D.P. Pharoah (Paul); O. Polasek (Ozren); A.S. Plump (Andrew); A. Pouta (Anneli); E. Porcu (Eleonora); T. Rafnar (Thorunn); J.P. Rice (John); S.M. Ring (Susan); F. Rivadeneira Ramirez (Fernando); I. Rudan (Igor); C. Sala (Cinzia); V. Salomaa (Veikko); S. Sanna (Serena); D. Schlessinger; N.J. Schork (Nicholas); A. Scuteri (Angelo); A.V. Segrè (Ayellet); A.R. Shuldiner (Alan); N. Soranzo (Nicole); U. Sovio (Ulla); S.R. Srinivasan (Sathanur); D.P. Strachan (David); M.L. Tammesoo; E. Tikkanen (Emmi); D. Toniolo (Daniela); K. Tsui (Kim); L. Tryggvadottir (Laufey); J.P. Tyrer (Jonathan); M. Uda (Manuela); R.M. van Dam (Rob); J.B.J. van Meurs (Joyce); P. Vollenweider (Peter); G. Waeber (Gérard); N.J. Wareham (Nick); D. Waterworth (Dawn); H.E. Wichmann (Heinz Erich); G.A.H.M. Willemsen (Gonneke); J.F. Wilson (James); A.F. Wright (Alan); L. Young (Lauren); G. Zhai (Guangju); W.V. Zhuang; L.J. Bierut (Laura); D.I. Boomsma (Dorret); H.A. Boyd (Heather); L. Crisponi (Laura); E.W. Demerath (Ellen); P. Tikka-Kleemola (Päivi); M.J. Econs (Michael); T.B. Harris (Tamara); D. Hunter (David); R.J.F. Loos (Ruth); A. Metspalu (Andres); G.W. Montgomery (Grant); P.M. Ridker (Paul); T.D. Spector (Tim); E.A. Streeten (Elizabeth); K. Stefansson (Kari); U. Thorsteinsdottir (Unnur); A.G. Uitterlinden (André); E. Widen (Elisabeth); J. Murabito (Joanne); K. Ong (Ken); M.N. Weedon (Michael)

    2010-01-01

    textabstractTo identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10 -60) and 9q31.2 (P = 2.2 × 10 -33), we identified 30

  12. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies

    DEFF Research Database (Denmark)

    Elks, Cathy E; Perry, John R B; Sulem, Patrick

    2010-01-01

    To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarc...

  13. The genetic architecture of susceptibility to parasites.

    Science.gov (United States)

    Wilfert, Lena; Schmid-Hempel, Paul

    2008-06-30

    The antagonistic co-evolution of hosts and their parasites is considered to be a potential driving force in maintaining host genetic variation including sexual reproduction and recombination. The examination of this hypothesis calls for information about the genetic basis of host-parasite interactions - such as how many genes are involved, how big an effect these genes have and whether there is epistasis between loci. We here examine the genetic architecture of quantitative resistance in animal and plant hosts by concatenating published studies that have identified quantitative trait loci (QTL) for host resistance in animals and plants. Collectively, these studies show that host resistance is affected by few loci. We particularly show that additional epistatic interactions, especially between loci on different chromosomes, explain a majority of the effects. Furthermore, we find that when experiments are repeated using different host or parasite genotypes under otherwise identical conditions, the underlying genetic architecture of host resistance can vary dramatically - that is, involves different QTLs and epistatic interactions. QTLs and epistatic loci vary much less when host and parasite types remain the same but experiments are repeated in different environments. This pattern of variability of the genetic architecture is predicted by strong interactions between genotypes and corroborates the prevalence of varying host-parasite combinations over varying environmental conditions. Moreover, epistasis is a major determinant of phenotypic variance for host resistance. Because epistasis seems to occur predominantly between, rather than within, chromosomes, segregation and chromosome number rather than recombination via cross-over should be the major elements affecting adaptive change in host resistance.

  14. Large-scale genotyping identifies 41 new loci associated with breast cancer risk

    DEFF Research Database (Denmark)

    Michailidou, Kyriaki; Hall, Per; Gonzalez-Neira, Anna

    2013-01-01

    Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ∼9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10......,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part...

  15. GLANET: genomic loci annotation and enrichment tool.

    Science.gov (United States)

    Otlu, Burçak; Firtina, Can; Keles, Sündüz; Tastan, Oznur

    2017-09-15

    Genomic studies identify genomic loci representing genetic variations, transcription factor (TF) occupancy, or histone modification through next generation sequencing (NGS) technologies. Interpreting these loci requires evaluating them with known genomic and epigenomic annotations. We present GLANET as a comprehensive annotation and enrichment analysis tool which implements a sampling-based enrichment test that accounts for GC content and/or mappability biases, jointly or separately. GLANET annotates and performs enrichment analysis on these loci with a rich library. We introduce and perform novel data-driven computational experiments for assessing the power and Type-I error of its enrichment procedure which show that GLANET has attained high statistical power and well-controlled Type-I error rate. As a key feature, users can easily extend its library with new gene sets and genomic intervals. Other key features include assessment of impact of single nucleotide variants (SNPs) on TF binding sites and regulation based pathway enrichment analysis. GLANET can be run using its GUI or on command line. GLANET's source code is available at https://github.com/burcakotlu/GLANET . Tutorials are provided at https://glanet.readthedocs.org . burcak@ceng.metu.edu.tr or oznur.tastan@cs.bilkent.edu.tr. Supplementary data are available at Bioinformatics online.

  16. Characterization of microsatellite loci isolated in trumpeter swan (Cygnus buccinator)

    Science.gov (United States)

    John, J. St; Ransler, F.A.; Quinn, T.W.; Oyler-McCance, S.J.

    2006-01-01

    Primers for 16 microsatellite loci were developed for the trumpeter swan (Cygnus buccinator), a species recovering from a recent population bottleneck. In a screen of 158 individuals, the 16 loci were found to have levels of variability ranging from two to seven alleles. No loci were found to be linked, although two loci repeatedly revealed significant departures from Hardy-Weinberg equilibrium. Amplification in the closely related tundra swan (Cygnus columbianus) was successful for all except one locus. These microsatellite loci will be applicable for population genetic analyses and ultimately aid in management efforts. ?? 2006 The Authors.