WorldWideScience

Sample records for cancer genome-wide association

  1. 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) in ...

  2. 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...

  3. [Genome-wide association study(GWAS) and genetic risk of prostate cancer].

    Science.gov (United States)

    Nakagawa, Hidewaki; Akamatsu, Shusuke; Takata, Ryo

    2016-01-01

    It is evident that genetic factors play critical roles in prostate cancer development. GWAS (genome-wide association studies) in multiple ethnic groups have been identifying more than 100 loci or genes which was significantly associated with prostate cancer susceptibility. They include several loci at 8q24, prostate-specific gene, inflammation gene, and metabolism-related genes. Risk prediction for prostate cancer by combining multiple SNPs is still primitive and not sufficiently accurate for clinical use, but this model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA or very high risk of prostate cancer. PMID:26793876

  4. Genome-wide association study of susceptibility loci for breast cancer in Sardinian population

    International Nuclear Information System (INIS)

    Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 10−6 level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10−5, we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16x10−5), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population. The online version of this article (doi:10.1186/s12885-015-1392-9) contains supplementary material, which is available to authorized users

  5. Genome-wide assessment of the association of rare and common copy number variations to testicular germ cell cancer

    DEFF Research Database (Denmark)

    Edsgard, Stefan Daniel; Dalgaard, Marlene Danner; Weinhold, Nils; Wesolowska, Agata; Rajpert-De Meyts, Ewa; Ottesen, Anne Marie; Juul, Anders; Skakkebæk, Niels Erik; Jensen, Thomas Skøt; Gupta, Ramneek; Leffers, Henrik; Brunak, Søren

    2013-01-01

    Testicular germ cell cancer (TGCC) is one of the most heritable forms of cancer. Previous genome-wide association studies have focused on single nucleotide polymorphisms, largely ignoring the influence of copy number variants (CNVs). Here we present a genome-wide study of CNV on a cohort of 212...

  6. Five endometrial cancer risk loci identified through genome-wide association analysis.

    Science.gov (United States)

    Cheng, Timothy H T; Thompson, Deborah J; O'Mara, Tracy A; Painter, Jodie N; Glubb, Dylan M; Flach, Susanne; Lewis, Annabelle; French, Juliet D; Freeman-Mills, Luke; Church, David; Gorman, Maggie; Martin, Lynn; Hodgson, Shirley; Webb, Penelope M; Attia, John; Holliday, Elizabeth G; McEvoy, Mark; Scott, Rodney J; Henders, Anjali K; Martin, Nicholas G; Montgomery, Grant W; Nyholt, Dale R; Ahmed, Shahana; Healey, Catherine S; Shah, Mitul; Dennis, Joe; Fasching, Peter A; Beckmann, Matthias W; Hein, Alexander; Ekici, Arif B; Hall, Per; Czene, Kamila; Darabi, Hatef; Li, Jingmei; Dörk, Thilo; Dürst, Matthias; Hillemanns, Peter; Runnebaum, Ingo; Amant, Frederic; Schrauwen, Stefanie; Zhao, Hui; Lambrechts, Diether; Depreeuw, Jeroen; Dowdy, Sean C; Goode, Ellen L; Fridley, Brooke L; Winham, Stacey J; Njølstad, Tormund S; Salvesen, Helga B; Trovik, Jone; Werner, Henrica M J; Ashton, Katie; Otton, Geoffrey; Proietto, Tony; Liu, Tao; Mints, Miriam; Tham, Emma; Li, Mulin Jun; Yip, Shun H; Wang, Junwen; Bolla, Manjeet K; Michailidou, Kyriaki; Wang, Qin; Tyrer, Jonathan P; Dunlop, Malcolm; Houlston, Richard; Palles, Claire; Hopper, John L; Peto, Julian; Swerdlow, Anthony J; Burwinkel, Barbara; Brenner, Hermann; Meindl, Alfons; Brauch, Hiltrud; Lindblom, Annika; Chang-Claude, Jenny; Couch, Fergus J; Giles, Graham G; Kristensen, Vessela N; Cox, Angela; Cunningham, Julie M; Pharoah, Paul D P; Dunning, Alison M; Edwards, Stacey L; Easton, Douglas F; Tomlinson, Ian; Spurdle, Amanda B

    2016-06-01

    We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer. PMID:27135401

  7. A genome-wide association study of breast cancer in women of African ancestry

    OpenAIRE

    Chen, Fang; Chen, Gary K.; Stram, Daniel O.; Millikan, Robert C.; Ambrosone, Christine B.; John, Esther M; Bernstein, Leslie; Zheng, Wei; Palmer, Julie R.; Jennifer J Hu; Rebbeck, Tim R.; Ziegler, Regina G.; Nyante, Sarah; Bandera, Elisa V.; Sue A Ingles

    2012-01-01

    Genome-wide association studies (GWAS) in diverse populations are needed to reveal variants that are more common and/or limited to defined populations. We conducted a GWAS of breast cancer in women of African ancestry, with genotyping of > 1,000,000 SNPs in 3,153 African American cases and 2,831 controls, and replication testing of the top 66 associations in an additional 3,607 breast cancer cases and 11,330 controls of African ancestry. Two of the 66 SNPs replicated (p < 0.05) in stage 2, wh...

  8. Genome-wide association study identifies a common variant in RAD51B associated with male breast cancer risk

    DEFF Research Database (Denmark)

    Orr, Nick; Lemnrau, Alina; Cooke, Rosie;

    2012-01-01

    We conducted a genome-wide association study of male breast cancer comprising 823 cases and 2,795 controls of European ancestry, with validation in independent sample sets totaling 438 cases and 474 controls. A SNP in RAD51B at 14q24.1 was significantly associated with male breast cancer risk (P ...

  9. Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study

    DEFF Research Database (Denmark)

    Song, Honglin; Ramus, Susan J; Kjaer, Susanne Krüger;

    2009-01-01

    Because both ovarian and breast cancer are hormone-related and are known to have some predisposition genes in common, we evaluated 11 of the most significant hits (six with confirmed associations with breast cancer) from the breast cancer genome-wide association study for association with invasive.......01-1.13, P-trend = 0.02 for all types of ovarian cancer and OR 1.14 95% CI 1.07-1.22, P-trend = 0.00017 for serous ovarian cancer]. In conclusion, we found that rs4954956 was associated with increased ovarian cancer risk, particularly for serous ovarian cancer. However, none of the six confirmed breast...... ovarian cancer. Eleven SNPs were initially genotyped in 2927 invasive ovarian cancer cases and 4143 controls from six ovarian cancer case-control studies. Genotype frequencies in cases and controls were compared using a likelihood ratio test in a logistic regression model stratified by study. Initially...

  10. Genome-wide association studies identify four ER negative–specific breast cancer risk loci

    OpenAIRE

    Garcia-Closas, Montserrat; Couch, Fergus J.; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K.; Brook, Mark N.; Orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather s; Le Marchand, Loic; Buring, Julie E.; Eccles, Diana; Miron, Penelope; Fasching, Peter A.

    2013-01-01

    Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast can...

  11. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.

    LENUS (Irish Health Repository)

    McKay, James D

    2011-03-01

    Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10⁻⁸) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸); rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

  12. A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.

    Directory of Open Access Journals (Sweden)

    James D McKay

    2011-03-01

    Full Text Available Genome-wide association studies (GWAS have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷. Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸ located near DNA repair related genes HEL308 and FAM175A (or Abraxas and a 12q24 variant (rs4767364, p =2 × 10⁻⁸ located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2 gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸; rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02. These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

  13. 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

  14. Genome-wide association study of colorectal cancer identifies six new susceptibility loci

    Science.gov (United States)

    Schumacher, Fredrick R.; Schmit, Stephanie L.; Jiao, Shuo; Edlund, Christopher K.; Wang, Hansong; Zhang, Ben; Hsu, Li; Huang, Shu-Chen; Fischer, Christopher P.; Harju, John F.; Idos, Gregory E.; Lejbkowicz, Flavio; Manion, Frank J.; McDonnell, Kevin; McNeil, Caroline E.; Melas, Marilena; Rennert, Hedy S.; Shi, Wei; Thomas, Duncan C.; Van Den Berg, David J.; Hutter, Carolyn M.; Aragaki, Aaron K.; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Chanock, Stephen J.; Curtis, Keith R.; Fuchs, Charles S.; Gala, Manish; Giovannucci, Edward L.; Gogarten, Stephanie M.; Hayes, Richard B.; Henderson, Brian; Hunter, David J.; Jackson, Rebecca D.; Kolonel, Laurence N.; Kooperberg, Charles; Küry, Sébastien; LaCroix, Andrea; Laurie, Cathy C.; Laurie, Cecelia A.; Lemire, Mathieu; Levine, David; Ma, Jing; Makar, Karen W.; Qu, Conghui; Taverna, Darin; Ulrich, Cornelia M.; Wu, Kana; Kono, Suminori; West, Dee W.; Berndt, Sonja I.; Bezieau, Stéphane; Brenner, Hermann; Campbell, Peter T.; Chan, Andrew T.; Chang-Claude, Jenny; Coetzee, Gerhard A.; Conti, David V.; Duggan, David; Figueiredo, Jane C.; Fortini, Barbara K.; Gallinger, Steven J.; Gauderman, W. James; Giles, Graham; Green, Roger; Haile, Robert; Harrison, Tabitha A.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jacobs, Eric; Iwasaki, Motoki; Jee, Sun Ha; Jenkins, Mark; Jia, Wei-Hua; Joshi, Amit; Li, Li; Lindor, Noralene M.; Matsuo, Keitaro; Moreno, Victor; Mukherjee, Bhramar; Newcomb, Polly A.; Potter, John D.; Raskin, Leon; Rennert, Gad; Rosse, Stephanie; Severi, Gianluca; Schoen, Robert E.; Seminara, Daniela; Shu, Xiao-Ou; Slattery, Martha L.; Tsugane, Shoichiro; White, Emily; Xiang, Yong-Bing; Zanke, Brent W.; Zheng, Wei; Le Marchand, Loic; Casey, Graham; Gruber, Stephen B.; Peters, Ulrike

    2016-01-01

    Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies. PMID:26151821

  15. 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 foll...

  16. Genome-wide association study of pancreatic cancer in Japanese population.

    Directory of Open Access Journals (Sweden)

    Siew-Kee Low

    Full Text Available Pancreatic cancer shows very poor prognosis and is the fifth leading cause of cancer death in Japan. Previous studies indicated some genetic factors contributing to the development and progression of pancreatic cancer; however, there are limited reports for common genetic variants to be associated with this disease, especially in the Asian population. We have conducted a genome-wide association study (GWAS using 991 invasive pancreatic ductal adenocarcinoma cases and 5,209 controls, and identified three loci showing significant association (P-value<5x10(-7 with susceptibility to pancreatic cancer. The SNPs that showed significant association carried estimated odds ratios of 1.29, 1.32, and 3.73 with 95% confidence intervals of 1.17-1.43, 1.19-1.47, and 2.24-6.21; P-value of 3.30x10(-7, 3.30x10(-7, and 4.41x10(-7; located on chromosomes 6p25.3, 12p11.21 and 7q36.2, respectively. These associated SNPs are located within linkage disequilibrium blocks containing genes that have been implicated some roles in the oncogenesis of pancreatic cancer.

  17. Use of genome-wide association studies for cancer research and drug repositioning.

    Directory of Open Access Journals (Sweden)

    Jizhun Zhang

    Full Text Available Although genome-wide association studies have identified many risk loci associated with colorectal cancer, the molecular basis of these associations are still unclear. We aimed to infer biological insights and highlight candidate genes of interest within GWAS risk loci. We used an in silico pipeline based on functional annotation, quantitative trait loci mapping of cis-acting gene, PubMed text-mining, protein-protein interaction studies, genetic overlaps with cancer somatic mutations and knockout mouse phenotypes, and functional enrichment analysis to prioritize the candidate genes at the colorectal cancer risk loci. Based on these analyses, we observed that these genes were the targets of approved therapies for colorectal cancer, and suggested that drugs approved for other indications may be repurposed for the treatment of colorectal cancer. This study highlights the use of publicly available data as a cost effective solution to derive biological insights, and provides an empirical evidence that the molecular basis of colorectal cancer can provide important leads for the discovery of new drugs.

  18. Genome-wide association study for ovarian cancer susceptibility using pooled DNA

    DEFF Research Database (Denmark)

    Lu, Yi; Chen, Xiaoqing; Beesley, Jonathan; Johnatty, Sharon E; Defazio, Anna; Lambrechts, Sandrina; Lambrechts, Diether; Despierre, Evelyn; Vergotes, Ignace; Chang-Claude, Jenny; Hein, Rebecca; Nickels, Stefan; Wang-Gohrke, Shan; Dörk, Thilo; Dürst, Matthias; Antonenkova, Natalia; Bogdanova, Natalia; Goodman, Marc T; Lurie, Galina; Wilkens, Lynne R; Carney, Michael E; Butzow, Ralf; Nevanlinna, Heli; Heikkinen, Tuomas; Leminen, Arto; Kiemeney, Lambertus A; Massuger, Leon F A G; van Altena, Anne M; Aben, Katja K; Kjaer, Susanne Krüger; Høgdall, Estrid; Jensen, Allan; Brooks-Wilson, Angela; Le, Nhu; Cook, Linda; Earp, Madalene; Kelemen, Linda; Easton, Douglas; Pharoah, Paul; Song, Honglin; Tyrer, Jonathan; Ramus, Susan; Menon, Usha; Gentry-Maharaj, Alexandra; Gayther, Simon A; Bandera, Elisa V; Olson, Sara H; Orlow, Irene; Rodriguez-Rodriguez, Lorna; Macgregor, Stuart; Chenevix-Trench, Georgia

    2012-01-01

    Recent Genome-Wide Association Studies (GWAS) have identified four low-penetrance ovarian cancer susceptibility loci. We hypothesized that further moderate- or low-penetrance variants exist among the subset of single-nucleotide polymorphisms (SNPs) not well tagged by the genotyping arrays used in...... the previous studies, which would account for some of the remaining risk. We therefore conducted a time- and cost-effective stage 1 GWAS on 342 invasive serous cases and 643 controls genotyped on pooled DNA using the high-density Illumina 1M-Duo array. We followed up 20 of the most significantly...... associated SNPs, which are not well tagged by the lower density arrays used by the published GWAS, and genotyping them on individual DNA. Most of the top 20 SNPs were clearly validated by individually genotyping the samples used in the pools. However, none of the 20 SNPs replicated when tested for...

  19. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.

    NARCIS (Netherlands)

    Lan, Q.; Hsiung, C.A.; Matsuo, K.; Hong, Y.C.; Seow, A.; Wang, Z.; Hosgood, H.D.; Chen, K.; Wang, J.C.; Chatterjee, N.; Hu, W.; Wong, M.P.; Zheng, W.; Caporaso, N.; Park, J.Y.; Chen, C.J.; Kim, Y.H.; Kim, Y.T.; Landi, M.T.; Shen, H.; Lawrence, C.; Burdett, L.; Yeager, M.; Yuenger, J.; Jacobs, K.B.; Chang, I.S.; Mitsudomi, T.; Kim, H.N.; Chang, G.C.; Bassig, B.A.; Tucker, M.; Wei, F.; Yin, Y.; Wu, C.; An, S.J.; Qian, B.; Lee, V.H.; Lu, D.; Liu, J.; Jeon, H.S.; Hsiao, C.F.; Sung, J.S.; Kim, J.H.; Gao, Y.T.; Tsai, Y.H.; Jung, Y.J.; Guo, H.; Hu, Z.; Hutchinson, A.; Wang, W.C.; Klein, R.; Chung, C.C.; Oh, I.J.; Chen, K.Y.; Berndt, S.I.; He, X.; Wu, W.; Chang, J.; Zhang, X.C.; Huang, M.S.; Zheng, H.; Wang, J.; Zhao, X.; Li, Y.; Choi, J.E.; Su, W.C.; Park, K.H.; Sung, S.W.; Shu, X.O.; Chen, Y.M.; Liu, L.; Kang, C.H.; Hu, L.; Chen, C.H.; Pao, W.; Kim, Y.C.; Yang, T.Y.; Xu, J.; Guan, P.; Tan, W.; Su, J.; Wang, C.L.; Li, H.; Sihoe, A.D.; Zhao, Z.; Chen, Y.; Choi, Y.Y.; Hung, J.Y.; Kim, J.S.; Yoon, H.I.; Cai, Q.; Lin, C.C.; Park, I.K.; Xu, P.; Dong, J.; Kim, C.; He, Q; Perng, R.P.; Kohno, T.; Kweon, S.S.; Chen, C.Y.; Vermeulen, R.; Wu, J.; Lim, W.Y.; Chen, K.C.; Chow, W.H.; Ji, B.T.; Chan, J.K.; Chu, M.; Li, Y.J.; Yokota, J.; Li, J.; Chen, H.; Xiang, Y.B.; Yu, C.J.; Kunitoh, H.; Wu, G.; Jin, L.; Lo, Y.L.; Shiraishi, K.; Chen, Y.H.; Lin, H.C.; Wu, T.; WU, Y.; Yang, P.C.; Zhou, B.; Shin, M.H.; Fraumeni, J.F.; Lin, D.; Chanock, S.J.; Rothman, N.

    2012-01-01

    To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland Ch

  20. Genome-wide association study of prostate cancer-specific survival

    DEFF Research Database (Denmark)

    Szulkin, Robert; Karlsson, Robert; Whitington, Thomas;

    2015-01-01

    BACKGROUND: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. METHODS: We performed a genome-wide survival analysis of cause-specific death in 24,...

  1. Genome-wide association study of coronary and aortic calcification in lung cancer screening CT

    Science.gov (United States)

    de Vos, Bob D.; van Setten, Jessica; de Jong, Pim A.; Mali, Willem P.; Oudkerk, Matthijs; Viergever, Max A.; Išgum, Ivana

    2016-03-01

    Arterial calcification has been related to cardiovascular disease (CVD) and osteoporosis. However, little is known about the role of genetics and exact pathways leading to arterial calcification and its relation to bone density changes indicating osteoporosis. In this study, we conducted a genome-wide association study of arterial calcification burden, followed by a look-up of known single nucleotide polymorphisms (SNPs) for coronary artery disease (CAD) and myocardial infarction (MI), and bone mineral density (BMD) to test for a shared genetic basis between the traits. The study included a subcohort of the Dutch-Belgian lung cancer screening trial comprised of 2,561 participants. Participants underwent baseline CT screening in one of two hospitals participating in the trial. Low-dose chest CT images were acquired without contrast enhancement and without ECG-synchronization. In these images coronary and aortic calcifications were identified automatically. Subsequently, the detected calcifications were quantified using coronary artery calcium Agatston and volume scores. Genotype data was available for these participants. A genome-wide association study was conducted on 10,220,814 SNPs using a linear regression model. To reduce multiple testing burden, known CAD/MI and BMD SNPs were specifically tested (45 SNPs from the CARDIoGRAMplusC4D consortium and 60 SNPS from the GEFOS consortium). No novel significant SNPs were found. Significant enrichment for CAD/MI SNPs was observed in testing Agatston and coronary artery calcium volume scores. Moreover, a significant enrichment of BMD SNPs was shown in aortic calcium volume scores. This may indicate genetic relation of BMD SNPs and arterial calcification burden.

  2. Epidemiological studies of esophageal cancer in the era of genome-wide association studies

    Institute of Scientific and Technical Information of China (English)

    An-Hui; Wang; Yuan; Liu; Bo; Wang; Yi-Xuan; He; Ye-Xian; Fang; Yong-Ping; Yan

    2014-01-01

    Esophageal cancer(EC) caused about 395000 deaths in 2010. China has the most cases of EC and EC is the fourth leading cause of cancer death in China. Esophageal squamous cell carcinoma(ESCC) is the predominant histologic type(90%-95%), while the incidence of esophageal adenocarcinoma(EAC) remains extremely low in China. Traditional epidemiological studies have revealed that environmental carcinogens are risk factors for EC. Molecular epidemiological studies revealed that susceptibility to EC is influenced by both environmental and genetic risk factors. Of all the risk factors for EC, some are associated with the risk of ESCC and others with the risk of EAC. However, the details and mechanisms of risk factors involved in the process for EC are unclear. The advanced methods and techniques used in human genome studies bring a great opportunity for researchers to explore and identify the details of those risk factors or susceptibility genes involved inthe process of EC. Human genome epidemiology is a new branch of epidemiology, which leads the epidemiology study from the molecular epidemiology era to the era of genome wide association studies(GWAS). Here we review the epidemiological studies of EC(especially ESCC) in the era of GWAS, and provide an overview of the general risk factors and those genomic variants(genes, SNPs, miRNAs, proteins) involved in the process of ESCC.

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

    DEFF Research Database (Denmark)

    Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara;

    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 15,748...

  4. A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study

    OpenAIRE

    Kreger Bernard E; Finger Daniel; Rosenberg Carol L; Murabito Joanne M; Levy Daniel; Splansky Greta; Antman Karen; Hwang Shih-Jen

    2007-01-01

    Abstract Background Breast and prostate cancer are two commonly diagnosed cancers in the United States. Prior work suggests that cancer causing genes and cancer susceptibility genes can be identified. Methods We conducted a genome-wide association study (Affymetrix 100K SNP GeneChip) of cancer in the community-based Framingham Heart Study. We report on 2 cancer traits – prostate cancer and breast cancer – in up to 1335 participants from 330 families (54% women, mean entry age 33 years). Multi...

  5. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

    OpenAIRE

    Amundadottir, Laufey; Kraft, Peter; Stolzenberg-Solomon, Rachael Z; Fuchs, Charles S; Petersen, Gloria M.; Arslan, Alan A.; Bueno-de-Mesquita, H Bas; Gross, Myron; Helzlsouer, Kathy; Jacobs, Eric J.; LaCroix, Andrea; Zheng, Wei; Albanes, Demetrius; Bamlet, William; Berg, Christine D

    2009-01-01

    We conducted a two-stage genome-wide association study (GWAS) of pancreatic cancer, a cancer with one of the poorest survival rates worldwide. Initially, we genotyped 558,542 single nucleotide polymorphisms in 1,896 incident cases and 1,939 controls drawn from twelve prospective cohorts plus one hospital-based case-control study. In a combined analysis adjusted for study, sex, ancestry and five principal components that included an additional 2,457 cases and 2,654 controls from eight case-con...

  6. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer

    OpenAIRE

    Li, Donghui; Duell, Eric J.; Yu, Kai; Risch, Harvey A.; Olson, Sara H.; Kooperberg, Charles; Wolpin, Brian M.; Jiao, Li; Dong, Xiaoqun; Wheeler, Bill; Arslan, Alan A.; Bueno-De-Mesquita, H Bas; Fuchs, Charles S; Gallinger, Steven; Gross, Myron

    2012-01-01

    Four loci have been associated with pancreatic cancer through genome-wide association studies (GWAS). Pathway-based analysis of GWAS data is a complementary approach to identify groups of genes or biological pathways enriched with disease-associated single-nucleotide polymorphisms (SNPs) whose individual effect sizes may be too small to be detected by standard single-locus methods. We used the adaptive rank truncated product method in a pathway-based analysis of GWAS data from 3851 pancreatic...

  7. 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.

    2015-01-01

    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 (P<5×10−8) loci for dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B, SGSM3/MKL1), non-dense area (8p11.23) and percent density (PRDM6, 8p11.23, TMEM184B). Four of these regions are known breast cancer susceptibility loci, and four additional regions were found to be associated with breast cancer (P<0.05) in a large meta-analysis. These results provide further evidence of a shared genetic basis between mammographic density and breast cancer and illustrate the power of studying intermediate quantitative phenotypes to identify putative disease susceptibility loci. PMID:25342443

  8. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia

    OpenAIRE

    Lan, Qing; Hsiung, Chao A.; Matsuo, Keitaro; Hong, Yun-Chul; Seow, Adeline; Wang, Zhaoming; Hosgood, H Dean; Chen, Kexin; Wang, Jiu-Cun; Chatterjee, Nilanjan; Hu, Wei; Wong, Maria Pik; Zheng, Wei; Caporaso, Neil; PARK, JAE YONG

    2012-01-01

    To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three...

  9. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

    Science.gov (United States)

    Amundadottir, Laufey; Kraft, Peter; Stolzenberg-Solomon, Rachael Z.; Fuchs, Charles S.; Petersen, Gloria M.; Arslan, Alan A.; Bueno-de-Mesquita, H. Bas; Gross, Myron; Helzlsouer, Kathy; Jacobs, Eric J.; LaCroix, Andrea; Zheng, Wei; Albanes, Demetrius; Bamlet, William; Berg, Christine D.; Berrino, Franco; Bingham, Sheila; Buring, Julie E.; Bracci, Paige M.; Canzian, Federico; Clavel-Chapelon, Françoise; Clipp, Sandra; Cotterchio, Michelle; de Andrade, Mariza; Duell, Eric J.; Fox, John W.; Gallinger, Steven; Gaziano, J. Michael; Giovannucci, Edward L.; Goggins, Michael; González, Carlos A.; Hallmans, Göran; Hankinson, Susan E.; Hassan, Manal; Holly, Elizabeth A.; Hunter, David J.; Hutchinson, Amy; Jackson, Rebecca; Jacobs, Kevin B.; Jenab, Mazda; Kaaks, Rudolf; Klein, Alison P.; Kooperberg, Charles; Kurtz, Robert C.; Li, Donghui; Lynch, Shannon M.; Mandelson, Margaret; McWilliams, Robert R.; Mendelsohn, Julie B.; Michaud, Dominique S.; Olson, Sara H.; Overvad, Kim; Patel, Alpa V.; Peeters, Petra H.M.; Rajkovic, Aleksandar; Riboli, Elio; Risch, Harvey A.; Shu, Xiao-Ou; Thomas, Gilles; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Van Den Eeden, Stephen K.; Virtamo, Jarmo; Wactawski-Wende, Jean; Wolpin, Brian M.; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Chanock, Stephen J.; Hartge, Patricia; Hoover, Robert N.

    2010-01-01

    We conducted a two-stage genome-wide association study (GWAS) of pancreatic cancer, a cancer with one of the poorest survival rates worldwide. Initially, we genotyped 558,542 single nucleotide polymorphisms in 1,896 incident cases and 1,939 controls drawn from twelve prospective cohorts plus one hospital-based case-control study. In a combined analysis adjusted for study, sex, ancestry and five principal components that included an additional 2,457 cases and 2,654 controls from eight case-control studies, we identified an association between a locus on 9q34 and pancreatic cancer marked by the single nucleotide polymorphism, rs505922 (combined P=5.37 × 10-8; multiplicative per-allele odds ratio (OR) 1.20; 95% CI 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B. PMID:19648918

  10. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

    DEFF Research Database (Denmark)

    Earp, Madalene A; Kelemen, Linda E; Magliocco, Anthony M;

    2014-01-01

    Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by...... pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC......], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated...

  11. Genome-wide Analysis Identifies Novel Loci Associated with Ovarian Cancer Outcomes

    DEFF Research Database (Denmark)

    Johnatty, Sharon E; Tyrer, Jonathan P; Kar, Siddhartha;

    2015-01-01

    PURPOSE: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. EXPERIMENTAL DESIGN: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for ...

  12. 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...

  13. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia.

    Science.gov (United States)

    Lan, Qing; Hsiung, Chao A; Matsuo, Keitaro; Hong, Yun-Chul; Seow, Adeline; Wang, Zhaoming; Hosgood, H Dean; Chen, Kexin; Wang, Jiu-Cun; Chatterjee, Nilanjan; Hu, Wei; Wong, Maria Pik; Zheng, Wei; Caporaso, Neil; Park, Jae Yong; Chen, Chien-Jen; Kim, Yeul Hong; Kim, Young Tae; Landi, Maria Teresa; Shen, Hongbing; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Yuenger, Jeffrey; Jacobs, Kevin B; Chang, I-Shou; Mitsudomi, Tetsuya; Kim, Hee Nam; Chang, Gee-Chen; Bassig, Bryan A; Tucker, Margaret; Wei, Fusheng; Yin, Zhihua; Wu, Chen; An, She-Juan; Qian, Biyun; Lee, Victor Ho Fun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Kim, Jin Hee; Gao, Yu-Tang; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Hutchinson, Amy; Wang, Wen-Chang; Klein, Robert; Chung, Charles C; Oh, In-Jae; Chen, Kuan-Yu; Berndt, Sonja I; He, Xingzhou; Wu, Wei; Chang, Jiang; Zhang, Xu-Chao; Huang, Ming-Shyan; Zheng, Hong; Wang, Junwen; Zhao, Xueying; Li, Yuqing; Choi, Jin Eun; Su, Wu-Chou; Park, Kyong Hwa; Sung, Sook Whan; Shu, Xiao-Ou; Chen, Yuh-Min; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Pao, William; Kim, Young-Chul; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Su, Jian; Wang, Chih-Liang; Li, Haixin; Sihoe, Alan Dart Loon; Zhao, Zhenhong; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Kohno, Takashi; Kweon, Sun-Seog; Chen, Chih-Yi; Vermeulen, Roel; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chow, Wong-Ho; Ji, Bu-Tian; Chan, John K C; Chu, Minjie; Li, Yao-Jen; Yokota, Jun; Li, Jihua; Chen, Hongyan; Xiang, Yong-Bing; Yu, Chong-Jen; Kunitoh, Hideo; Wu, Guoping; Jin, Li; Lo, Yen-Li; Shiraishi, Kouya; Chen, Ying-Hsiang; Lin, Hsien-Chih; Wu, Tangchun; Wu, Yi-Long; Yang, Pan-Chyr; Zhou, Baosen; Shin, Min-Ho; Fraumeni, Joseph F; Lin, Dongxin; Chanock, Stephen J; Rothman, Nathaniel

    2012-12-01

    To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10(-6)) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10(-18)), 6q22.2 (rs9387478, P = 4.14 × 10(-10)) and 6p21.32 (rs2395185, P = 9.51 × 10(-9)). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking. PMID:23143601

  14. Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia

    Science.gov (United States)

    Lan, Qing; Hsiung, Chao A; Matsuo, Keitaro; Hong, Yun-Chul; Seow, Adeline; Wang, Zhaoming; Hosgood, H Dean; Chen, Kexin; Wang, Jiu-Cun; Chatterjee, Nilanjan; Hu, Wei; Wong, Maria Pik; Zheng, Wei; Caporaso, Neil; Park, Jae Yong; Chen, Chien-Jen; Kim, Yeul Hong; Kim, Young Tae; Landi, Maria Teresa; Shen, Hongbing; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Yuenger, Jeffrey; Jacobs, Kevin B; Chang, I-Shou; Mitsudomi, Tetsuya; Kim, Hee Nam; Chang, Gee-Chen; Bassig, Bryan A; Tucker, Margaret; Wei, Fusheng; Yin, Zhihua; Wu, Chen; An, She-Juan; Qian, Biyun; Lee, Victor Ho Fun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Kim, Jin Hee; Gao, Yu-Tang; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Hutchinson, Amy; Wang, Wen-Chang; Klein, Robert; Chung, Charles C; Oh, In-Jae; Chen, Kuan-Yu; Berndt, Sonja I; He, Xingzhou; Wu, Wei; Chang, Jiang; Zhang, Xu-Chao; Huang, Ming-Shyan; Zheng, Hong; Wang, Junwen; Zhao, Xueying; Li, Yuqing; Choi, Jin Eun; Su, Wu-Chou; Park, Kyong Hwa; Sung, Sook Whan; Shu, Xiao-Ou; Chen, Yuh-Min; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Pao, William; Kim, Young-Chul; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Su, Jian; Wang, Chih-Liang; Li, Haixin; Sihoe, Alan Dart Loon; Zhao, Zhenhong; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Kohno, Takashi; Kweon, Sun-Seog; Chen, Chih-Yi; Vermeulen, Roel; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chow, Wong-Ho; Ji, Bu-Tian; Chan, John K C; Chu, Minjie; Li1, Yao-Jen; Yokota, Jun; Li, Jihua; Chen, Hongyan; Xiang, Yong-Bing; Yu, Chong-Jen; Kunitoh, Hideo; Wu, Guoping; Jin, Li; Lo, Yen-Li; Shiraishi, Kouya; Chen, Ying-Hsiang; Lin, Hsien-Chih; Wu, Tangchun; Wu, Yi-Long; Yang, Pan-Chyr; Zhou, Baosen; Shin, Min-Ho; Fraumeni, Joseph F; Lin, Dongxin; Chanock, Stephen J; Rothman, Nathaniel

    2014-01-01

    To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking. PMID:23143601

  15. 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

  16. FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women

    OpenAIRE

    Barnholtz-Sloan, Jill S; Shetty, Priya B; Guan, Xiaowei; Nyante, Sarah J; Luo, Jingchun; Brennan, Donal J.; Millikan, Robert C.

    2010-01-01

    Twenty-nine single-nucleotide polymorphisms (SNPs) from previously published genome-wide association studies (GWAS) and multiple ancestry informative markers were genotyped in the Carolina Breast Cancer Study (CBCS) (742 African-American (AA) cases, 1230 White cases; 658 AA controls, 1118 White controls). In the entire study population, 9/10 SNPs in fibroblast growth factor receptor 2 (FGFR2) were significantly associated with breast cancer after adjusting for age, race and European ancestry ...

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

    Science.gov (United States)

    Kote-Jarai, Zsofia; Olama, Ali Amin Al; Giles, Graham G.; Severi, Gianluca; Schleutker, Johanna; Weischer, Maren; Canzian, Frederico; Riboli, Elio; Key, Tim; Gronberg, Henrik; Hunter, David J.; Kraft, Peter; Thun, Michael J; Ingles, Sue; Chanock, Stephen; Albanes, Demetrius; Hayes, Richard B; Neal, David E.; Hamdy, Freddie C.; Donovan, Jenny L.; Pharoah, Paul; Schumacher, Fredrick; Henderson, Brian E.; Stanford, Janet L.; Ostrander, Elaine A.; Sorensen, Karina Dalsgaard; Dörk, Thilo; Andriole, Gerald; Dickinson, Joanne L.; Cybulski, Cezary; Lubinski, Jan; Spurdle, Amanda; Clements, Judith A.; Chambers, Suzanne; Aitken, Joanne; Frank Gardiner, R. A.; Thibodeau, Stephen N.; Schaid, Dan; John, Esther M.; Maier, Christiane; Vogel, Walther; Cooney, Kathleen A.; Park, Jong Y.; Cannon-Albright, Lisa; Brenner, Hermann; Habuchi, Tomonori; Zhang, Hong-Wei; Lu, Yong-Jie; Kaneva, Radka; Muir, Ken; Benlloch, Sara; Leongamornlert, Daniel A.; Saunders, Edward J.; Tymrakiewicz, Malgorzata; Mahmud, Nadiya; Guy, Michelle; 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; Christmas, Tim; Ogden, Chris; Cooper, Colin S.; Lophatonanon, Aritaya; Southey, Melissa C.; Hopper, John L.; English, Dallas; Wahlfors, Tiina; Tammela, Teuvo LJ; Klarskov, Peter; Nordestgaard, Børge G.; Røder, M. Andreas; Tybjærg-Hansen, Anne; Bojesen, Stig E.; Travis, Ruth; Campa, Daniele; Kaaks, Rudolf; Wiklund, Fredrik; Aly, Markus; Lindstrom, Sara; Diver, W Ryan; Gapstur, Susan; Stern, Mariana C; Corral, Roman; Virtamo, Jarmo; Cox, Angela; Haiman, Christopher A.; Le Marchand, Loic; FitzGerald, Liesel; Kolb, Suzanne; Kwon, Erika M.; Karyadi, Danielle M.; Orntoft, Torben Falck; Borre, Michael; Meyer, Andreas; Serth, Jürgen; Yeager, Meredith; Berndt, Sonja I.; Marthick, James R; Patterson, Briony; Wokolorczyk, Dominika; Batra, Jyotsna; Lose, Felicity; McDonnell, Shannon K; Joshi, Amit D.; Shahabi, Ahva; Rinckleb, Antje E.; Ray, Ana; Sellers, Thomas A.; Lin, Huo-Yi; Stephenson, Robert A; Farnham, James; Muller, Heiko; Rothenbacher, Dietrich; Tsuchiya, Norihiko; Narita, Shintaro; Cao, Guang-Wen; Slavov, Chavdar; Mitev, Vanio; Easton, Douglas F.; Eeles, Rosalind A.

    2012-01-01

    Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we conducted a multi-stage genome-wide association study and previously reported the results of the first two stages, which identified 16 novel susceptibility loci for PrCa. Here we report the results of stage 3 in which we evaluated 1,536 SNPs in 4,574 cases and 4,164 controls. Ten novel association signals were followed up through genotyping in 51,311 samples in 30 studies through the international PRACTICAL consortium. In addition to previously reported loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2p, 3q, 5p, 6p, 12q and Xq (P=4.0 ×10−8 to P=2.7 ×10−24). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ~25% of the familial risk in this disease, have now been identified. PMID:21743467

  18. Pathway-based analysis using genome-wide association data from a Korean non-small cell lung cancer study.

    Directory of Open Access Journals (Sweden)

    Donghoon Lee

    Full Text Available Pathway-based analysis, used in conjunction with genome-wide association study (GWAS techniques, is a powerful tool to detect subtle but systematic patterns in genome that can help elucidate complex diseases, like cancers. Here, we stepped back from genetic polymorphisms at a single locus and examined how multiple association signals can be orchestrated to find pathways related to lung cancer susceptibility. We used single-nucleotide polymorphism (SNP array data from 869 non-small cell lung cancer (NSCLC cases from a previous GWAS at the National Cancer Center and 1,533 controls from the Korean Association Resource project for the pathway-based analysis. After mapping single-nucleotide polymorphisms to genes, considering their coding region and regulatory elements (±20 kbp, multivariate logistic regression of additive and dominant genetic models were fitted against disease status, with adjustments for age, gender, and smoking status. Pathway statistics were evaluated using Gene Set Enrichment Analysis (GSEA and Adaptive Rank Truncated Product (ARTP methods. Among 880 pathways, 11 showed relatively significant statistics compared to our positive controls (PGSEA≤0.025, false discovery rate≤0.25. Candidate pathways were validated using the ARTP method and similarities between pathways were computed against each other. The top-ranked pathways were ABC Transporters (PGSEA<0.001, PARTP = 0.001, VEGF Signaling Pathway (PGSEA<0.001, PARTP = 0.008, G1/S Check Point (PGSEA = 0.004, PARTP = 0.013, and NRAGE Signals Death through JNK (PGSEA = 0.006, PARTP = 0.001. Our results demonstrate that pathway analysis can shed light on post-GWAS research and help identify potential targets for cancer susceptibility.

  19. Genome-wide association studies identify four ER negative-specific breast cancer risk loci

    DEFF Research Database (Denmark)

    Garcia-Closas, Montserrat; Couch, Fergus J; Lindstrom, Sara;

    2013-01-01

    Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including diff...

  20. 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

    identified at least 30 distinct loci associated with small differences in risk. We conducted a GWAS in 2782 advanced PrCa cases (Gleason grade ≥ 8 or tumor stage C/D) and 4458 controls with 571 243 single nucleotide polymorphisms (SNPs). Based on in silico replication of 4679 SNPs (Stage 1, P <0.02) in two...... 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 for these...

  1. Genome Wide Methylome Alterations in Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Nandita Mullapudi

    Full Text Available Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC, we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T-non-tumor (NT pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16. Further, when DM was coupled to differential transcriptome (DE in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents.

  2. Genome-wide association study identifies a region on chromosome 11q14.3 associated with late rectal bleeding following radiation therapy for prostate cancer*

    Science.gov (United States)

    Kerns, Sarah L.; Stock, Richard; Stone, Nelson N.; Blacksburg, Seth R.; Rath, Lynda; Vega, Ana; Fachal, Laura; Gómez-Caamaño, Antonio; De Ruysscher, Dirk; Lammering, Guido; Parliament, Matthew; Blackshaw, Michael; Sia, Michael; Cesaretti, Jamie; Terk, Mitchell; Hixson, Rosetta; Rosenstein, Barry S.; Ostrer, Harry

    2013-01-01

    Background and Purpose Rectal bleeding can occur following radiotherapy for prostate cancer and negatively impacts quality of life for cancer survivors. Treatment and clinical factors do not fully predict for rectal bleeding, and genetic factors may be important. Materials and Methods A genome-wide association study (GWAS) was performed to identify SNPs associated with development of late rectal bleeding following radiotherapy for prostate cancer. Logistic regression was used to test association between 614,453 SNPs and rectal bleeding in a discovery cohort (79 cases, 289 controls), and top-ranking SNPs were tested in a replication cohort (108 cases, 673 controls) from four independent sites. Results rs7120482 and rs17630638, which tag a single locus on chromosome 11q14.3, reached genome-wide significance for association with rectal bleeding (combined p-values 5.4×10−8 and 6.9×10−7 respectively). Several other SNPs had p-values trending towards genome-wide significance, and a polygenic risk score including these SNPs shows a strong rank-correlation with rectal bleeding (Sommers’ d = 5.0×10−12 in the replication cohort). Conclusions This GWAS identified novel genetic markers of rectal bleeding following prostate radiotherapy. These findings could lead to development of a predictive assay to identify patients at risk for this adverse treatment outcome so that dose or treatment modality could be modified. PMID:23719583

  3. Genome-wide association study identifies a region on chromosome 11q14.3 associated with late rectal bleeding following radiation therapy for prostate cancer

    International Nuclear Information System (INIS)

    Background and purpose: Rectal bleeding can occur following radiotherapy for prostate cancer and negatively impacts quality of life for cancer survivors. Treatment and clinical factors do not fully predict rectal bleeding, and genetic factors may be important. Materials and methods: A genome-wide association study (GWAS) was performed to identify SNPs associated with the development of late rectal bleeding following radiotherapy for prostate cancer. Logistic regression was used to test the association between 614,453 SNPs and rectal bleeding in a discovery cohort (79 cases, 289 controls), and top-ranking SNPs were tested in a replication cohort (108 cases, 673 controls) from four independent sites. Results: rs7120482 and rs17630638, which tag a single locus on chromosome 11q14.3, reached genome-wide significance for association with rectal bleeding (combined p-values 5.4 × 10−8 and 6.9 × 10−7 respectively). Several other SNPs had p-values trending toward genome-wide significance, and a polygenic risk score including these SNPs shows a strong rank-correlation with rectal bleeding (Sommers’ d = 5.0 × 10−12 in the replication cohort). Conclusions: This GWAS identified novel genetic markers of rectal bleeding following prostate radiotherapy. These findings could lead to the development of a predictive assay to identify patients at risk for this adverse treatment outcome so that dose or treatment modality could be modified

  4. Evaluating genome-wide association study-identified breast cancer risk variants in African-American women.

    Directory of Open Access Journals (Sweden)

    Jirong Long

    Full Text Available Genome-wide association studies (GWAS, conducted mostly in European or Asian descendants, have identified approximately 67 genetic susceptibility loci for breast cancer. Given the large differences in genetic architecture between the African-ancestry genome and genomes of Asians and Europeans, it is important to investigate these loci in African-ancestry populations. We evaluated index SNPs in all 67 breast cancer susceptibility loci identified to date in our study including up to 3,300 African-American women (1,231 cases and 2,069 controls, recruited in the Southern Community Cohort Study (SCCS and the Nashville Breast Health Study (NBHS. Seven SNPs were statistically significant (P ≤ 0.05 with the risk of overall breast cancer in the same direction as previously reported: rs10069690 (5p15/TERT, rs999737 (14q24/RAD51L1, rs13387042 (2q35/TNP1, rs1219648 (10q26/FGFR2, rs8170 (19p13/BABAM1, rs17817449 (16q12/FTO, and rs13329835 (16q23/DYL2. A marginally significant association (P<0.10 was found for three additional SNPs: rs1045485 (2q33/CASP8, rs4849887 (2q14/INHBB, and rs4808801 (19p13/ELL. Three additional SNPs, including rs1011970 (9p21/CDKN2A/2B, rs941764 (14q32/CCDC88C, and rs17529111 (6q14/FAM46A, showed a significant association in analyses conducted by breast cancer subtype. The risk of breast cancer was elevated with an increasing number of risk variants, as measured by quintile of the genetic risk score, from 1.00 (reference, to 1.75 (1.30-2.37, 1.56 (1.15-2.11, 2.02 (1.50-2.74 and 2.63 (1.96-3.52, respectively, (P = 7.8 × 10(-10. Results from this study highlight the need for large genetic studies in AAs to identify risk variants impacting this population.

  5. Genome-wide analysis identifies novel loci associated with ovarian cancer outcomes: findings from the Ovarian Cancer Association Consortium

    Science.gov (United States)

    Johnatty, Sharon E.; Tyrer, Jonathan P.; Kar, Siddhartha; Beesley, Jonathan; Lu, Yi; Gao, Bo; Fasching, Peter A.; Hein, Alexander; Ekici, Arif B.; Beckmann, Matthias W.; Lambrechts, Diether; Nieuwenhuysen, Els Van; Vergote, Ignace; Lambrechts, Sandrina; Rossing, Mary Anne; Doherty, Jennifer A.; Chang-Claude, Jenny; Modugno, Francesmary; Ness, Roberta B.; Moysich, Kirsten B.; Levine, Douglas A.; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; Gronwald, Jacek; Lubiński, Jan; Jakubowska, Anna; Cybulski, Cezary; Brinton, Louise; Lissowska, Jolanta; Wentzensen, Nicolas; Song, Honglin; Rhenius, Valerie; Campbell, Ian; Eccles, Diana; Sieh, Weiva; Whittemore, Alice S.; McGuire, Valerie; Rothstein, Joseph H.; Sutphen, Rebecca; Anton-Culver, Hoda; Ziogas, Argyrios; Gayther, Simon A.; Gentry-Maharaj, Aleksandra; Menon, Usha; Ramus, Susan J.; Pearce, Celeste L; Pike, Malcolm C; Stram, Daniel O.; Wu, Anna H.; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Rzepecka, Iwona K.; Spiewankiewicz, Beata; Goodman, Marc T.; Wilkens, Lynne R.; Carney, Michael E.; Thompson, Pamela J; Heitz, Florian; du Bois, Andreas; Schwaab, Ira; Harter, Philipp; Pisterer, Jacobus; Hillemanns, Peter; Karlan, Beth Y.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Winham, Stacey J; Earp, Madalene; Larson, Melissa C.; Fogarty, Zachary C.; Høgdall, Estrid; Jensen, Allan; Kjaer, Susanne Kruger; Fridley, Brooke L.; Cunningham, Julie M.; Vierkant, Robert A.; Schildkraut, Joellen M.; Iversen, Edwin S.; Terry, Kathryn L.; Cramer, Daniel W.; Bandera, Elisa V.; Orlow, Irene; Pejovic, Tanja; Bean, Yukie; Høgdall, Claus; Lundvall, Lene; McNeish, Ian; Paul, James; Carty, Karen; Siddiqui, Nadeem; Glasspool, Rosalind; Sellers, Thomas; Kennedy, Catherine; Chiew, Yoke-Eng; Berchuck, Andrew; MacGregor, Stuart; deFazio, Anna; Pharoah, Paul D.P.; Goode, Ellen L.; deFazio, Anna; Webb, Penelope M.; Chenevix-Trench, Georgia

    2015-01-01

    Purpose Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design We analyzed ~2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent firstline treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients including patients from The Cancer Genome Atlas. Additionally we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results Five SNPs were significantly associated (p≤1.0x10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23) and rs6674079 (1q22) were located in long non-coding RNAs (lncRNAs) RP11–179A10.1, RP11–314O13.1 and RP11–284F21.8 respectively (p≤7.1x10−6). ENCODE ChIP-seq data at 1q22 for normal ovary shows evidence of histone modification around RP11–284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression, and HDL-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA≤6x10−3). Conclusion We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. PMID:26152742

  6. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    DEFF Research Database (Denmark)

    Couch, Fergus J; Wang, Xianshu; McGuffog, Lesley;

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a fur...

  7. Genome-wide association study of circulating retinol levels

    OpenAIRE

    Mondul, Alison M.; Yu, Kai; Wheeler, William; Zhang, Hong; Weinstein, Stephanie J.; Major, Jacqueline M.; Cornelis, Marilyn C; Männistö, Satu; Hazra, Aditi; Hsing, Ann W.; Jacobs, Kevin B.; Eliassen, Heather; Tanaka, Toshiko; Reding, Douglas J.; Hendrickson, Sara

    2011-01-01

    Retinol is one of the most biologically active forms of vitamin A and is hypothesized to influence a wide range of human diseases including asthma, cardiovascular disease, infectious diseases and cancer. We conducted a genome-wide association study of 5006 Caucasian individuals drawn from two cohorts of men: the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study and the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. We identified two independent single-nucl...

  8. Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

    Directory of Open Access Journals (Sweden)

    Fergus J Couch

    Full Text Available BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer, with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8, HR = 1.14, 95% CI: 1.09-1.20. In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8, HR = 1.27, 95% CI: 1.17-1.38 and 4q32.3 (rs4691139, P = 3.4 × 10(-8, HR = 1.20, 95% CI: 1.17-1.38. The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4. These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

  9. Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

    Science.gov (United States)

    Wang, Xianshu; McGuffog, Lesley; Lee, Andrew; Olswold, Curtis; Kuchenbaecker, Karoline B.; Soucy, Penny; Fredericksen, Zachary; Barrowdale, Daniel; Dennis, Joe; Gaudet, Mia M.; Dicks, Ed; Kosel, Matthew; Healey, Sue; Sinilnikova, Olga M.; Lee, Adam; Bacot, François; Vincent, Daniel; Hogervorst, Frans B. L.; Peock, Susan; Stoppa-Lyonnet, Dominique; Jakubowska, Anna; Investigators, kConFab; Radice, Paolo; Schmutzler, Rita Katharina; Domchek, Susan M.; Piedmonte, Marion; Singer, Christian F.; Friedman, Eitan; Thomassen, Mads; Hansen, Thomas V. O.; Neuhausen, Susan L.; Szabo, Csilla I.; Blanco, Ignacio; Greene, Mark H.; Karlan, Beth Y.; Garber, Judy; Phelan, Catherine M.; Weitzel, Jeffrey N.; Montagna, Marco; Olah, Edith; Andrulis, Irene L.; Godwin, Andrew K.; Yannoukakos, Drakoulis; Goldgar, David E.; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; Terry, Mary Beth; Daly, Mary B.; van Rensburg, Elizabeth J.; Hamann, Ute; Ramus, Susan J.; Ewart Toland, Amanda; Caligo, Maria A.; Olopade, Olufunmilayo I.; Tung, Nadine; Claes, Kathleen; Beattie, Mary S.; Southey, Melissa C.; Imyanitov, Evgeny N.; Tischkowitz, Marc; Janavicius, Ramunas; John, Esther M.; Kwong, Ava; Diez, Orland; Balmaña, Judith; Barkardottir, Rosa B.; Arun, Banu K.; Rennert, Gad; Teo, Soo-Hwang; Ganz, Patricia A.; Campbell, Ian; van der Hout, Annemarie H.; van Deurzen, Carolien H. M.; Seynaeve, Caroline; Gómez Garcia, Encarna B.; van Leeuwen, Flora E.; Meijers-Heijboer, Hanne E. J.; Gille, Johannes J. P.; Ausems, Margreet G. E. M.; Blok, Marinus J.; Ligtenberg, Marjolijn J. L.; Rookus, Matti A.; Devilee, Peter; Verhoef, Senno; van Os, Theo A. M.; Wijnen, Juul T.; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D. Gareth; Izatt, Louise; Eeles, Rosalind A.; Adlard, Julian; Eccles, Diana M.; Cook, Jackie; Brewer, Carole; Douglas, Fiona; Hodgson, Shirley; Morrison, Patrick J.; Side, Lucy E.; Donaldson, Alan; Houghton, Catherine; Rogers, Mark T.; Dorkins, Huw; Eason, Jacqueline; Gregory, Helen; McCann, Emma; Murray, Alex; Calender, Alain; Hardouin, Agnès; Berthet, Pascaline; Delnatte, Capucine; Nogues, Catherine; Lasset, Christine; Houdayer, Claude; Leroux, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Sobol, Hagay; Coupier, Isabelle; Venat-Bouvet, Laurence; Castera, Laurent; Gauthier-Villars, Marion; Léoné, Mélanie; Pujol, Pascal; Mazoyer, Sylvie; Bignon, Yves-Jean; Złowocka-Perłowska, Elżbieta; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Huzarski, Tomasz; Spurdle, Amanda B.; Viel, Alessandra; Peissel, Bernard; Bonanni, Bernardo; Melloni, Giulia; Ottini, Laura; Papi, Laura; Varesco, Liliana; Tibiletti, Maria Grazia; Peterlongo, Paolo; Volorio, Sara; Manoukian, Siranoush; Pensotti, Valeria; Arnold, Norbert; Engel, Christoph; Deissler, Helmut; Gadzicki, Dorothea; Gehrig, Andrea; Kast, Karin; Rhiem, Kerstin; Meindl, Alfons; Niederacher, Dieter; Ditsch, Nina; Plendl, Hansjoerg; Preisler-Adams, Sabine; Engert, Stefanie; Sutter, Christian; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Weber, Bernhard H. F.; Arver, Brita; Stenmark-Askmalm, Marie; Loman, Niklas; Rosenquist, Richard; Einbeigi, Zakaria; Nathanson, Katherine L.; Rebbeck, Timothy R.; Blank, Stephanie V.; Cohn, David E.; Rodriguez, Gustavo C.; Small, Laurie; Friedlander, Michael; Bae-Jump, Victoria L.; Fink-Retter, Anneliese; Rappaport, Christine; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Tea, Muy-Kheng; Lindor, Noralane M.; Kaufman, Bella; Shimon Paluch, Shani; Laitman, Yael; Skytte, Anne-Bine; Gerdes, Anne-Marie; Pedersen, Inge Sokilde; Moeller, Sanne Traasdahl; Kruse, Torben A.; Jensen, Uffe Birk; Vijai, Joseph; Sarrel, Kara; Robson, Mark; Kauff, Noah; Mulligan, Anna Marie; Glendon, Gord; Ozcelik, Hilmi; Ejlertsen, Bent; Nielsen, Finn C.; Jønson, Lars; Andersen, Mette K.; Ding, Yuan Chun; Steele, Linda; Foretova, Lenka; Teulé, Alex; Lazaro, Conxi; Brunet, Joan; Pujana, Miquel Angel; Mai, Phuong L.; Loud, Jennifer T.; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Narod, Steven A.; Herzog, Josef; Sand, Sharon R.; Tognazzo, Silvia; Agata, Simona; Vaszko, Tibor; Weaver, Joellen; Stavropoulou, Alexandra V.; Buys, Saundra S.; Romero, Atocha; de la Hoya, Miguel; Aittomäki, Kristiina; Muranen, Taru A.; Duran, Mercedes; Chung, Wendy K.; Lasa, Adriana; Dorfling, Cecilia M.; Miron, Alexander; Benitez, Javier; Senter, Leigha; Huo, Dezheng; Chan, Salina B.; Sokolenko, Anna P.; Chiquette, Jocelyne; Tihomirova, Laima; Friebel, Tara M.; Agnarsson, Bjarni A.; Lu, Karen H.; Lejbkowicz, Flavio; James, Paul A.; Hall, Per; Dunning, Alison M.; Tessier, Daniel; Cunningham, Julie; Slager, Susan L.; Wang, Chen; Hart, Steven; Stevens, Kristen; Simard, Jacques; Pastinen, Tomi; Pankratz, Vernon S.; Offit, Kenneth; Antoniou, Antonis C.

    2013-01-01

    BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, HR = 1.20, 95% CI: 1.17–1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10−4). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%–50% compared to 81%–100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers. PMID:23544013

  10. A 2-Stage Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms Associated With Development of Erectile Dysfunction Following Radiation Therapy for Prostate Cancer

    International Nuclear Information System (INIS)

    Purpose: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy. Methods and Materials: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays. Results: Twelve SNPs identified in the discovery cohort and validated in the replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1 × 10−5 to 6.2 × 10−4). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers’ D P value = 1.7 × 10−29). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value = 2.1 × 10−19). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage. Conclusions: This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.

  11. A 2-Stage Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms Associated With Development of Erectile Dysfunction Following Radiation Therapy for Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kerns, Sarah L. [Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York (United States); Departments of Pathology and Genetics, Albert Einstein College of Medicine, Bronx, New York (United States); Stock, Richard [Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York (United States); Stone, Nelson [Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York (United States); Department of Urology, Mount Sinai School of Medicine, New York, New York (United States); Buckstein, Michael [Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York (United States); Shao, Yongzhao [Division of Biostatistics, New York University School of Medicine, New York, New York (United States); Campbell, Christopher [Departments of Pathology and Genetics, Albert Einstein College of Medicine, Bronx, New York (United States); Rath, Lynda [Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York (United States); De Ruysscher, Dirk; Lammering, Guido [Department of Radiation Oncology, Maastricht University Medical Center, Maastricht (Netherlands); Hixson, Rosetta; Cesaretti, Jamie; Terk, Mitchell [Florida Radiation Oncology Group, Jacksonville, Florida (United States); Ostrer, Harry [Departments of Pathology and Genetics, Albert Einstein College of Medicine, Bronx, New York (United States); Rosenstein, Barry S., E-mail: barry.rosenstein@mssm.edu [Department of Radiation Oncology, Mount Sinai School of Medicine, New York, New York (United States); Department of Radiation Oncology, New York University School of Medicine, New York, New York (United States); Departments of Dermatology and Preventive Medicine, Mount Sinai School of Medicine, New York, New York (United States)

    2013-01-01

    Purpose: To identify single nucleotide polymorphisms (SNPs) associated with development of erectile dysfunction (ED) among prostate cancer patients treated with radiation therapy. Methods and Materials: A 2-stage genome-wide association study was performed. Patients were split randomly into a stage I discovery cohort (132 cases, 103 controls) and a stage II replication cohort (128 cases, 102 controls). The discovery cohort was genotyped using Affymetrix 6.0 genome-wide arrays. The 940 top ranking SNPs selected from the discovery cohort were genotyped in the replication cohort using Illumina iSelect custom SNP arrays. Results: Twelve SNPs identified in the discovery cohort and validated in the replication cohort were associated with development of ED following radiation therapy (Fisher combined P values 2.1 Multiplication-Sign 10{sup -5} to 6.2 Multiplication-Sign 10{sup -4}). Notably, these 12 SNPs lie in or near genes involved in erectile function or other normal cellular functions (adhesion and signaling) rather than DNA damage repair. In a multivariable model including nongenetic risk factors, the odds ratios for these SNPs ranged from 1.6 to 5.6 in the pooled cohort. There was a striking relationship between the cumulative number of SNP risk alleles an individual possessed and ED status (Sommers' D P value = 1.7 Multiplication-Sign 10{sup -29}). A 1-allele increase in cumulative SNP score increased the odds for developing ED by a factor of 2.2 (P value = 2.1 Multiplication-Sign 10{sup -19}). The cumulative SNP score model had a sensitivity of 84% and specificity of 75% for prediction of developing ED at the radiation therapy planning stage. Conclusions: This genome-wide association study identified a set of SNPs that are associated with development of ED following radiation therapy. These candidate genetic predictors warrant more definitive validation in an independent cohort.

  12. Genome Wide Methylome Alterations in Lung Cancer.

    Science.gov (United States)

    Mullapudi, Nandita; Ye, Bin; Suzuki, Masako; Fazzari, Melissa; Han, Weiguo; Shi, Miao K; Marquardt, Gaby; Lin, Juan; Wang, Tao; Keller, Steven; Zhu, Changcheng; Locker, Joseph D; Spivack, Simon D

    2015-01-01

    Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; pLAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents. PMID:26683690

  13. Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms (SNPs) Associated With the Development of Erectile Dysfunction in African-American Men After Radiotherapy for Prostate Cancer

    International Nuclear Information System (INIS)

    Purpose: To identify single nucleotide polymorphisms (SNPs) associated with erectile dysfunction (ED) among African-American prostate cancer patients treated with external beam radiation therapy. Methods and Materials: A cohort of African-American prostate cancer patients treated with external beam radiation therapy was observed for the development of ED by use of the five-item Sexual Health Inventory for Men (SHIM) questionnaire. Final analysis included 27 cases (post-treatment SHIM score ≤7) and 52 control subjects (post-treatment SHIM score ≥16). A genome-wide association study was performed using approximately 909,000 SNPs genotyped on Affymetrix 6.0 arrays (Affymetrix, Santa Clara, CA). Results: We identified SNP rs2268363, located in the follicle-stimulating hormone receptor (FSHR) gene, as significantly associated with ED after correcting for multiple comparisons (unadjusted p = 5.46 x 10-8, Bonferroni p = 0.028). We identified four additional SNPs that tended toward a significant association with an unadjusted p value -6. Inference of population substructure showed that cases had a higher proportion of African ancestry than control subjects (77% vs. 60%, p = 0.005). A multivariate logistic regression model that incorporated estimated ancestry and four of the top-ranked SNPs was a more accurate classifier of ED than a model that included only clinical variables. Conclusions: To our knowledge, this is the first genome-wide association study to identify SNPs associated with adverse effects resulting from radiotherapy. It is important to note that the SNP that proved to be significantly associated with ED is located within a gene whose encoded product plays a role in male gonad development and function. Another key finding of this project is that the four SNPs most strongly associated with ED were specific to persons of African ancestry and would therefore not have been identified had a cohort of European ancestry been screened. This study demonstrates the

  14. Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC.

    Directory of Open Access Journals (Sweden)

    Rebecca Hein

    Full Text Available The 6q25.1 locus was first identified via a genome-wide association study (GWAS in Chinese women and marked by single nucleotide polymorphism (SNP rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR and 95% confidence intervals (CI. Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+ versus negative (ER- tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G = 1.36 (95% CI 1.26-1.48, p = 7.6 × 10(-14 in Asians and 1.09 (95% CI 1.07-1.11, p = 6.8 × 10(-18 in Europeans. rs12662670: OR (G/T = 1.29 (95% CI 1.19-1.41, p = 1.2 × 10(-9 in Asians and 1.12 (95% CI 1.08-1.17, p = 3.8 × 10(-9 in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER- = 1.20 (95% CI 1.15-1.25, p = 1.8 × 10(-17 versus OR (ER+ = 1.07 (95% CI 1.04-1.1, p = 1.3 × 10(-7, p(heterogeneity = 5.1 × 10(-6]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater

  15. Cancer associated epigenetic transitions identified by genome-wide histone methylation binding profiles in human colorectal cancer samples and paired normal mucosa

    International Nuclear Information System (INIS)

    Despite their well-established functional roles, histone modifications have received less attention than DNA methylation in the cancer field. In order to evaluate their importance in colorectal cancer (CRC), we generated the first genome-wide histone modification profiles in paired normal colon mucosa and tumor samples. Chromatin immunoprecipitation and microarray hybridization (ChIP-chip) was used to identify promoters enriched for histone H3 trimethylated on lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in paired normal colon mucosa and tumor samples from two CRC patients and for the CRC cell line HT29. By comparing histone modification patterns in normal mucosa and tumors, we found that alterations predicted to have major functional consequences were quite rare. Furthermore, when normal or tumor tissue samples were compared to HT29, high similarities were observed for H3K4me3. However, the differences found for H3K27me3, which is important in determining cellular identity, indicates that cell lines do not represent optimal tissue models. Finally, using public expression data, we uncovered previously unknown changes in CRC expression patterns. Genes positive for H3K4me3 in normal and/or tumor samples, which are typically already active in normal mucosa, became hyperactivated in tumors, while genes with H3K27me3 in normal and/or tumor samples and which are expressed at low levels in normal mucosa, became hypersilenced in tumors. Genome wide histone modification profiles can be used to find epigenetic aberrations in genes associated with cancer. This strategy gives further insights into the epigenetic contribution to the oncogenic process and may identify new biomarkers

  16. Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women.

    Science.gov (United States)

    Wang, Zhaoming; Seow, Wei Jie; Shiraishi, Kouya; Hsiung, Chao A; Matsuo, Keitaro; Liu, Jie; Chen, Kexin; Yamji, Taiki; Yang, Yang; Chang, I-Shou; Wu, Chen; Hong, Yun-Chul; Burdett, Laurie; Wyatt, Kathleen; Chung, Charles C; Li, Shengchao A; Yeager, Meredith; Hutchinson, Amy; Hu, Wei; Caporaso, Neil; Landi, Maria T; Chatterjee, Nilanjan; Song, Minsun; Fraumeni, Joseph F; Kohno, Takashi; Yokota, Jun; Kunitoh, Hideo; Ashikawa, Kyota; Momozawa, Yukihide; Daigo, Yataro; Mitsudomi, Tetsuya; Yatabe, Yasushi; Hida, Toyoaki; Hu, Zhibin; Dai, Juncheng; Ma, Hongxia; Jin, Guangfu; Song, Bao; Wang, Zhehai; Cheng, Sensen; Yin, Zhihua; Li, Xuelian; Ren, Yangwu; Guan, Peng; Chang, Jiang; Tan, Wen; Chen, Chien-Jen; Chang, Gee-Chen; Tsai, Ying-Huang; Su, Wu-Chou; Chen, Kuan-Yu; Huang, Ming-Shyan; Chen, Yuh-Min; Zheng, Hong; Li, Haixin; Cui, Ping; Guo, Huan; Xu, Ping; Liu, Li; Iwasaki, Motoki; Shimazu, Taichi; Tsugane, Shoichiro; Zhu, Junjie; Jiang, Gening; Fei, Ke; Park, Jae Yong; Kim, Yeul Hong; Sung, Jae Sook; Park, Kyong Hwa; Kim, Young Tae; Jung, Yoo Jin; Kang, Chang Hyun; Park, In Kyu; Kim, Hee Nam; Jeon, Hyo-Sung; Choi, Jin Eun; Choi, Yi Young; Kim, Jin Hee; Oh, In-Jae; Kim, Young-Chul; Sung, Sook Whan; Kim, Jun Suk; Yoon, Ho-Il; Kweon, Sun-Seog; Shin, Min-Ho; Seow, Adeline; Chen, Ying; Lim, Wei-Yen; Liu, Jianjun; Wong, Maria Pik; Lee, Victor Ho Fun; Bassig, Bryan A; Tucker, Margaret; Berndt, Sonja I; Chow, Wong-Ho; Ji, Bu-Tian; Wang, Junwen; Xu, Jun; Sihoe, Alan Dart Loon; Ho, James C M; Chan, John K C; Wang, Jiu-Cun; Lu, Daru; Zhao, Xueying; Zhao, Zhenhong; Wu, Junjie; Chen, Hongyan; Jin, Li; Wei, Fusheng; Wu, Guoping; An, She-Juan; Zhang, Xu-Chao; Su, Jian; Wu, Yi-Long; Gao, Yu-Tang; Xiang, Yong-Bing; He, Xingzhou; Li, Jihua; Zheng, Wei; Shu, Xiao-Ou; Cai, Qiuyin; Klein, Robert; Pao, William; Lawrence, Charles; Hosgood, H Dean; Hsiao, Chin-Fu; Chien, Li-Hsin; Chen, Ying-Hsiang; Chen, Chung-Hsing; Wang, Wen-Chang; Chen, Chih-Yi; Wang, Chih-Liang; Yu, Chong-Jen; Chen, Hui-Ling; Su, Yu-Chun; Tsai, Fang-Yu; Chen, Yi-Song; Li, Yao-Jen; Yang, Tsung-Ying; Lin, Chien-Chung; Yang, Pan-Chyr; Wu, Tangchun; Lin, Dongxin; Zhou, Baosen; Yu, Jinming; Shen, Hongbing; Kubo, Michiaki; Chanock, Stephen J; Rothman, Nathaniel; Lan, Qing

    2016-02-01

    Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings. PMID:26732429

  17. 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.

    2013-01-01

    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 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. PMID:23065704

  18. Genome-wide association study of multiplex schizophrenia pedigrees

    DEFF Research Database (Denmark)

    Levinson, Douglas F; Shi, Jianxin; Wang, Kai;

    2012-01-01

    The authors used a genome-wide association study (GWAS) of multiply affected families to investigate the association of schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare copy number variants (CNVs)....

  19. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2

    DEFF Research Database (Denmark)

    Song, Honglin; Ramus, Susan J; Tyrer, Jonathan;

    2009-01-01

    ,817 cases and 2,353 controls from the UK and approximately 2 million imputed SNPs. We genotyped the 22,790 top ranked SNPs in 4,274 cases and 4,809 controls of European ancestry from Europe, USA and Australia. We identified 12 SNPs at 9p22 associated with disease risk (P < 10(-8)). The most significant SNP...... (rs3814113; P = 2.5 x 10(-17)) was genotyped in a further 2,670 ovarian cancer cases and 4,668 controls, confirming its association (combined data odds ratio (OR) = 0.82, 95% confidence interval (CI) 0.79-0.86, P(trend) = 5.1 x 10(-19)). The association differs by histological subtype, being strongest...

  20. Identification of a breast cancer susceptibility locus at 4q31.22 using a genome-wide association study paradigm.

    Directory of Open Access Journals (Sweden)

    Yadav Sapkota

    Full Text Available More than 40 single nucleotide polymorphisms (SNPs for breast cancer susceptibility were identified by genome-wide association studies (GWASs. However, additional SNPs likely contribute to breast cancer susceptibility and overall genetic risk, prompting this investigation for additional variants. Six putative breast cancer susceptibility SNPs identified in a two-stage GWAS that we reported earlier were replicated in a follow-up stage 3 study using an independent set of breast cancer cases and controls from Canada, with an overall cumulative sample size of 7,219 subjects across all three stages. The study design also encompassed the 11 variants from GWASs previously reported by various consortia between the years 2007-2009 to (i enable comparisons of effect sizes, and (ii identify putative prognostic variants across studies. All SNP associations reported with breast cancer were also adjusted for body mass index (BMI. We report a strong association with 4q31.22-rs1429142 (combined per allele odds ratio and 95% confidence interval = 1.28 [1.17-1.41] and P combined = 1.5×10(-7, when adjusted for BMI. Ten of the 11 breast cancer susceptibility loci reported by consortia also showed associations in our predominantly Caucasian study population, and the associations were independent of BMI; four FGFR2 SNPs and TNRC9-rs3803662 were among the most notable associations. Since the original report by Garcia-Closas et al. 2008, this is the second study to confirm the association of 8q24.21-rs13281615 with breast cancer outcomes.

  1. Genome-Wide Scan Reveals Mutation Associated with Melanoma

    Science.gov (United States)

    ... 1999 Spotlight on Research 2012 July 2012 (historical) Genome-Wide Scan Reveals Mutation Associated with Melanoma A ... out to see if a technology called whole genome sequencing would help them find other genetic risk ...

  2. Genome-wide association study of serum selenium concentrations

    DEFF Research Database (Denmark)

    Gong, Jian; Hsu, Li; Harrison, Tabitha;

    2013-01-01

    Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated this...... hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening and the Women’s Health Initiative (WHI). We...... tested association between 2,474,333 single nucleotide polymorphisms (SNPs) and serum selenium concentrations using linear regression models. In the first stage (PLCO) 41 SNPs clustered in 15 regions had p < 1 × 10−5. None of these 41 SNPs reached the significant threshold (p = 0.05/15 regions = 0...

  3. Genome-wide association study of clinical dimensions of schizophrenia

    DEFF Research Database (Denmark)

    Fanous, Ayman H; Zhou, Baiyu; Aggen, Steven H;

    2012-01-01

    Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia.......Multiple sources of evidence suggest that genetic factors influence variation in clinical features of schizophrenia. The authors present the first genome-wide association study (GWAS) of dimensional symptom scores among individuals with schizophrenia....

  4. Systems-Level Analysis of Genome-Wide Association Data

    OpenAIRE

    Farber, Charles R

    2013-01-01

    Genome-wide association studies (GWAS) have emerged as the method of choice for identifying common variants affecting complex disease. In a GWAS, particular attention is placed, for obvious reasons, on single-nucleotide polymorphisms (SNPs) that exceed stringent genome-wide significance thresholds. However, it is expected that many SNPs with only nominal evidence of association (e.g., P < 0.05) truly influence disease. Efforts to extract additional biological information from entire GWAS data...

  5. GWAMA: software for genome-wide association meta-analysis

    Directory of Open Access Journals (Sweden)

    Mägi Reedik

    2010-05-01

    Full Text Available Abstract Background Despite the recent success of genome-wide association studies in identifying novel loci contributing effects to complex human traits, such as type 2 diabetes and obesity, much of the genetic component of variation in these phenotypes remains unexplained. One way to improving power to detect further novel loci is through meta-analysis of studies from the same population, increasing the sample size over any individual study. Although statistical software analysis packages incorporate routines for meta-analysis, they are ill equipped to meet the challenges of the scale and complexity of data generated in genome-wide association studies. Results We have developed flexible, open-source software for the meta-analysis of genome-wide association studies. The software incorporates a variety of error trapping facilities, and provides a range of meta-analysis summary statistics. The software is distributed with scripts that allow simple formatting of files containing the results of each association study and generate graphical summaries of genome-wide meta-analysis results. Conclusions The GWAMA (Genome-Wide Association Meta-Analysis software has been developed to perform meta-analysis of summary statistics generated from genome-wide association studies of dichotomous phenotypes or quantitative traits. Software with source files, documentation and example data files are freely available online at http://www.well.ox.ac.uk/GWAMA.

  6. Association between novel PLCE1 variants identified in published esophageal cancer genome-wide association studies and risk of squamous cell carcinoma of the head and neck

    International Nuclear Information System (INIS)

    Phospholipase C epsilon 1 (PLCE1) (an effector of Ras) belonging to the phospholipase family plays crucial roles in carcinogenesis and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN). A single nucleotide polymorphism (SNP, rs2274223) in PLCE1 has been identified as a novel susceptibility locus in genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) that share similar risk factors with SCCHN. Therefore, we investigated the association between potentially functional SNPs in PLCE1 and susceptibility to SCCHN. We genotyped three potentially functional SNPs (rs2274223A/G, rs3203713A/G and rs11599672T/G) of PLCE1 in 1,098 SCCHN patients and 1,090 controls matched by age and sex in a non-Hispanic white population. Although none of three SNPs was alone significantly associated with overall risk of SCCHN, their combined effects of risk alleles (rs2274223G, rs3203713G and rs11599672G) were found to be associated with risk of SCCHN in a locus-dose effect manner (Ptrend = 0.046), particularly for non-oropharyngeal tumors (Ptrend = 0.017); specifically, rs2274223 was associated with a significantly increased risk (AG vs. AA: adjusted OR = 1.29, 95% CI = 1.01-1.64; AG/GG vs. AA: adjusted OR = 1.30, 95% CI = 1.03-1.64), while rs11599672 was associated with a significantly decreased risk (GG vs. TT: adjusted OR = 0.54, 95% CI = 0.34-0.86; TG/GG vs. TT: adjusted OR = 0.76, 95% CI = 0.61-0.95). Our findings suggest that PLCE1 variants may have an effect on risk of SCCHN associated with tobacco and alcohol exposure, particularly for those tumors arising at non-oropharyngeal sites. These findings, although need to be validated by larger studies, are consistent with those in esophageal and gastric cancers

  7. Genome-wide multi-omics profiling of colorectal cancer identifies immune determinants strongly associated with relapse

    Directory of Open Access Journals (Sweden)

    Subha eMadhavan

    2013-11-01

    Full Text Available The use and benefit of adjuvant chemotherapy to treat state II colorectal cancer (CRC patients is not well understood since the majority of these patients are cured by surgery alone. Identification of biological markers of relapse is a critical challenge to effectively target treatments to the ~20% of patients destined to relapse. We have integrated molecular profiling results of several ‘omics’ data types to determine the most reliable prognostic biomarkers for relapse in CRC, using data from 40 stage I and II CRC patients. We identified 31 multi-omics features that highly correlate with relapse. The data types were integrated using multi-step analytical approach with consecutive elimination of redundant molecular features. For each data type a systems biology analysis was performed to identify pathways, biological processes and disease categories most affected in relapse. The biomarkers detected in tumors, urine and blood of patients indicated a strong association of immune processes, including aberrant regulation of T-cell and B-cell activation that could lead to overall differences in lymphocyte recruitment for tumor infiltration and markers indicating likelihood of future relapse. The immune response was the biologically most coherent signature that emerged from our analyses among several other biological processes, and corroborates other studies showing a strong immune response in patients less likely to relapse.

  8. Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types

    NARCIS (Netherlands)

    Sampson, Joshua N; Wheeler, William A; Yeager, Meredith; Panagiotou, Orestis; Wang, Zhaoming; Berndt, Sonja I; Lan, Qing; Abnet, Christian C; Amundadottir, Laufey T; Figueroa, Jonine D; Landi, Maria Teresa; Mirabello, Lisa; Savage, Sharon A; Taylor, Philip R; Vivo, Immaculata De; McGlynn, Katherine A; Purdue, Mark P; Rajaraman, Preetha; Adami, Hans-Olov; Ahlbom, Anders; Albanes, Demetrius; Amary, Maria Fernanda; An, She-Juan; Andersson, Ulrika; Andriole, Gerald; Andrulis, Irene L; Angelucci, Emanuele; Ansell, Stephen M; Arici, Cecilia; Armstrong, Bruce K; Arslan, Alan A; Austin, Melissa A; Baris, Dalsu; Barkauskas, Donald A; Bassig, Bryan A; Becker, Nikolaus; Benavente, Yolanda; Benhamou, Simone; Berg, Christine; Van Den Berg, David; Bernstein, Leslie; Bertrand, Kimberly A; Birmann, Brenda M; Black, Amanda; Boeing, Heiner; Boffetta, Paolo; Boutron-Ruault, Marie-Christine; Bracci, Paige M; Brinton, Louise; Brooks-Wilson, Angela R; Bueno-de-Mesquita, H Bas; Burdett, Laurie; Buring, Julie; Butler, Mary Ann; Cai, Qiuyin; Cancel-Tassin, Geraldine; Canzian, Federico; Carrato, Alfredo; Carreon, Tania; Carta, Angela; Chan, John K C; Chang, Ellen T; Chang, Gee-Chen; Chang, I-Shou; Chang, Jiang; Chang-Claude, Jenny; Chen, Chien-Jen; Chen, Chih-Yi; Chen, Chu; Chen, Chung-Hsing; Chen, Constance; Chen, Hongyan; Chen, Kexin; Chen, Kuan-Yu; Chen, Kun-Chieh; Chen, Ying; Chen, Ying-Hsiang; Chen, Yi-Song; Chen, Yuh-Min; Chien, Li-Hsin; Chirlaque, María-Dolores; Choi, Jin Eun; Choi, Yi Young; Chow, Wong-Ho; Chung, Charles C; Clavel, Jacqueline; Clavel-Chapelon, Françoise; Cocco, Pierluigi; Colt, Joanne S; Comperat, Eva; Conde, Lucia; Connors, Joseph M; Conti, David; Cortessis, Victoria K; Cotterchio, Michelle; Cozen, Wendy; Crouch, Simon; Crous-Bou, Marta; Cussenot, Olivier; Davis, Faith G; Ding, Ti; Diver, W Ryan; Dorronsoro, Miren; Dossus, Laure; Duell, Eric J; Ennas, Maria Grazia; Erickson, Ralph L; Feychting, Maria; Flanagan, Adrienne M; Foretova, Lenka; Fraumeni, Joseph F; Freedman, Neal D; Beane Freeman, Laura E; Fuchs, Charles; Gago-Dominguez, Manuela; Gallinger, Steven; Gao, Yu-Tang; Gapstur, Susan M; Garcia-Closas, Montserrat; García-Closas, Reina; Gascoyne, Randy D; Gastier-Foster, Julie; Gaudet, Mia M; Gaziano, J Michael; Giffen, Carol; Giles, Graham G; Giovannucci, Edward; Glimelius, Bengt; Goggins, Michael; Gokgoz, Nalan; Goldstein, Alisa M; Gorlick, Richard; Gross, Myron; Grubb, Robert; Gu, Jian; Guan, Peng; Gunter, Marc; Guo, Huan; Habermann, Thomas M; Haiman, Christopher A; Halai, Dina; Hallmans, Goran; Hassan, Manal; Hattinger, Claudia; He, Qincheng; He, Xingzhou; Helzlsouer, Kathy; Henderson, Brian; Henriksson, Roger; Hjalgrim, Henrik; Hoffman-Bolton, Judith; Hohensee, Chancellor; Holford, Theodore R; Holly, Elizabeth A; Hong, Yun-Chul; Hoover, Robert N; Horn-Ross, Pamela L; Hosain, G M Monawar; Hosgood, H Dean; Hsiao, Chin-Fu; Hu, Nan; Hu, Wei; Hu, Zhibin; Huang, Ming-Shyan; Huerta, Jose-Maria; Hung, Jen-Yu; Hutchinson, Amy; Inskip, Peter D; Jackson, Rebecca D; Jacobs, Eric J; Jenab, Mazda; Jeon, Hyo-Sung; Ji, Bu-Tian; Jin, Guangfu; Jin, Li; Johansen, Christoffer; Johnson, Alison; Jung, Yoo Jin; Kaaks, Rudolph; Kamineni, Aruna; Kane, Eleanor; Kang, Chang Hyun; Karagas, Margaret R; Kelly, Rachel S; Khaw, Kay-Tee; Kim, Christopher; Kim, Hee Nam; Kim, Jin Hee; Kim, Jun Suk; Kim, Yeul Hong; Kim, Young Tae; Kim, Young-Chul; Kitahara, Cari M; Klein, Alison P; Klein, Robert J; Kogevinas, Manolis; Kohno, Takashi; Kolonel, Laurence N; Kooperberg, Charles; Kricker, Anne; Krogh, Vittorio; Kunitoh, Hideo; Kurtz, Robert C; Kweon, Sun-Seog; LaCroix, Andrea; Lawrence, Charles; Lecanda, Fernando; Lee, Victor Ho Fun; Li, Donghui; Li, Haixin; Li, Jihua; Li, Yao-Jen; Li, Yuqing; Liao, Linda M; Liebow, Mark; Lightfoot, Tracy; Lim, Wei-Yen; Lin, Chien-Chung; Lin, Dongxin; Lindstrom, Sara; Linet, Martha S; Link, Brian K; Liu, Chenwei; Liu, Jianjun; Liu, Li; Ljungberg, Börje; Lloreta, Josep; Lollo, Simonetta Di; Lu, Daru; Lund, Eiluv; Malats, Nuria; Mannisto, Satu; Marchand, Loic Le; Marina, Neyssa; Masala, Giovanna; Mastrangelo, Giuseppe; Matsuo, Keitaro; Maynadie, Marc; McKay, James; McKean-Cowdin, Roberta; Melbye, Mads; Melin, Beatrice S; Michaud, Dominique S; Mitsudomi, Tetsuya; Monnereau, Alain; Montalvan, Rebecca; Moore, Lee E; Mortensen, Lotte Maxild; Nieters, Alexandra; North, Kari E; Novak, Anne J; Oberg, Ann L; Offit, Kenneth; Oh, In-Jae; Olson, Sara H; Palli, Domenico; Pao, William; Park, In Kyu; Park, Jae Yong; Park, Kyong Hwa; Patiño-Garcia, Ana; Pavanello, Sofia; Peeters, Petra H M; Perng, Reury-Perng; Peters, Ulrike; Petersen, Gloria M; Picci, Piero; Pike, Malcolm C; Porru, Stefano; Prescott, Jennifer; Prokunina-Olsson, Ludmila; Qian, Biyun; Qiao, You-Lin; Rais, Marco; Riboli, Elio; Riby, Jacques; Risch, Harvey A; Rizzato, Cosmeri; Rodabough, Rebecca; Roman, Eve; Roupret, Morgan; Ruder, Avima M; Sanjose, Silvia de; Scelo, Ghislaine; Schned, Alan; Schumacher, Fredrick; Schwartz, Kendra; Schwenn, Molly; Scotlandi, Katia; Seow, Adeline; Serra, Consol; Serra, Massimo; Sesso, Howard D; Setiawan, Veronica Wendy; Severi, Gianluca; Severson, Richard K; Shanafelt, Tait D; Shen, Hongbing; Shen, Wei; Shin, Min-Ho; Shiraishi, Kouya; Shu, Xiao-Ou; Siddiq, Afshan; Sierrasesúmaga, Luis; Sihoe, Alan Dart Loon; Skibola, Christine F; Smith, Alex; Smith, Martyn T; Southey, Melissa C; Spinelli, John J; Staines, Anthony; Stampfer, Meir; Stern, Marianna C; Stevens, Victoria L; Stolzenberg-Solomon, Rachael S; Su, Jian; Su, Wu-Chou; Sund, Malin; Sung, Jae Sook; Sung, Sook Whan; Tan, Wen; Tang, Wei; Tardón, Adonina; Thomas, David; Thompson, Carrie A; Tinker, Lesley F; Tirabosco, Roberto; Tjønneland, Anne; Travis, Ruth C; Trichopoulos, Dimitrios; Tsai, Fang-Yu; Tsai, Ying-Huang; Tucker, Margaret; Turner, Jenny; Vajdic, Claire M; Vermeulen, Roel C H; Villano, Danylo J; Vineis, Paolo; Virtamo, Jarmo; Visvanathan, Kala; Wactawski-Wende, Jean; Wang, Chaoyu; Wang, Chih-Liang; Wang, Jiu-Cun; Wang, Junwen; Wei, Fusheng; Weiderpass, Elisabete; Weiner, George J; Weinstein, Stephanie; Wentzensen, Nicolas; White, Emily; Witzig, Thomas E; Wolpin, Brian M; Wong, Maria Pik; Wu, Chen; Wu, Guoping; Wu, Junjie; Wu, Tangchun; Wu, Wei; Wu, Xifeng; Wu, Yi-Long; Wunder, Jay S; Xiang, Yong-Bing; Xu, Jun; Xu, Ping; Yang, Pan-Chyr; Yang, Tsung-Ying; Ye, Yuanqing; Yin, Zhihua; Yokota, Jun; Yoon, Ho-Il; Yu, Chong-Jen; Yu, Herbert; Yu, Kai; Yuan, Jian-Min; Zelenetz, Andrew; Zeleniuch-Jacquotte, Anne; Zhang, Xu-Chao; Zhang, Yawei; Zhao, Xueying; Zhao, Zhenhong; Zheng, Hong; Zheng, Tongzhang; Zheng, Wei; Zhou, Baosen; Zhu, Meng; Zucca, Mariagrazia; Boca, Simina M; Cerhan, James R; Ferri, Giovanni M; Hartge, Patricia; Hsiung, Chao Agnes; Magnani, Corrado; Miligi, Lucia; Morton, Lindsay M; Smedby, Karin E; Teras, Lauren R; Vijai, Joseph; Wang, Sophia S; Brennan, Paul; Caporaso, Neil E; Hunter, David J; Kraft, Peter; Rothman, Nathaniel; Silverman, Debra T; Slager, Susan L; Chanock, Stephen J; Chatterjee, Nilanjan

    2015-01-01

    BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. METHO

  9. Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types

    DEFF Research Database (Denmark)

    Sampson, Joshua N; Wheeler, William A; Yeager, Meredith;

    2015-01-01

    BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. ME...

  10. Genome-wide association study identifies five new schizophrenia loci

    OpenAIRE

    Ripke, Stephan; Sanders, Alan R.; Kendler, Kenneth S.; Levinson, Douglas F.; Sklar, Pamela; Holmans, Peter A.; Lin, Dan-Yu; Duan, Jubao; Ophoff, Roel A.; Andreassen, Ole A; Scolnick, Edward; Cichon, Sven; St. Clair, David; Corvin, Aiden; Gurling, Hugh

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated ...

  11. Genome-wide association study identifies five new schizophrenia loci.

    OpenAIRE

    Ripke, Stephan; Sanders, Alan R.; Kendler, Kenneth S.; Levinson, Douglas F.; Sklar, Pamela; Holmans, Peter A.; Lin, Dan-Yu; Duan, Jubao; Ophoff, Roel A.; Andreassen, Ole A; Scolnick, Edward; Cichon, Sven; St. Clair, David; Corvin, Aiden; Gurling, Hugh

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated ...

  12. Genome-Wide Association Analysis in Primary Sclerosing Cholangitis

    NARCIS (Netherlands)

    Karlsen, Tom H.; Franke, Andre; Melum, Espen; Kaser, Arthur; Hov, Johannes Roksund; Balschun, Tobias; Lie, Benedicte A.; Bergquist, Annika; Schramm, Christoph; Weismueller, Tobias J.; Gotthardt, Daniel; Rust, Christian; Philipp, Eva E. R.; Fritz, Teresa; Henckaerts, Liesbet; Weersma, Rinse K.; Stokkers, Pieter; Ponsioen, Cyriel Y.; Wijmenga, Cisca; Sterneck, Martina; Nothnagel, Michael; Hampe, Jochen; Teufel, Andreas; Runz, Heiko; Rosenstiel, Philip; Stiehl, Adolf; Vermeire, Severine; Beuers, Ulrich; Manns, Michael P.; Schrumpf, Erik; Boberg, Kirsten Muri; Schreiber, Stefan

    2010-01-01

    BACKGROUND & AIMS: We aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers. METHODS: A total of 443,816 SNPs on the Affymetrix SNP Array 5.0 (Affymetrix, Santa Clara, CA

  13. Genome-wide association study identifies five new schizophrenia loci

    DEFF Research Database (Denmark)

    Ripke, Stephan; Sanders, Alan R; Kendler, Kenneth S;

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis...

  14. Genome-wide association study identifies five new schizophrenia loci

    DEFF Research Database (Denmark)

    Ripke, Stephan; Sanders, Alan R; Kendler, Kenneth S;

    2011-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yiel...

  15. Genome-Wide Association Study of Serum Selenium Concentrations

    Directory of Open Access Journals (Sweden)

    Ulrike Peters

    2013-05-01

    Full Text Available Selenium is an essential trace element and circulating selenium concentrations have been associated with a wide range of diseases. Candidate gene studies suggest that circulating selenium concentrations may be impacted by genetic variation; however, no study has comprehensively investigated this hypothesis. Therefore, we conducted a two-stage genome-wide association study to identify genetic variants associated with serum selenium concentrations in 1203 European descents from two cohorts: the Prostate, Lung, Colorectal, and Ovarian (PLCO Cancer Screening and the Women’s Health Initiative (WHI. We tested association between 2,474,333 single nucleotide polymorphisms (SNPs and serum selenium concentrations using linear regression models. In the first stage (PLCO 41 SNPs clustered in 15 regions had p < 1 × 10−5. None of these 41 SNPs reached the significant threshold (p = 0.05/15 regions = 0.003 in the second stage (WHI. Three SNPs had p < 0.05 in the second stage (rs1395479 and rs1506807 in 4q34.3/AGA-NEIL3; and rs891684 in 17q24.3/SLC39A11 and had p between 2.62 × 10−7 and 4.04 × 10−7 in the combined analysis (PLCO + WHI. Additional studies are needed to replicate these findings. Identification of genetic variation that impacts selenium concentrations may contribute to a better understanding of which genes regulate circulating selenium concentrations.

  16. Genome-wide association study identifies five new schizophrenia loci.

    LENUS (Irish Health Repository)

    Ripke, Stephan

    2011-10-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10(-9)), ANK3 (rs10994359, P = 2.5 × 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10(-9)).

  17. A genome-wide association study of anorexia nervosa

    OpenAIRE

    2014-01-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were...

  18. Genome-wide Association Study of Periodontal Pathogen Colonization

    OpenAIRE

    Divaris, K.; Monda, K.L.; North, K. E.; Olshan, A F; Lange, E.M.; K. Moss; Barros, S.P.; Beck, J.D.; Offenbacher, S.

    2012-01-01

    Pathological shifts of the human microbiome are characteristic of many diseases, including chronic periodontitis. To date, there is limited evidence on host genetic risk loci associated with periodontal pathogen colonization. We conducted a genome-wide association (GWA) study among 1,020 white participants of the Atherosclerosis Risk in Communities Study, whose periodontal diagnosis ranged from healthy to severe chronic periodontitis, and for whom “checkerboard” DNA-DNA hybridization quantifi...

  19. Genome-wide identification of significant aberrations in cancer genome

    Directory of Open Access Journals (Sweden)

    Yuan Xiguo

    2012-07-01

    Full Text Available Abstract Background Somatic Copy Number Alterations (CNAs in human genomes are present in almost all human cancers. Systematic efforts to characterize such structural variants must effectively distinguish significant consensus events from random background aberrations. Here we introduce Significant Aberration in Cancer (SAIC, a new method for characterizing and assessing the statistical significance of recurrent CNA units. Three main features of SAIC include: (1 exploiting the intrinsic correlation among consecutive probes to assign a score to each CNA unit instead of single probes; (2 performing permutations on CNA units that preserve correlations inherent in the copy number data; and (3 iteratively detecting Significant Copy Number Aberrations (SCAs and estimating an unbiased null distribution by applying an SCA-exclusive permutation scheme. Results We test and compare the performance of SAIC against four peer methods (GISTIC, STAC, KC-SMART, CMDS on a large number of simulation datasets. Experimental results show that SAIC outperforms peer methods in terms of larger area under the Receiver Operating Characteristics curve and increased detection power. We then apply SAIC to analyze structural genomic aberrations acquired in four real cancer genome-wide copy number data sets (ovarian cancer, metastatic prostate cancer, lung adenocarcinoma, glioblastoma. When compared with previously reported results, SAIC successfully identifies most SCAs known to be of biological significance and associated with oncogenes (e.g., KRAS, CCNE1, and MYC or tumor suppressor genes (e.g., CDKN2A/B. Furthermore, SAIC identifies a number of novel SCAs in these copy number data that encompass tumor related genes and may warrant further studies. Conclusions Supported by a well-grounded theoretical framework, SAIC has been developed and used to identify SCAs in various cancer copy number data sets, providing useful information to study the landscape of cancer genomes

  20. GWAMA: software for genome-wide association meta-analysis

    OpenAIRE

    Mägi Reedik; Morris Andrew P

    2010-01-01

    Abstract Background Despite the recent success of genome-wide association studies in identifying novel loci contributing effects to complex human traits, such as type 2 diabetes and obesity, much of the genetic component of variation in these phenotypes remains unexplained. One way to improving power to detect further novel loci is through meta-analysis of studies from the same population, increasing the sample size over any individual study. Although statistical software analysis packages in...

  1. Genome-Wide Association Study of Proneness to Anger

    OpenAIRE

    Mick, Eric; Mcgough, James,; Deutsch, Curtis K.; Jean A. Frazier; Kennedy, David; Goldberg, Robert J.

    2014-01-01

    Background Community samples suggest that approximately 1 in 20 children and adults exhibit clinically significant anger, hostility, and aggression. Individuals with dysregulated emotional control have a greater lifetime burden of psychiatric morbidity, severe impairment in role functioning, and premature mortality due to cardiovascular disease. Methods With publically available data secured from dbGaP, we conducted a genome-wide association study of proneness to anger using the Spielberger S...

  2. Genome-wide association study of parity in Bangladeshi women.

    Science.gov (United States)

    Aschebrook-Kilfoy, Briseis; Argos, Maria; Pierce, Brandon L; Tong, Lin; Jasmine, Farzana; Roy, Shantanu; Parvez, Faruque; Ahmed, Alauddin; Islam, Tariqul; Kibriya, Muhammad G; Ahsan, Habibul

    2015-01-01

    Human fertility is a complex trait determined by gene-environment interactions in which genetic factors represent a significant component. To better understand inter-individual variability in fertility, we performed one of the first genome-wide association studies (GWAS) of common fertility phenotypes, lifetime number of pregnancies and number of children in a developing country population. The fertility phenotype data and DNA samples were obtained at baseline recruitment from individuals participating in a large prospective cohort study in Bangladesh. GWAS analyses of fertility phenotypes were conducted among 1,686 married women. One SNP on chromosome 4 was non-significantly associated with number of children at P pregnancies at P pregnancies. This SNP is located near C5orf64, an open reading frame, and ZSWIM6, a zinc ion binding gene. We also estimated the heritability of these phenotypes from our genotype data using GCTA (Genome-wide Complex Trait Analysis) for number of children (hg2 = 0.149, SE = 0.24, p-value = 0.265) and number of pregnancies (hg2 = 0.007, SE = 0.22, p-value = 0.487). Our genome-wide association study and heritability estimates of number of pregnancies and number of children in Bangladesh did not confer strong evidence of common variants for parity variation. However, our results suggest that future studies may want to consider the role of 3 notable SNPs in their analysis. PMID:25742292

  3. [New insight of genome-wide association study (GWAS)].

    Science.gov (United States)

    Hotta, Kikuko

    2013-02-01

    The number of obese patients is increasing in Japan, due to the westernization of lifestyle. Obesity, especially visceral fat obesity, is important for the development of metabolic syndrome. Genetic factors are important for the development of obesity as well as environmental factors. Importance of genetic factors of fat distribution is also reported. Recent genome-wide association studies (GWASs) have revealed the obesity and fat distribution-related polymorphisms. GWAS will highlight a better understanding of the underlying molecular mechanisms in the regulation of obesity and distribution of body fat. PMID:23631198

  4. [Genome-wide association study for adolescent idiopathic scoliosis].

    Science.gov (United States)

    Ogura, Yoji; Kou, Ikuyo; Scoliosis, Japan; Matsumoto, Morio; Watanabe, Kota; Ikegawa, Shiro

    2016-04-01

    Adolescent idiopathic scoliosis(AIS)is a polygenic disease. Genome-wide association studies(GWASs)have been performed for a lot of polygenic diseases. For AIS, we conducted GWAS and identified the first AIS locus near LBX1. After the discovery, we have extended our study by increasing the numbers of subjects and SNPs. In total, our Japanese GWAS has identified four susceptibility genes. GWASs for AIS have also been performed in the USA and China, which identified one and three susceptibility genes, respectively. Here we review GWASs in Japan and abroad and functional analysis to clarify the pathomechanism of AIS. PMID:27013625

  5. Genome-wide association study of obsessive-compulsive disorder.

    Science.gov (United States)

    Stewart, S E; Yu, D; Scharf, J M; Neale, B M; Fagerness, J A; Mathews, C A; Arnold, P D; Evans, P D; Gamazon, E R; Davis, L K; Osiecki, L; McGrath, L; Haddad, S; Crane, J; Hezel, D; Illman, C; Mayerfeld, C; Konkashbaev, A; Liu, C; Pluzhnikov, A; Tikhomirov, A; Edlund, C K; Rauch, S L; Moessner, R; Falkai, P; Maier, W; Ruhrmann, S; Grabe, H-J; Lennertz, L; Wagner, M; Bellodi, L; Cavallini, M C; Richter, M A; Cook, E H; Kennedy, J L; Rosenberg, D; Stein, D J; Hemmings, S M J; Lochner, C; Azzam, A; Chavira, D A; Fournier, E; Garrido, H; Sheppard, B; Umaña, P; Murphy, D L; Wendland, J R; Veenstra-VanderWeele, J; Denys, D; Blom, R; Deforce, D; Van Nieuwerburgh, F; Westenberg, H G M; Walitza, S; Egberts, K; Renner, T; Miguel, E C; Cappi, C; Hounie, A G; Conceição do Rosário, M; Sampaio, A S; Vallada, H; Nicolini, H; Lanzagorta, N; Camarena, B; Delorme, R; Leboyer, M; Pato, C N; Pato, M T; Voyiaziakis, E; Heutink, P; Cath, D C; Posthuma, D; Smit, J H; Samuels, J; Bienvenu, O J; Cullen, B; Fyer, A J; Grados, M A; Greenberg, B D; McCracken, J T; Riddle, M A; Wang, Y; Coric, V; Leckman, J F; Bloch, M; Pittenger, C; Eapen, V; Black, D W; Ophoff, R A; Strengman, E; Cusi, D; Turiel, M; Frau, F; Macciardi, F; Gibbs, J R; Cookson, M R; Singleton, A; Hardy, J; Crenshaw, A T; Parkin, M A; Mirel, D B; Conti, D V; Purcell, S; Nestadt, G; Hanna, G L; Jenike, M A; Knowles, J A; Cox, N; Pauls, D L

    2013-07-01

    Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (Pquantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD. PMID:22889921

  6. Genome-Wide Association Study of Antiphospholipid Antibodies

    Directory of Open Access Journals (Sweden)

    M. Ilyas Kamboh

    2013-01-01

    Full Text Available Background. The persistent presence of antiphospholipid antibodies (APA may lead to the development of primary or secondary antiphospholipid syndrome. Although the genetic basis of APA has been suggested, the identity of the underlying genes is largely unknown. In this study, we have performed a genome-wide association study (GWAS in an effort to identify susceptibility loci/genes for three main APA: anticardiolipin antibodies (ACL, lupus anticoagulant (LAC, and anti-β2 glycoprotein I antibodies (anti-β2GPI. Methods. DNA samples were genotyped using the Affymetrix 6.0 array containing 906,600 single-nucleotide polymorphisms (SNPs. Association of SNPs with the antibody status (positive/negative was tested using logistic regression under the additive model. Results. We have identified a number of suggestive novel loci with Pgenome-wide significance, many of the suggestive loci are potential candidates for the production of APA. We have replicated the previously reported associations of HLA genes and APOH with APA but these were not the top loci. Conclusions. We have identified a number of suggestive novel loci for APA that will stimulate follow-up studies in independent and larger samples to replicate our findings.

  7. Genome-wide association study of periodontal pathogen colonization.

    Science.gov (United States)

    Divaris, K; Monda, K L; North, K E; Olshan, A F; Lange, E M; Moss, K; Barros, S P; Beck, J D; Offenbacher, S

    2012-07-01

    Pathological shifts of the human microbiome are characteristic of many diseases, including chronic periodontitis. To date, there is limited evidence on host genetic risk loci associated with periodontal pathogen colonization. We conducted a genome-wide association (GWA) study among 1,020 white participants of the Atherosclerosis Risk in Communities Study, whose periodontal diagnosis ranged from healthy to severe chronic periodontitis, and for whom "checkerboard" DNA-DNA hybridization quantification of 8 periodontal pathogens was performed. We examined 3 traits: "high red" and "high orange" bacterial complexes, and "high" Aggregatibacter actinomycetemcomitans (Aa) colonization. Genotyping was performed on the Affymetrix 6.0 platform. Imputation to 2.5 million markers was based on HapMap II-CEU, and a multiple-test correction was applied (genome-wide threshold of p orange" complex microbiota, but not for Aa, had the same effect direction in a second sample of 123 African-American participants. None of these polymorphisms was associated with periodontitis diagnosis. Investigations replicating these findings may lead to an improved understanding of the complex nature of host-microbiome interactions that characterizes states of health and disease. PMID:22699663

  8. A Pooled Genome-Wide Association Study of Asperger Syndrome.

    Directory of Open Access Journals (Sweden)

    Varun Warrier

    Full Text Available Asperger Syndrome (AS is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC, which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448 were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448 lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision.

  9. Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma.

    Science.gov (United States)

    Chahal, Harvind S; Wu, Wenting; Ransohoff, Katherine J; Yang, Lingyao; Hedlin, Haley; Desai, Manisha; Lin, Yuan; Dai, Hong-Ji; Qureshi, Abrar A; Li, Wen-Qing; Kraft, Peter; Hinds, David A; Tang, Jean Y; Han, Jiali; Sarin, Kavita Y

    2016-01-01

    Basal cell carcinoma (BCC) is the most common cancer worldwide with an annual incidence of 2.8 million cases in the United States alone. Previous studies have demonstrated an association between 21 distinct genetic loci and BCC risk. Here, we report the results of a two-stage genome-wide association study of BCC, totalling 17,187 cases and 287,054 controls. We confirm 17 previously reported loci and identify 14 new susceptibility loci reaching genome-wide significance (P<5 × 10(-8), logistic regression). These newly associated SNPs lie within predicted keratinocyte regulatory elements and in expression quantitative trait loci; furthermore, we identify candidate genes and non-coding RNAs involved in telomere maintenance, immune regulation and tumour progression, providing deeper insight into the pathogenesis of BCC. PMID:27539887

  10. Genetic association with overall survival of taxane-treated lung cancer patients - a genome-wide association study in human lymphoblastoid cell lines followed by a clinical association study

    International Nuclear Information System (INIS)

    Taxane is one of the first line treatments of lung cancer. In order to identify novel single nucleotide polymorphisms (SNPs) that might contribute to taxane response, we performed a genome-wide association study (GWAS) for two taxanes, paclitaxel and docetaxel, using 276 lymphoblastoid cell lines (LCLs), followed by genotyping of top candidate SNPs in 874 lung cancer patient samples treated with paclitaxel. GWAS was performed using 1.3 million SNPs and taxane cytotoxicity IC50 values for 276 LCLs. The association of selected SNPs with overall survival in 76 small or 798 non-small cell lung cancer (SCLC, NSCLC) patients were analyzed by Cox regression model, followed by integrated SNP-microRNA-expression association analysis in LCLs and siRNA screening of candidate genes in SCLC (H196) and NSCLC (A549) cell lines. 147 and 180 SNPs were associated with paclitaxel or docetaxel IC50s with p-values <10-4 in the LCLs, respectively. Genotyping of 153 candidate SNPs in 874 lung cancer patient samples identified 8 SNPs (p-value < 0.05) associated with either SCLC or NSCLC patient overall survival. Knockdown of PIP4K2A, CCT5, CMBL, EXO1, KMO and OPN3, genes within 200 kb up-/downstream of the 3 SNPs that were associated with SCLC overall survival (rs1778335, rs2662411 and rs7519667), significantly desensitized H196 to paclitaxel. SNPs rs2662411 and rs1778335 were associated with mRNA expression of CMBL or PIP4K2A through microRNA (miRNA) hsa-miR-584 or hsa-miR-1468. GWAS in an LCL model system, joined with clinical translational and functional studies, might help us identify genetic variations associated with overall survival of lung cancer patients treated paclitaxel

  11. Genome-wide significant risk associations for mucinous ovarian carcinoma

    DEFF Research Database (Denmark)

    Kelemen, Linda E; Lawrenson, Kate; Tyrer, Jonathan;

    2015-01-01

    Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2......q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at...

  12. Genetic association with overall survival of taxane-treated lung cancer patients - a genome-wide association study in human lymphoblastoid cell lines followed by a clinical association study

    Directory of Open Access Journals (Sweden)

    Niu Nifang

    2012-09-01

    Full Text Available Abstract Background Taxane is one of the first line treatments of lung cancer. In order to identify novel single nucleotide polymorphisms (SNPs that might contribute to taxane response, we performed a genome-wide association study (GWAS for two taxanes, paclitaxel and docetaxel, using 276 lymphoblastoid cell lines (LCLs, followed by genotyping of top candidate SNPs in 874 lung cancer patient samples treated with paclitaxel. Methods GWAS was performed using 1.3 million SNPs and taxane cytotoxicity IC50 values for 276 LCLs. The association of selected SNPs with overall survival in 76 small or 798 non-small cell lung cancer (SCLC, NSCLC patients were analyzed by Cox regression model, followed by integrated SNP-microRNA-expression association analysis in LCLs and siRNA screening of candidate genes in SCLC (H196 and NSCLC (A549 cell lines. Results 147 and 180 SNPs were associated with paclitaxel or docetaxel IC50s with p-values -4 in the LCLs, respectively. Genotyping of 153 candidate SNPs in 874 lung cancer patient samples identified 8 SNPs (p-value PIP4K2A, CCT5, CMBL, EXO1, KMO and OPN3, genes within 200 kb up-/downstream of the 3 SNPs that were associated with SCLC overall survival (rs1778335, rs2662411 and rs7519667, significantly desensitized H196 to paclitaxel. SNPs rs2662411 and rs1778335 were associated with mRNA expression of CMBL or PIP4K2A through microRNA (miRNA hsa-miR-584 or hsa-miR-1468. Conclusions GWAS in an LCL model system, joined with clinical translational and functional studies, might help us identify genetic variations associated with overall survival of lung cancer patients treated paclitaxel.

  13. Genome-wide association studies in asthma: progress and pitfalls

    Directory of Open Access Journals (Sweden)

    March ME

    2015-01-01

    Full Text Available Michael E March,1 Patrick MA Sleiman,1,2 Hakon Hakonarson1,2 1Center for Applied Genomics, Children's Hospital of Philadelphia Research Institute, 2Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Abstract: Genetic studies of asthma have revealed that there is considerable heritability to the phenotype. An extensive history of candidate-gene studies has identified a long list of genes associated with immune function that are potentially involved in asthma pathogenesis. However, many of the results of candidate-gene studies have failed to be replicated, leaving in question the true impact of the implicated biological pathways on asthma. With the advent of genome-wide association studies, geneticists are able to examine the association of hundreds of thousands of genetic markers with a phenotype, allowing the hypothesis-free identification of variants associated with disease. Many such studies examining asthma or related phenotypes have been published, and several themes have begun to emerge regarding the biological pathways underpinning asthma. The results of many genome-wide association studies have currently not been replicated, and the large sample sizes required for this experimental strategy invoke difficulties with sample stratification and phenotypic heterogeneity. Recently, large collaborative groups of researchers have formed consortia focused on asthma, with the goals of sharing material and data and standardizing diagnosis and experimental methods. Additionally, research has begun to focus on genetic variants that affect the response to asthma medications and on the biology that generates the heterogeneity in the asthma phenotype. As this work progresses, it will move asthma patients closer to more specific, personalized medicine. Keywords: asthma, genetics, GWAS, pharmacogenetics, biomarkers

  14. A comparison of multivariate genome-wide association methods

    DEFF Research Database (Denmark)

    Galesloot, Tessel E; Van Steen, Kristel; Kiemeney, Lambertus A L M;

    2014-01-01

    Joint association analysis of multiple traits in a genome-wide association study (GWAS), i.e. a multivariate GWAS, offers several advantages over analyzing each trait in a separate GWAS. In this study we directly compared a number of multivariate GWAS methods using simulated data. We focused on six...... methods that are implemented in the software packages PLINK, SNPTEST, MultiPhen, BIMBAM, PCHAT and TATES, and also compared them to standard univariate GWAS, analysis of the first principal component of the traits, and meta-analysis of univariate results. We simulated data (N = 1000) for three...... correlation. We compared the power of the methods using empirically fixed significance thresholds (α = 0.05). Our results showed that the multivariate methods implemented in PLINK, SNPTEST, MultiPhen and BIMBAM performed best for the majority of the tested scenarios, with a notable increase in power...

  15. Genome wide association identifies novel loci involved in fungal communication.

    Science.gov (United States)

    Palma-Guerrero, Javier; Hall, Charles R; Kowbel, David; Welch, Juliet; Taylor, John W; Brem, Rachel B; Glass, N Louise

    2013-01-01

    Understanding how genomes encode complex cellular and organismal behaviors has become the outstanding challenge of modern genetics. Unlike classical screening methods, analysis of genetic variation that occurs naturally in wild populations can enable rapid, genome-scale mapping of genotype to phenotype with a medium-throughput experimental design. Here we describe the results of the first genome-wide association study (GWAS) used to identify novel loci underlying trait variation in a microbial eukaryote, harnessing wild isolates of the filamentous fungus Neurospora crassa. We genotyped each of a population of wild Louisiana strains at 1 million genetic loci genome-wide, and we used these genotypes to map genetic determinants of microbial communication. In N. crassa, germinated asexual spores (germlings) sense the presence of other germlings, grow toward them in a coordinated fashion, and fuse. We evaluated germlings of each strain for their ability to chemically sense, chemotropically seek, and undergo cell fusion, and we subjected these trait measurements to GWAS. This analysis identified one gene, NCU04379 (cse-1, encoding a homolog of a neuronal calcium sensor), at which inheritance was strongly associated with the efficiency of germling communication. Deletion of cse-1 significantly impaired germling communication and fusion, and two genes encoding predicted interaction partners of CSE1 were also required for the communication trait. Additionally, mining our association results for signaling and secretion genes with a potential role in germling communication, we validated six more previously unknown molecular players, including a secreted protease and two other genes whose deletion conferred a novel phenotype of increased communication and multi-germling fusion. Our results establish protein secretion as a linchpin of germling communication in N. crassa and shed light on the regulation of communication molecules in this fungus. Our study demonstrates the power

  16. A genome-wide scan for breast cancer risk haplotypes among African American women.

    Directory of Open Access Journals (Sweden)

    Chi Song

    Full Text Available Genome-wide association studies (GWAS simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyzed the haplotype effects for breast cancer risk among 5,761 African American women (3,016 cases and 2,745 controls using a sliding window approach on the genome-wide scale. Three regions on chromosomes 1, 4 and 18 exhibited moderate haplotype effects. Furthermore, among 21 breast cancer susceptibility loci previously established in European populations, 10p15 and 14q24 are likely to harbor novel haplotype effects. We also proposed a heuristic of determining the significance level and the effective number of independent tests by the permutation analysis on chromosome 22 data. It suggests that the effective number was approximately half of the total (7,794 out of 15,645, thus the half number could serve as a quick reference to evaluating genome-wide significance if a similar sliding window approach of haplotype analysis is adopted in similar populations using similar genotype density.

  17. Genome-Wide Association Studies of the Human Gut Microbiota.

    Directory of Open Access Journals (Sweden)

    Emily R Davenport

    Full Text Available The bacterial composition of the human fecal microbiome is influenced by many lifestyle factors, notably diet. It is less clear, however, what role host genetics plays in dictating the composition of bacteria living in the gut. In this study, we examined the association of ~200K host genotypes with the relative abundance of fecal bacterial taxa in a founder population, the Hutterites, during two seasons (n = 91 summer, n = 93 winter, n = 57 individuals collected in both. These individuals live and eat communally, minimizing variation due to environmental exposures, including diet, which could potentially mask small genetic effects. Using a GWAS approach that takes into account the relatedness between subjects, we identified at least 8 bacterial taxa whose abundances were associated with single nucleotide polymorphisms in the host genome in each season (at genome-wide FDR of 20%. For example, we identified an association between a taxon known to affect obesity (genus Akkermansia and a variant near PLD1, a gene previously associated with body mass index. Moreover, we replicate a previously reported association from a quantitative trait locus (QTL mapping study of fecal microbiome abundance in mice (genus Lactococcus, rs3747113, P = 3.13 x 10-7. Finally, based on the significance distribution of the associated microbiome QTLs in our study with respect to chromatin accessibility profiles, we identified tissues in which host genetic variation may be acting to influence bacterial abundance in the gut.

  18. Genome wide association study on early puberty in Bos indicus.

    Science.gov (United States)

    Nascimento, A V; Matos, M C; Seno, L O; Romero, A R S; Garcia, J F; Grisolia, A B

    2016-01-01

    The aim of this study was to evaluate a genome wide association study (GWAS) approach to identify single nucleotide polymorphisms (SNPs) associated with fertility traits (early puberty) in Nellore cattle (Bos indicus). Fifty-five Nellore cows were selected from a herd monitored for early puberty onset (positive pregnancy at 18 months of age). Extremes of this phenotype were selected; 30 and 25 individuals were pregnant and non-pregnant, respectively, at that age. DNA samples were genotyped using a high-density SNP chip (>777.000 SNP). GWAS using a case-control strategy highlighted a number of significant markers based on their proximity with the Bonferroni correction line. Results indicated that chromosomes 5, 6, 9, 10, and 22 were associated with the traits of interest. The most significant SNPs on these chromosomes were rs133039577, rs110013280, rs134702839, rs109551605, and rs41639155. Candidate genes, as well as quantitative trait loci (QTL) previously reported in the Ensembl and Cattle QTLdb databases, were further investigated. Analysis of the regions close to the SNP on chromosomes 9 and 10 revealed that four QTL had been previously classified under the reproduction category. In conclusion, we have identified SNPs in close proximity to genes associated with reproductive traits. Moreover, U6 spliceosomal RNA was present on three different chromosomes, which is possibly associated with age at first calving, suggesting that it might be a strong candidate for future studies. PMID:26909970

  19. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33

    OpenAIRE

    Petersen, Gloria M.; Amundadottir, Laufey; Fuchs, Charles S; Kraft, Peter; Stolzenberg-Solomon, Rachael Z; Jacobs, Kevin B.; Arslan, Alan A.; Bueno-de-Mesquita, H Bas; Gallinger, Steven; Gross, Myron; Helzlsouer, Kathy; Holly, Elizabeth A.; Jacobs, Eric J.; Klein, Alison P; LaCroix, Andrea

    2010-01-01

    We conducted a genome-wide association study (GWAS) of pancreatic cancer in 3,851 cases and 3,934 controls drawn from twelve prospective cohort studies and eight case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P=3.27×10−11; per allele odds ra...

  20. Genome-wide significant risk associations for mucinous ovarian carcinoma

    Science.gov (United States)

    Kelemen, Linda E.; Lawrenson, Kate; Tyrer, Jonathan; Li, Qiyuan; M. Lee, Janet; Seo, Ji-Heui; Phelan, Catherine M.; Beesley, Jonathan; Chen, Xiaoqin; Spindler, Tassja J.; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chen, Y. Ann; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Engelholm, Svend Aage; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Nevanlinna, Heli; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste Leigh; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wlodzimierz, Sawicki; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Sellers, Thomas A.; Freedman, Matthew L.; Chenevix-Trench, Georgia; Pharoah, Paul D.; Gayther, Simon A.; Berchuck, Andrew

    2015-01-01

    Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease. PMID:26075790

  1. Genome-wide association study of aggressive behaviour in chicken

    Science.gov (United States)

    Li, Zhenhui; Zheng, Ming; Abdalla, Bahareldin Ali; Zhang, Zhe; Xu, Zhenqiang; Ye, Qiao; Xu, Haiping; Luo, Wei; Nie, Qinghua; Zhang, Xiquan

    2016-01-01

    In the poultry industry, aggressive behaviour is a large animal welfare issue all over the world. To date, little is known about the underlying genetics of the aggressive behaviour. Here, we performed a genome-wide association study (GWAS) to explore the genetic mechanism associated with aggressive behaviour in chickens. The GWAS results showed that a total of 33 SNPs were associated with aggressive behaviour traits (P < 4.6E-6). rs312463697 on chromosome 4 was significantly associated with aggression (P = 2.10905E-07), and it was in the intron region of the sortilin-related VPS10 domain containing receptor 2 (SORCS2) gene. In addition, biological function analysis of the nearest 26 genes around the significant SNPs was performed with Ingenuity Pathway Analysis. An interaction network contained 17 genes was obtained and SORCS2 was involved in this network, interacted with nerve growth factor (NGF), nerve growth factor receptor (NGFR), dopa decarboxylase (L-dopa) and dopamine. After knockdown of SORCS2, the mRNA levels of NGF, L-dopa and dopamine receptor genes DRD1, DRD2, DRD3 and DRD4 were significantly decreased (P < 0.05). In summary, our data indicated that SORCS2 might play an important role in chicken aggressive behaviour through the regulation of dopaminergic pathways and NGF. PMID:27485826

  2. Genome-wide association studies in pharmacogenetics research debate

    Science.gov (United States)

    Bailey, Kent R; Cheng, Cheng

    2016-01-01

    Will genome-wide association studies (GWAS) ‘work’ for pharmacogenetics research? This question was the topic of a staged debate, with pro and con sides, aimed to bring out the strengths and weaknesses of GWAS for pharmacogenetics studies. After a full day of seminars at the Fifth Statistical Analysis Workshop of the Pharmacogenetics Research Network, the lively debate was held – appropriately – at Goonies Comedy Club in Rochester (MN, USA). The pro side emphasized that the many GWAS successes for identifying genetic variants associated with disease risk show that it works; that the current genotyping platforms are efficient, with good imputation methods to fill in missing data; that its global assessment is always a success even if no significant associations are detected; and that genetic effects are likely to be large because humans have not evolved in a drug-therapy environment. By contrast, the con side emphasized that we have limited knowledge of the complexity of the genome; limited clinical phenotypes compromise studies; the likely multifactorial nature of drug response clouding the small genetic effects; and limitations of sample size and replication studies in pharmacogenetic studies. Lively and insightful discussions emphasized further research efforts that might benefit GWAS in pharmacogenetics. PMID:20235786

  3. Genome-Wide Association Studies in Primary Biliary Cirrhosis.

    Science.gov (United States)

    Gulamhusein, Aliya F; Juran, Brian D; Lazaridis, Konstantinos N

    2015-11-01

    Genome-wide association studies (GWASs) have been a significant technological advance in our ability to evaluate the genetic architecture of complex diseases such as primary biliary cirrhosis (PBC). To date, six large-scale studies have been performed that have identified 27 risk loci in addition to human leukocyte antigen (HLA) associated with PBC. The identified risk variants emphasize important disease concepts; namely, that disturbances in immunoregulatory pathways are important in the pathogenesis of PBC and that such perturbations are shared among a diverse number of autoimmune diseases-suggesting the risk architecture may confer a generalized propensity to autoimmunity not necessarily specific to PBC. Furthermore, the impact of non-HLA risk variants, particularly in genes involved with interleukin-12 signaling, and ethnic variation in conferring susceptibility to PBC have been highlighted. Although GWASs have been a critical stepping stone in understanding common genetic variation contributing to PBC, limitations pertaining to power, sample availability, and strong linkage disequilibrium across genes have left us with an incomplete understanding of the genetic underpinnings of disease pathogenesis. Future efforts to gain insight into this missing heritability, the genetic variation that contributes to important disease outcomes, and the functional consequences of associated variants will be critical if practical clinical translation is to be realized. PMID:26676814

  4. Genome-wide association study of proneness to anger.

    Directory of Open Access Journals (Sweden)

    Eric Mick

    Full Text Available BACKGROUND: Community samples suggest that approximately 1 in 20 children and adults exhibit clinically significant anger, hostility, and aggression. Individuals with dysregulated emotional control have a greater lifetime burden of psychiatric morbidity, severe impairment in role functioning, and premature mortality due to cardiovascular disease. METHODS: With publically available data secured from dbGaP, we conducted a genome-wide association study of proneness to anger using the Spielberger State-Trait Anger Scale in the Atherosclerosis Risk in Communities (ARIC study (n = 8,747. RESULTS: Subjects were, on average, 54 (range 45-64 years old at baseline enrollment, 47% (n = 4,117 were male, and all were of European descent by self-report. The mean Angry Temperament and Angry Reaction scores were 5.8 ± 1.8 and 7.6 ± 2.2. We observed a nominally significant finding (p = 2.9E-08, λ = 1.027 - corrected pgc = 2.2E-07, λ = 1.0015 on chromosome 6q21 in the gene coding for the non-receptor protein-tyrosine kinase, Fyn. CONCLUSIONS: Fyn interacts with NDMA receptors and inositol-1,4,5-trisphosphate (IP3-gated channels to regulate calcium influx and intracellular release in the post-synaptic density. These results suggest that signaling pathways regulating intracellular calcium homeostasis, which are relevant to memory, learning, and neuronal survival, may in part underlie the expression of Angry Temperament.

  5. Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax.

    Science.gov (United States)

    Sousa, Inês; Abrantes, Patrícia; Francisco, Vânia; Teixeira, Gilberto; Monteiro, Marta; Neves, João; Norte, Ana; Robalo Cordeiro, Carlos; Moura E Sá, João; Reis, Ernestina; Santos, Patrícia; Oliveira, Manuela; Sousa, Susana; Fradinho, Marta; Malheiro, Filipa; Negrão, Luís; Feijó, Salvato; Oliveira, Sofia A

    2016-01-01

    Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22-2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08-2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29-2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis. PMID:27203581

  6. Genome-wide association mapping of soybean aphid resistance traits

    Science.gov (United States)

    Soybean aphid is the most damaging insect pest of soybean in the Upper Midwest and is primarily controlled by insecticides. Soybean aphid resistance (i.e., Rag genes) has been documented in some soybean lines at chromosomes 6, 7, 13, and 16, but more sources of resistance are needed. Genome-wide ass...

  7. Genome-Wide Association Study and Linkage Analysis of the Healthy Aging Index

    DEFF Research Database (Denmark)

    Minster, Ryan L; Sanders, Jason L; Singh, Jatinder;

    2015-01-01

    BACKGROUND: The Healthy Aging Index (HAI) is a tool for measuring the extent of health and disease across multiple systems. METHODS: We conducted a genome-wide association study and a genome-wide linkage analysis to map quantitative trait loci associated with the HAI and a modified HAI weighted for......: There were no genome-wide significant findings from the genome-wide association study; however, several single-nucleotide polymorphisms near ZNF704 on chromosome 8q21.13 were suggestively associated with the HAI in the Long Life Family Study (p < 10(-) (6)) and nominally replicated in the Cardiovascular...

  8. A genome-wide linkage and association study using COGA data

    OpenAIRE

    Cao Guichan; Kan Donghui; Cooper Richard; Zhu Xiaofeng; Wu Xiaodong

    2005-01-01

    Abstract Background Genome-wide association will soon be available to use as an adjunct to traditional linkage analysis. We studied alcoholism in 119 families collected by the Collaborative Study on the Genetics of Alcoholism and made available in Genetic Analysis Workshop 14, using genome-wide linkage and association analyses. Methods Genome-wide linkage analysis was first performed using microsatellite markers and a region with the strongest linkage evidence was further analyzed using singl...

  9. A genome-wide linkage and association study using COGA data

    OpenAIRE

    Zhu, Xiaofeng; Cooper, Richard; Kan, Donghui; Cao, Guichan; Wu, Xiaodong

    2005-01-01

    Background Genome-wide association will soon be available to use as an adjunct to traditional linkage analysis. We studied alcoholism in 119 families collected by the Collaborative Study on the Genetics of Alcoholism and made available in Genetic Analysis Workshop 14, using genome-wide linkage and association analyses. Methods Genome-wide linkage analysis was first performed using microsatellite markers and a region with the strongest linkage evidence was further analyzed using single-nucleot...

  10. Voxelwise genome-wide association study (vGWAS)

    OpenAIRE

    Stein, Jason L; Hua, Xue; Lee, Suh; Ho, April J.; Leow, Alex D.; Toga, Arthur W.; Saykin, Andrew J.; Shen, Li; Foroud, Tatiana; Pankratz, Nathan; Matthew J. Huentelman; Craig, David W.; Gerber, Jill D.; Allen, April N.; Corneveaux, Jason J.

    2010-01-01

    The structure of the human brain is highly heritable, and is thought to be influenced by many common genetic variants, many of which are currently unknown. Recent advances in neuroimaging and genetics have allowed collection of both highly detailed structural brain scans and genome-wide genotype information. This wealth of information presents a new opportunity to find the genes influencing brain structure. Here we explore the relation between 448,293 single nucleotide polymorphisms in each o...

  11. Genome-wide search for gene-gene interactions in colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Shuo Jiao

    Full Text Available Genome-wide association studies (GWAS have successfully identified a number of single-nucleotide polymorphisms (SNPs associated with colorectal cancer (CRC risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI. With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p<10(-4. For the known locus rs10795668 (10p14, we found an interacting SNP rs367615 (5q21 with replication p = 0.01 and combined p = 4.19×10(-8. Among the top marginal SNPs after LD pruning (n = 163, we identified an interaction between rs1571218 (20p12.3 and rs10879357 (12q21.1 (nominal combined p = 2.51×10(-6; Bonferroni adjusted p = 0.03. Our study represents the first comprehensive search for GxG in CRC, and our results may provide new insight into the genetic etiology of CRC.

  12. Meta-Analysis in Genome-Wide Association Datasets: Strategies and Application in Parkinson Disease

    OpenAIRE

    Evangelou, Evangelos; Maraganore, Demetrius M.; Ioannidis, John P. A.

    2007-01-01

    Background Genome-wide association studies hold substantial promise for identifying common genetic variants that regulate susceptibility to complex diseases. However, for the detection of small genetic effects, single studies may be underpowered. Power may be improved by combining genome-wide datasets with meta-analytic techniques. Methodology/Principal Findings Both single and two-stage genome-wide data may be combined and there are several possible strategies. In the two-stage framework, we...

  13. Quality control and conduct of genome-wide association meta-analyses

    DEFF Research Database (Denmark)

    Winkler, Thomas W; Day, Felix R; Croteau-Chonka, Damien C;

    2014-01-01

    Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) Q...

  14. Family-Based Genome-Wide Association Scan of Attention-Deficit/Hyperactivity Disorder

    Science.gov (United States)

    Mick, Eric; Todorov, Alexandre; Smalley, Susan; Hu, Xiaolan; Loo, Sandra; Todd, Richard D.; Biederman, Joseph; Byrne, Deirdre; Dechairo, Bryan; Guiney, Allan; McCracken, James; McGough, James; Nelson, Stanley F.; Reiersen, Angela M.; Wilens, Timothy E.; Wozniak, Janet; Neale, Benjamin M.; Faraone, Stephen V.

    2010-01-01

    Objective: Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of…

  15. Genome-Wide Analysis Identifies Germ-Line Risk Factors Associated with Canine Mammary Tumours

    Science.gov (United States)

    Melin, Malin; Murén, Eva; Gustafson, Ulla; Starkey, Mike; Borge, Kaja Sverdrup; Lingaas, Frode; Saellström, Sara; Rönnberg, Henrik; Lindblad-Toh, Kerstin

    2016-01-01

    Canine mammary tumours (CMT) are the most common neoplasia in unspayed female dogs. CMTs are suitable naturally occurring models for human breast cancer and share many characteristics, indicating that the genetic causes could also be shared. We have performed a genome-wide association study (GWAS) in English Springer Spaniel dogs and identified a genome-wide significant locus on chromosome 11 (praw = 5.6x10-7, pperm = 0.019). The most associated haplotype spans a 446 kb region overlapping the CDK5RAP2 gene. The CDK5RAP2 protein has a function in cell cycle regulation and could potentially have an impact on response to chemotherapy treatment. Two additional loci, both on chromosome 27, were nominally associated (praw = 1.97x10-5 and praw = 8.30x10-6). The three loci explain 28.1±10.0% of the phenotypic variation seen in the cohort, whereas the top ten associated regions account for 38.2±10.8% of the risk. Furthermore, the ten GWAS loci and regions with reduced genetic variability are significantly enriched for snoRNAs and tumour-associated antigen genes, suggesting a role for these genes in CMT development. We have identified several candidate genes associated with canine mammary tumours, including CDK5RAP2. Our findings enable further comparative studies to investigate the genes and pathways in human breast cancer patients. PMID:27158822

  16. Genome-Wide Analysis Identifies Germ-Line Risk Factors Associated with Canine Mammary Tumours.

    Science.gov (United States)

    Melin, Malin; Rivera, Patricio; Arendt, Maja; Elvers, Ingegerd; Murén, Eva; Gustafson, Ulla; Starkey, Mike; Borge, Kaja Sverdrup; Lingaas, Frode; Häggström, Jens; Saellström, Sara; Rönnberg, Henrik; Lindblad-Toh, Kerstin

    2016-05-01

    Canine mammary tumours (CMT) are the most common neoplasia in unspayed female dogs. CMTs are suitable naturally occurring models for human breast cancer and share many characteristics, indicating that the genetic causes could also be shared. We have performed a genome-wide association study (GWAS) in English Springer Spaniel dogs and identified a genome-wide significant locus on chromosome 11 (praw = 5.6x10-7, pperm = 0.019). The most associated haplotype spans a 446 kb region overlapping the CDK5RAP2 gene. The CDK5RAP2 protein has a function in cell cycle regulation and could potentially have an impact on response to chemotherapy treatment. Two additional loci, both on chromosome 27, were nominally associated (praw = 1.97x10-5 and praw = 8.30x10-6). The three loci explain 28.1±10.0% of the phenotypic variation seen in the cohort, whereas the top ten associated regions account for 38.2±10.8% of the risk. Furthermore, the ten GWAS loci and regions with reduced genetic variability are significantly enriched for snoRNAs and tumour-associated antigen genes, suggesting a role for these genes in CMT development. We have identified several candidate genes associated with canine mammary tumours, including CDK5RAP2. Our findings enable further comparative studies to investigate the genes and pathways in human breast cancer patients. PMID:27158822

  17. Meta-Analysis of Genome-Wide Association Studies of Attention-Deficit/Hyperactivity Disorder

    Science.gov (United States)

    Neale, Benjamin M.; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; Franke, Barbara; Lesch, Klaus-Peter; Faraone, Stephen V.; Nguyen, Thuy Trang; Schafer, Helmut; Holmans, Peter; Daly, Mark; Steinhausen, Hans-Christoph; Freitag, Christine; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Walitza, Susanne; Warnke, Andreas; Meyer, Jobst; Palmason, Haukur; Buitelaar, Jan; Vasquez, Alejandro Arias; Lambregts-Rommelse, Nanda; Gill, Michael; Anney, Richard J. L.; Langely, Kate; O'Donovan, Michael; Williams, Nigel; Owen, Michael; Thapar, Anita; Kent, Lindsey; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph; Doyle, Alysa; Smalley, Susan; Loo, Sandra; Hakonarson, Hakon; Elia, Josephine; Todorov, Alexandre; Miranda, Ana; Mulas, Fernando; Ebstein, Richard P.; Rothenberger, Aribert; Banaschewski, Tobias; Oades, Robert D.; Sonuga-Barke, Edmund; McGough, James; Nisenbaum, Laura; Middleton, Frank; Hu, Xiaolan; Nelson, Stan

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of…

  18. Case-Control Genome-Wide Association Study of Attention-Deficit/Hyperactivity Disorder

    Science.gov (United States)

    Neale, Benjamin M.; Medland, Sarah; Ripke, Stephan; Anney, Richard J. L.; Asherson, Philip; Buitelaar, Jan; Franke, Barbara; Gill, Michael; Kent, Lindsey; Holmans, Peter; Middleton, Frank; Thapar, Anita; Lesch, Klaus-Peter; Faraone, Stephen V.; Daly, Mark; Nguyen, Thuy Trang; Schafer, Helmut; Steinhausen, Hans-Christoph; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Warnke, Andreas; Walitza, Susanne; Freitag, Christine; Meyer, Jobst; Palmason, Haukur; Rothenberger, Aribert; Hawi, Ziarih; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus additional genome-wide association studies (GWAS) are needed. Method: We used case-control analyses of 896 cases…

  19. A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33

    Science.gov (United States)

    Petersen, Gloria M.; Amundadottir, Laufey; Fuchs, Charles S.; Kraft, Peter; Stolzenberg-Solomon, Rachael Z.; Jacobs, Kevin B.; Arslan, Alan A.; Bueno-de-Mesquita, H. Bas; Gallinger, Steven; Gross, Myron; Helzlsouer, Kathy; Holly, Elizabeth A.; Jacobs, Eric J.; Klein, Alison P.; LaCroix, Andrea; Li, Donghui; Mandelson, Margaret T.; Olson, Sara H.; Risch, Harvey A.; Zheng, Wei; Albanes, Demetrius; Bamlet, William R.; Berg, Christine D.; Boutron-Ruault, Marie-Christine; Buring, Julie E.; Bracci, Paige M.; Canzian, Federico; Clipp, Sandra; Cotterchio, Michelle; de Andrade, Mariza; Duell, Eric J.; Gaziano, J. Michael; Giovannucci, Edward L.; Goggins, Michael; Hallmans, Göran; Hankinson, Susan E.; Hassan, Manal; Howard, Barbara; Hunter, David J.; Hutchinson, Amy; Jenab, Mazda; Kaaks, Rudolf; Kooperberg, Charles; Krogh, Vittorio; Kurtz, Robert C.; Lynch, Shannon M.; McWilliams, Robert R.; Mendelsohn, Julie B.; Michaud, Dominique S.; Parikh, Hemang; Patel, Alpa V.; Peeters, Petra H.M.; Rajkovic, Aleksandar; Riboli, Elio; Rodriguez, Laudina; Seminara, Daniela; Shu, Xiao-Ou; Thomas, Gilles; Tjønneland, Anne; Tobias, Geoffrey S.; Trichopoulos, Dimitrios; Van Den Eeden, Stephen K.; Virtamo, Jarmo; Wactawski-Wende, Jean; Wang, Zhaoming; Wolpin, Brian M.; Yu, Herbert; Yu, Kai; Zeleniuch-Jacquotte, Anne; Fraumeni, Joseph F.; Hoover, Robert N.; Hartge, Patricia; Chanock, Stephen J.

    2010-01-01

    We conducted a genome-wide association study (GWAS) of pancreatic cancer in 3,851 cases and 3,934 controls drawn from twelve prospective cohort studies and eight case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P=3.27×10−11; per allele odds ratio, OR 1.26, 95% CI=1.18-1.35) and rs9564966 (P=5.86×10−8; per allele OR 1.21, 95% CI=1.13-1.30) map to a non-genic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2; the strongest signal was rs3790844 (P=2.45×10−10; per allele OR 0.77, 95% CI=0.71-0.84). A single SNP, rs401681 (P=3.66×10−7; per allele OR 1.19, 95% CI=1.11-1.27) maps to the CLPTM1L-TERT locus on 5p15.33, associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies. PMID:20101243

  20. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients

    DEFF Research Database (Denmark)

    Győrffy, Balázs; Lánczky, András; Szállási, Zoltán

    2012-01-01

    ). A Kaplan–Meier survival plot was generated and significance was computed. The tool can be accessed online at www.kmplot.com/ovar. We used this integrative data analysis tool to validate the prognostic power of 37 biomarkers identified in the literature. Of these, CA125 (MUC16; P=3.7x10–5, hazard...... biomarker validation platform that mines all available microarray data to assess the prognostic power of 22 277 genes in 1287 ovarian cancer patients. We specifically used this tool to evaluate the effect of 37 previously published biomarkers on ovarian cancer prognosis....... set up using gene expression data and survival information of 1287 ovarian cancer patients downloaded from Gene Expression Omnibus and The Cancer Genome Atlas (Affymetrix HG-U133A, HG-U133A 2.0, and HG-U133 Plus 2.0 microarrays). After quality control and normalization, only probes present on all...

  1. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

    Czech Academy of Sciences Publication Activity Database

    Tomlinson, I.P.M.; Webb, E.; Carvajal-Carmona, L.; Broderick, P.; Howarth, K.; Pittman, A.M.; Spain, S.; Lubbe, S.; Walter, A.; Sullivan, K.; Jaeger, E.; Fielding, S.; Rowan, A.; Vijayakrishnan, J.; Domingo, E.; Chandler, I.; Kemp, Z.; Qureshi, M.; Farrington, S.M.; Tenesa, A.; Prendergast, J.G.D.; Barnetson, R.A.; Penegar, S.; Barclay, E.; Wood, W.; Martin, L.; Gorman, M.; Thomas, H.; Peto, J.; Bishop, D.T.; Gray, R.; Maher, E.R.; Lucassen, A.; Kerr, D.; Evans, D.G.R.; Schafmayer, C.; Buch, S.; Völzke, H.; Hampe, J.; Schreber, S.; John, U.; Koessler, T.; Pharoah, P.; van Wezel, T.; Morreau, H.; Wijnen, J.T.; Hopper, J.L.; Southey, M.C.; Giles, G.G.; Severi, G.; Castellví-Bel, S.; Ruiz-Ponte, C.; Carracedo, A.; Castells, A.; Försti, A.; Hemminki, K.; Vodička, Pavel; Naccarati, Alessio; Lipton, L.; Ho, J.W.C.; Cheng, K.K.; Sham, P.C.; Luk, J.; Agúndez, J.A.G.; Ladero, J.M.; de la Hoya, M.; Caldés, T.; Niittymäki, I.; Tuupanene, S.; Karhu, A.; Aaltonen, L.; Cazier, J.B.; Campbell, H.; Dunlop, M.G.; Houlston, R.S.

    2008-01-01

    Roč. 40, č. 5 (2008), s. 623-630. ISSN 1061-4036 R&D Projects: GA ČR GA310/07/1430 Institutional research plan: CEZ:AV0Z50390703 Keywords : Colorectal cancer Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 30.259, year: 2008

  2. Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility

    Czech Academy of Sciences Publication Activity Database

    Lascors, J.; Försti, A.; Chen, B.; Buch, S.; Steinke, V.; Rahner, N.; Holinski-Feder, E.; Morak, M.; Schackert, H. K.; Görgens, H.; Schulmann, K.; Goecke, T.; Kloor, M.; Engel, C.; Büttner, R.; Kunkel, N.; Weires, M.; Hoffmeister, M.; Pardini, Barbara; Naccarati, Alessio; Vodičková, Ludmila; Novotný, J.; Schreiber, S.; Krawczak, M.; Bröring, C. D.; Völzke, H.; Schafmayer, C.; Vodička, Pavel; Chang-Claude, J.; Brenner, H.; Burwinkel, B.; Propping, P.; Hampe, J.; Hemminki, K.

    2010-01-01

    Roč. 31, č. 9 (2010), s. 1612-1619. ISSN 0143-3334 R&D Projects: GA ČR GA310/07/1430 Grant ostatní: EU(XE) HEALTH-F4-2007-200767 Institutional research plan: CEZ:AV0Z50390512 Keywords : colorectal cancer * gene ontology * confidence interval Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.402, year: 2010

  3. Genome-wide association analysis identifies six new loci associated with forced vital capacity

    NARCIS (Netherlands)

    D.W. Loth (Daan); M.S. Artigas; S.A. Gharib (Sina); L.V. Wain (Louise); N. Franceschini (Nora); B. Koch (Beate); T.D. Pottinger (Tess); G.D. Smith; Q. Duan (Qing); C. Oldmeadow (Christopher); M.K. Lee (Mi Kyeong); D.P. Strachan (David); A.L. James (Alan); J.E. Huffman (Jennifer); V. Vitart (Veronique); A. Ramasamy (Adaikalavan); N.J. Wareham (Nick); J. Kaprio (Jaakko); X.-Q. Wang (Xin-Qun); H. Trochet (Holly); M. Kähönen (Mika); C. Flexeder (Claudia); E. Albrecht (Eva); L.M. Lopez (Lorna); B. Thyagarajan (Bharat); A.C. Alves (Alexessander Couto); S. Enroth (Stefan); E. Omenaas (Ernst); P.K. Joshi (Peter); M. Fall (Magnus); A. Viñuela (Ana); L.J. Launer (Lenore); L.R. Loehr (Laura); M. Fornage (Myriam); G. Li (Guo); J.B. Wilk (Jemma); W. Tang (Wenbo); A. Manichaikul (Ani); L. Lahousse (Lies); T.B. Harris (Tamara); K.E. North (Kari); A.R. Rudnicka (Alicja); J. Hui (Jennie); X. Gu (Xiangjun); T. Lumley (Thomas); A.F. Wright (Alan); N. Hastie (Nick); S. Campbell (Susan); R. Kumar (Rajesh); I. Pin (Isabelle); R.A. Scott (Robert); K.H. Pietilainen (Kirsi Hannele); I. Surakka (Ida); Y. Liu (Yongmei); E.G. Holliday (Elizabeth); H. Schulz (Holger); J. Heinrich (Joachim); G. Davies (Gail); J.M. Vonk (Judith); M.K. Wojczynski (Mary ); A. Pouta (Anneli); A. Johansson (Åsa); S.H. Wild (Sarah); E. Ingelsson (Erik); F. Rivadeneira Ramirez (Fernando); H. Völzke (Henry); P.G. Hysi (Pirro); G. Eiriksdottir (Gudny); A.C. Morrison (Alanna); J.I. Rotter (Jerome); W. Gao (Wei); D.S. Postma (Dirkje); W.B. White (Wendy); S.S. Rich (Stephen); A. Hofman (Albert); T. Aspelund (Thor); D. Couper (David); L.J. Smith (Lewis); B.M. Psaty (Bruce); K. Lohman (Kurt); E.G. Burchard (Esteban); A.G. Uitterlinden (André); M. Garcia (Melissa); B.R. Joubert (Bonnie); W.L. McArdle (Wendy); A.W. Musk (Arthur); C.R.W. Hansel (Christian); S.R. Heckbert (Susan); L. Zgaga (Lina); J.B.J. van Meurs (Joyce); P. Navarro (Pau); I. Rudan (Igor); Y.-M. Oh (Yeon-Mok); S. Redline (Susan); D.L. Jarvis (Deborah); J.H. Zhao (Jing); T. Rantanen (Taina); G.T. O'Connor (George); S. Ripatti (Samuli); R.J. Scott (Rodney); S. Karrasch (Stefan); H. Grallert (Harald); N.C. Gaddis (Nathan); J.M. Starr (John); C. Wijmenga (Cisca); R.L. Minster (Ryan); C.W. Lederer (Carsten); J. Pekkanen (Juha); U. Gyllensten (Ulf); H. Campbell (Harry); A.P. Morris (Andrew); S. Gläser (Sven); C.J. Hammond (Christopher); K.M. Burkart (Kristin); J.P. Beilby (John); S.B. Kritchevsky (Stephen); V. Gudnason (Vilmundur); D.B. Hancock (Dana); O.D. Williams (Dale); O. Polasek (Ozren); T. Zemunik (Tatijana); I. Kolcic (Ivana); M.F. Petrini (Marcy); K.T. de Jong (Kim); M. Wjst (Matthias); W.H. Kim (Woo); D.J. Porteous (David J.); G. Scotland (Generation); B.H. Smith (Blair); A. Viljanen (Anne); M. Heliovaara (Markku); J. Attia (John); I. Sayers (Ian); R. Hampel (Regina); C. Gieger (Christian); I.J. Deary (Ian); H.M. Boezen (H. Marike); A.B. Newman (Anne); M.-R. Jarvelin (Marjo-Riitta); J.F. Wilson (James); L. Lind (Lars); B.H.Ch. Stricker (Bruno); A. Teumer (Alexander); T.D. Spector (Timothy); E. Melén (Erik); M.J. Peters (Marjolein); L.A. Lange (Leslie); R.G. Barr (Graham); K.R. Bracke (Ken); F.M. Verhamme (Fien); J. Sung (Joohon); P.S. Hiemstra (Pieter); P.A. Cassano (Patricia); A. Sood (Akshay); C. Hayward (Caroline); J. Dupuis (Josée); I.P. Hall (Ian); G.G. Brusselle (Guy); M.D. Tobin (Martin); S.J. London (Stephanie)

    2014-01-01

    textabstractForced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in

  4. Genome-wide association analysis identifies six new loci associated with forced vital capacity

    NARCIS (Netherlands)

    Loth, Daan W.; Artigas, Maria Soler; Gharib, Sina A.; Wain, Louise V.; Franceschini, Nora; Koch, Beate; Pottinger, Tess D.; Smith, Albert Vernon; Duan, Qing; Oldmeadow, Chris; Lee, Mi Kyeong; Strachan, David P.; James, Alan L.; Huffman, Jennifer E.; Vitart, Veronique; Ramasamy, Adaikalavan; Wareham, Nicholas J.; Kaprio, Jaakko; Wang, Xin-Qun; Trochet, Holly; Kaonen, Mika; Flexeder, Claudia; Albrecht, Eva; Lopez, Lorna M.; de Jong, Kim; Thyagarajan, Bharat; Alves, Alexessander Couto; Enroth, Stefan; Omenaas, Ernst; Joshi, Peter K.; Fall, Tove; Vinuela, Ana; Launer, Lenore J.; Loehr, Laura R.; Fornage, Myriam; Li, Guo; Wik, Jemma B.; Tang, Wenbo; Manichaikul, Ani; Lahousse, Lies; Harris, Tamara B.; North, Kari E.; Rudnicka, Alicja R.; Hui, Jennie; Gu, Xiangjun; Lumley, Thomas; Wright, Alan F.; Hastie, Nicholas D.; Campbell, Susan; Kumar, Rajesh; Pin, Isabelle; Scott, Robert A.; Pietilainen, Kirsi H.; Surakka, Ida; Liu, Yongmei; Holliday, Elizabeth G.; Schulz, Holger; Heinrich, Joachim; Davies, Gail; Vonk, Judith M.; Wojczynski, Mary; Pouta, Anneli; Johansson, Asa; Wild, Sarah H.; Ingelsson, Erik; Rivadeneira, Fernando; Voezke, Henry; Hysi, Pirro G.; Eiriksdottir, Gudny; Morrison, Alanna C.; Rotter, Jerome I.; Gao, Wei; Postma, Dirkje S.; White, Wendy B.; Rich, Stephen S.; Hofman, Albert; Aspelund, Thor; Couper, David; Smith, Lewis J.; Psaty, Bruce M.; Lohman, Kurt; Burchard, Esteban G.; Uitterlinden, Andre G.; Garcia, Melissa; Joubert, Bonnie R.; McArdle, Wendy L.; Musk, A. Bill; Hansel, Nadia; Heckbert, Susan R.; Zgaga, Lina; van Meurs, Joyce B. J.; Navarro, Pau; Rudan, Igor; Oh, Yeon-Mok; Redline, Susan; Jarvis, Deborah L.; Rantanen, Taina; O'Connor, George T.; Ripatti, Samuli; Scott, Rodney J.; Karrasch, Stefan; Grallert, Harald; Gaddis, Nathan C.; Starr, John M.; Wijmenga, Cisca; Minster, Ryan L.; Lederer, David J.; Pekkanen, Juha; Gyllensten, Ulf; Campbe, Harry; Morris, Andrew P.; Glaeser, Sven; Hammond, Christopher J.; Burkart, Kristin M.; Beilby, John; Kritchevsky, Stephen B.; Gucinason, Vilrnundur; Hancock, Dana B.; Williams, Dale; Polasek, Ozren; Zemunik, Tatijana; Kolcic, Ivana; Petrini, Marcy F.; Wjst, Matthias; Kim, Woo Jin; Porteous, David J.; Scotland, Generation; Smith, Blair H.; Villanen, Anne; Heliovaara, Markku; Attia, John R.; Sayers, Ian; Hampel, Regina; Gieger, Christian; Deary, Ian J.; Boezen, Hendrika; Newman, Anne; Jarvelin, Marjo-Riitta; Wilson, James F.; Lind, Lars; Stricker, Bruno H.; Teumer, Alexander; Spector, Timothy D.; Melen, Erik; Peters, Marjolein J.; Lange, Leslie A.; Barr, R. Graham; Bracke, Ken R.; Verhamme, Fien M.; Sung, Joohon; Hiemstra, Pieter S.; Cassano, Patricia A.; Sood, Akshay; Hayward, Caroline; Dupuis, Josee; Hall, Ian P.; Brusselle, Guy G.; Tobin, Martin D.; London, Stephanie J.

    2014-01-01

    Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 addit

  5. Genome wide in silico SNP-tumor association analysis

    International Nuclear Information System (INIS)

    Carcinogenesis occurs, at least in part, due to the accumulation of mutations in critical genes that control the mechanisms of cell proliferation, differentiation and death. Publicly accessible databases contain millions of expressed sequence tag (EST) and single nucleotide polymorphism (SNP) records, which have the potential to assist in the identification of SNPs overrepresented in tumor tissue. An in silico SNP-tumor association study was performed utilizing tissue library and SNP information available in NCBI's dbEST (release 092002) and dbSNP (build 106). A total of 4865 SNPs were identified which were present at higher allele frequencies in tumor compared to normal tissues. A subset of 327 (6.7%) SNPs induce amino acid changes to the protein coding sequences. This approach identified several SNPs which have been previously associated with carcinogenesis, as well as a number of SNPs that now warrant further investigation This novel in silico approach can assist in prioritization of genes and SNPs in the effort to elucidate the genetic mechanisms underlying the development of cancer

  6. Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma

    OpenAIRE

    Dahlin, Amber; Litonjua, Augusto; Lima, John J.; Tamari, Mayumi; Kubo, Michiaki; Irvin, Charles G.; Peters, Stephen P.; Tantisira, Kelan G.

    2015-01-01

    Background: Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics. Methods: Using genome-wide genotype and phenotypic data available from American Lung Association -...

  7. Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma

    OpenAIRE

    Dahlin, Amber; Litonjua, Augusto; Lima, John J.; Tamari, Mayumi; Kubo, Michiaki; Irvin, Charles G.; Peters, Stephen P.; Tantisira, Kelan G.

    2015-01-01

    Background Genome-wide association study (GWAS) is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs). Leukotriene receptor antagonists (LTRAs) are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics. Methods Using genome-wide genotype and phenotypic data available from American Lung Association - A...

  8. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies

    OpenAIRE

    2014-01-01

    Summary Background The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilep...

  9. Genome-wide association study of smoking initiation and current smoking

    DEFF Research Database (Denmark)

    Vink, Jacqueline M; Smit, August B; de Geus, Eco J C;

    2009-01-01

    For the identification of genes associated with smoking initiation and current smoking, genome-wide association analyses were carried out in 3497 subjects. Significant genes that replicated in three independent samples (n = 405, 5810, and 1648) were visualized into a biologically meaningful network...... cell-adhesion molecules (e.g., CDH23). We conclude that a network-based genome-wide association approach can identify genes influencing smoking behavior....

  10. Integrated analysis of copy number variation and genome-wide expression profiling in colorectal cancer tissues.

    Directory of Open Access Journals (Sweden)

    Nur Zarina Ali Hassan

    Full Text Available Integrative analyses of multiple genomic datasets for selected samples can provide better insight into the overall data and can enhance our knowledge of cancer. The objective of this study was to elucidate the association between copy number variation (CNV and gene expression in colorectal cancer (CRC samples and their corresponding non-cancerous tissues. Sixty-four paired CRC samples from the same patients were subjected to CNV profiling using the Illumina HumanOmni1-Quad assay, and validation was performed using multiplex ligation probe amplification method. Genome-wide expression profiling was performed on 15 paired samples from the same group of patients using the Affymetrix Human Gene 1.0 ST array. Significant genes obtained from both array results were then overlapped. To identify molecular pathways, the data were mapped to the KEGG database. Whole genome CNV analysis that compared primary tumor and non-cancerous epithelium revealed gains in 1638 genes and losses in 36 genes. Significant gains were mostly found in chromosome 20 at position 20q12 with a frequency of 45.31% in tumor samples. Examples of genes that were associated at this cytoband were PTPRT, EMILIN3 and CHD6. The highest number of losses was detected at chromosome 8, position 8p23.2 with 17.19% occurrence in all tumor samples. Among the genes found at this cytoband were CSMD1 and DLC1. Genome-wide expression profiling showed 709 genes to be up-regulated and 699 genes to be down-regulated in CRC compared to non-cancerous samples. Integration of these two datasets identified 56 overlapping genes, which were located in chromosomes 8, 20 and 22. MLPA confirmed that the CRC samples had the highest gains in chromosome 20 compared to the reference samples. Interpretation of the CNV data in the context of the transcriptome via integrative analyses may provide more in-depth knowledge of the genomic landscape of CRC.

  11. A Genome-Wide Scan for Breast Cancer Risk Haplotypes among African American Women

    OpenAIRE

    Song, Chi; Chen, Gary K.; Millikan, Robert C.; Ambrosone, Christine B.; John, Esther M; Bernstein, Leslie; Zheng, Wei; Jennifer J Hu; Ziegler, Regina G.; Nyante, Sarah; Bandera, Elisa V.; Sue A Ingles; Michael F. Press; Deming, Sandra L.; Rodriguez-Gil, Jorge L.

    2013-01-01

    Genome-wide association studies (GWAS) simultaneously investigating hundreds of thousands of single nucleotide polymorphisms (SNP) have become a powerful tool in the investigation of new disease susceptibility loci. Haplotypes are sometimes thought to be superior to SNPs and are promising in genetic association analyses. The application of genome-wide haplotype analysis, however, is hindered by the complexity of haplotypes themselves and sophistication in computation. We systematically analyz...

  12. Genome-wide association study identifies four loci associated with eruption of permanent teeth

    DEFF Research Database (Denmark)

    Geller, Frank; Feenstra, Bjarke; Zhang, Hao;

    2011-01-01

    The sequence and timing of permanent tooth eruption is thought to be highly heritable and can have important implications for the risk of malocclusion, crowding, and periodontal disease. We conducted a genome-wide association study of number of permanent teeth erupted between age 6 and 14 years...

  13. Genome-wide association analyses identify variants in developmental genes associated with hypospadias

    DEFF Research Database (Denmark)

    Geller, Frank; Feenstra, Bjarke; Carstensen, Lisbeth;

    2014-01-01

    Hypospadias is a common congenital condition in boys in which the urethra opens on the underside of the penis. We performed a genome-wide association study on 1,006 surgery-confirmed hypospadias cases and 5,486 controls from Denmark. After replication genotyping of an additional 1,972 cases and 1...

  14. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function

    NARCIS (Netherlands)

    D.B. Hancock (Dana); M. Eijgelsheim (Mark); J.B. Wilk (Jemma); S.A. Gharib (Sina); L.R. Loehr (Laura); K. Marciante (Kristin); N. Franceschini (Nora); Y.M.T.A. van Durme; T.H. Chen; R.G. Barr (Graham); M.B. Schabath (Matthew); D.J. Couper (David); G.G. Brusselle (Guy); B.M. Psaty (Bruce); P. Tikka-Kleemola (Päivi); J.I. Rotter (Jerome); A.G. Uitterlinden (André); A. Hofman (Albert); N.M. Punjabi (Naresh); F. Rivadeneira Ramirez (Fernando); A.C. Morrison (Alanna); P.L. Enright (Paul); K.E. North (Kari); S.R. Heckbert (Susan); T. Lumley (Thomas); B.H.Ch. Stricker (Bruno); G.T. O'Connor (George); S.J. London (Stephanie)

    2010-01-01

    textabstractSpirometric measures of lung function are heritable traits that reflect respiratory health and predict morbidity and mortality. We meta-analyzed genome-wide association studies for two clinically important lung-function measures: forced expiratory volume in the first second (FEV1) and it

  15. Genome-wide association study identifies 74 loci associated with educational attainment

    NARCIS (Netherlands)

    Okbay, Aysu; Beauchamp, Jonathan P.; Fontana, Mark Alan; Lee, James J.; Pers, Tune H.; Rietveld, Cornelius A.; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S. Fleur W.; Oskarsson, Sven; Pickrell, Joseph K.; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S.; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H.; Concas, Maria Pina; Derringer, Jaime; Furlotte, Nicholas A.; Galesloot, Tessel E.; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M.; Harris, Sarah E.; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E.; Kaasik, Kadri; Kalafati, Ioanna P.; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J.; de Leeuw, Christiaan; Lind, Penelope A.; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B.; van der Most, Peter J.; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J.; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Brge; Schraut, Katharina E.; Shi, Jianxin; Smith, Albert V.; Poot, Raymond A.; St Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z.; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E.; Biino, Ginevra; Bonnelykke, Klaus; Boyle, Patricia A.; Campbell, Harry; Cappuccio, Francesco P.; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans, David M.; Faul, Jessica D.; Feitosa, Mary F.; Forstner, Andreas J.; Gandin, Ilaria; Gunnarsson, Bjarni; Halldorsson, Bjarni V.; Harris, Tamara B.; Heath, Andrew C.; Hocking, Lynne J.; Holliday, Elizabeth G.; Homuth, Georg; Horan, Michael A.; Hottenga, Jouke-Jan; de Jager, Philip L.; Joshi, Peter K.; Jugessur, Astanand; Kaakinen, Marika A.; Kahonen, Mika; Kanoni, Stavroula; Keltigangas-Jarvinen, Liisa; Kiemeney, Lambertus A. L. M.; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T.; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J.; Lebreton, Mael P.; Levinson, Douglas F.; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C. M.; Loukola, Anu; Madden, Pamela A.; Magi, Reedik; Maki-Opas, Tomi; Marioni, Riccardo E.; Marques-Vidal, Pedro; Meddens, Gerardus A.; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W.; Myhre, Ronny; Nelson, Christopher P.; Nyholt, Dale R.; Ollier, William E. R.; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L.; Petrovic, Katja E.; Porteous, David J.; Raikkonen, Katri; Ring, Susan M.; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R.; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J.; Smith, Blair H.; Smith, Jennifer A.; Staessen, Jan A.; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D.; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J. A.; Venturini, Cristina; Vinkhuyzen, Anna A. E.; Volker, Uwe; Volzke, Henry; Vonk, Judith M.; Waage, Johannes; Ware, Erin B.; Willemsen, Gonneke; Attia, John R.; Bennett, David A.; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I.; Borecki, Ingrid B.; Bultmann, Ute; Chabris, Christopher F.; Cucca, Francesco; Cusi, Daniele; Deary, Ian J.; Dedoussis, George V.; van Duijn, Cornelia M.; Eriksson, Johan G.; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V.; Gieger, Christian; Grabe, Hans-Jorgen; Gratten, Jacob; Groenen, Patrick J. F.; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A.; Hoffmann, Wolfgang; Hyppnen, Elina; Iacono, William G.; Jacobsson, Bo; Jarvelin, Marjo-Riitta; Jockel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L. R.; Lehtimaki, Terho; Lehrer, Steven F.; Magnusson, Patrik K. E.; Martin, Nicholas G.; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W. J. H.; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A.; Samani, Nilesh J.; Schlessinger, David; Schmidt, Reinhold; Sorensen, Thorkild I. A.; Spector, Tim D.; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tiemeier, Henning; Tung, Joyce Y.; Uitterlinden, Andre G.; Vitart, Veronique; Vollenweider, Peter; Weir, David R.; Wilson, James F.; Wright, Alan F.; Conley, Dalton C.; Krueger, Robert F.; Smith, George Davey; Hofman, Albert; Laibson, David I.; Medland, Sarah E.; Meyer, Michelle N.; Yang, Jian; Johannesson, Magnus; Visscher, Peter M.; Esko, Tonu; Koellinger, Philipp D.; Cesarini, David; Benjamin, Daniel J.

    2016-01-01

    Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals(1). Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends

  16. Genome-wide association study identifies shared risk loci common to two malignancies in golden retrievers.

    Science.gov (United States)

    Tonomura, Noriko; Elvers, Ingegerd; Thomas, Rachael; Megquier, Kate; Turner-Maier, Jason; Howald, Cedric; Sarver, Aaron L; Swofford, Ross; Frantz, Aric M; Ito, Daisuke; Mauceli, Evan; Arendt, Maja; Noh, Hyun Ji; Koltookian, Michele; Biagi, Tara; Fryc, Sarah; Williams, Christina; Avery, Anne C; Kim, Jong-Hyuk; Barber, Lisa; Burgess, Kristine; Lander, Eric S; Karlsson, Elinor K; Azuma, Chieko; Modiano, Jaime F; Breen, Matthew; Lindblad-Toh, Kerstin

    2015-02-01

    Dogs, with their breed-determined limited genetic background, are great models of human disease including cancer. Canine B-cell lymphoma and hemangiosarcoma are both malignancies of the hematologic system that are clinically and histologically similar to human B-cell non-Hodgkin lymphoma and angiosarcoma, respectively. Golden retrievers in the US show significantly elevated lifetime risk for both B-cell lymphoma (6%) and hemangiosarcoma (20%). We conducted genome-wide association studies for hemangiosarcoma and B-cell lymphoma, identifying two shared predisposing loci. The two associated loci are located on chromosome 5, and together contribute ~20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6×10-7 and 2.7×10-6, respectively. Whole genome resequencing of nine cases and controls followed by genotyping and detailed analysis identified three shared and one B-cell lymphoma specific risk haplotypes within the two loci, but no coding changes were associated with the risk haplotypes. Gene expression analysis of B-cell lymphoma tumors revealed that carrying the risk haplotypes at the first locus is associated with down-regulation of several nearby genes including the proximal gene TRPC6, a transient receptor Ca2+-channel involved in T-cell activation, among other functions. The shared risk haplotype in the second locus overlaps the vesicle transport and release gene STX8. Carrying the shared risk haplotype is associated with gene expression changes of 100 genes enriched for pathways involved in immune cell activation. Thus, the predisposing germ-line mutations in B-cell lymphoma and hemangiosarcoma appear to be regulatory, and affect pathways involved in T-cell mediated immune response in the tumor. This suggests that the interaction between the immune system and malignant cells plays a common role in the tumorigenesis of these relatively different cancers. PMID:25642983

  17. Genetic associations with neuroendocrine tumor risk: results from a genome-wide association study.

    Science.gov (United States)

    Du, Yeting; Ter-Minassian, Monica; Brais, Lauren; Brooks, Nichole; Waldron, Amanda; Chan, Jennifer A; Lin, Xihong; Kraft, Peter; Christiani, David C; Kulke, Matthew H

    2016-08-01

    The etiology of neuroendocrine tumors remains poorly defined. Although neuroendocrine tumors are in some cases associated with inherited genetic syndromes, such syndromes are rare. The majority of neuroendocrine tumors are thought to be sporadic. We performed a genome-wide association study (GWAS) to identify potential genetic risk factors for sporadic neuroendocrine tumors. Using germline DNA from blood specimens, we genotyped 909,622 SNPs using the Affymetrix 6.0 GeneChip, in a cohort comprising 832 neuroendocrine tumor cases from Dana-Farber Cancer Institute and Massachusetts General Hospital and 4542 controls from the Harvard School of Public Health. An additional 241 controls from Dana-Farber Cancer Institute were used for quality control. We assessed risk associations in the overall cohort, and in neuroendocrine tumor subgroups. We identified no potential risk associations in the cohort overall. In the small intestine neuroendocrine tumor subgroup, comprising 293 cases, we identified risk associations with three SNPs on chromosome 12, all in strong LD. The three SNPs are located upstream of ELK3, a transcription factor implicated in angiogenesis. We did not identify clear risk associations in the bronchial or pancreatic neuroendocrine subgroups. This large-scale study provides initial evidence that presumed sporadic small intestine neuroendocrine tumors may have a genetic etiology. Our results provide a basis for further exploring the role of genes implicated in this analysis, and for replication studies to confirm the observed associations. Additional studies to evaluate potential genetic risk factors for sporadic pancreatic and bronchial neuroendocrine tumors are warranted. PMID:27492634

  18. Meta-analysis of genome-wide association studies of attention deficit/hyperactivity disorder

    OpenAIRE

    Neale, Benjamin M.; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; Franke, Barbara; Lesch, Klaus-Peter; Faraone, Stephen V.; Nguyen, Thuy Trang; Schaefer, Helmut; Holmans, Peter; Daly, Mark; STEINHAUSEN, HANS-CHRISTOPH; Freitag, Christine,; Reif, Andreas; Tobias J Renner

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method: We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of ...

  19. Genome-wide association study of age at menarche in African-American women

    OpenAIRE

    Demerath, Ellen W; Liu, Ching-Ti; Franceschini, Nora; Chen, Gary; Palmer, Julie R.; Smith, Erin N.; Chen, Christina T. L.; Ambrosone, Christine B.; Arnold, Alice M.; Bandera, Elisa V.; Berenson, Gerald S.; Bernstein, Leslie; Britton, Angela; Cappola, Anne R.; Carlson, Christopher S.

    2013-01-01

    African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide associati...

  20. Susceptibility to Chronic Mucus Hypersecretion, a Genome Wide Association Study

    DEFF Research Database (Denmark)

    Dijkstra, Akkelies E; Smolonska, Joanna; van den Berge, Maarten; Wijmenga, Ciska; Zanen, Pieter; Luinge, Marjan A; Platteel, Mathieu; Lammers, Jan-Willem; Dahlback, Magnus; Tosh, Kerrie; Hiemstra, Pieter S; Sterk, Peter J; Spira, Avi; Vestbo, Jorgen; Nordestgaard, Børge; Benn, Marianne; Nielsen, Sune F; Dahl, Morten; Verschuren, W Monique; Picavet, H Susan J; Smit, Henriette A; Owsijewitsch, Michael; Kauczor, Hans U; de Koning, Harry J; Nizankowska-Mogilnicka, Eva; Mejza, Filip; Nastalek, Pawel; van Diemen, Cleo C; Cho, Michael H; Silverman, Edwin K; Crapo, James D; Beaty, Terri H; Lomas, David A; Bakke, Per; Gulsvik, Amund; Bossé, Yohan; Obeidat, M A; Loth, Daan W; Lahousse, Lies; Rivadeneira, Fernando; Uitterlinden, Andre G; Hofman, Andre; Stricker, Bruno H; Brusselle, Guy G; van Duijn, Cornelia M; Brouwer, Uilke; Koppelman, Gerard H; Vonk, Judith M; Nawijn, Martijn C; Groen, Harry J M; Timens, Wim; Boezen, H Marike; Postma, Dirkje S

    2014-01-01

    BACKGROUND: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of sm...

  1. Genome-wide association analysis identifies six new loci associated with forced vital capacity.

    Science.gov (United States)

    Loth, Daan W; Soler Artigas, María; Gharib, Sina A; Wain, Louise V; Franceschini, Nora; Koch, Beate; Pottinger, Tess D; Smith, Albert Vernon; Duan, Qing; Oldmeadow, Chris; Lee, Mi Kyeong; Strachan, David P; James, Alan L; Huffman, Jennifer E; Vitart, Veronique; Ramasamy, Adaikalavan; Wareham, Nicholas J; Kaprio, Jaakko; Wang, Xin-Qun; Trochet, Holly; Kähönen, Mika; Flexeder, Claudia; Albrecht, Eva; Lopez, Lorna M; de Jong, Kim; Thyagarajan, Bharat; Alves, Alexessander Couto; Enroth, Stefan; Omenaas, Ernst; Joshi, Peter K; Fall, Tove; Viñuela, Ana; Launer, Lenore J; Loehr, Laura R; Fornage, Myriam; Li, Guo; Wilk, Jemma B; Tang, Wenbo; Manichaikul, Ani; Lahousse, Lies; Harris, Tamara B; North, Kari E; Rudnicka, Alicja R; Hui, Jennie; Gu, Xiangjun; Lumley, Thomas; Wright, Alan F; Hastie, Nicholas D; Campbell, Susan; Kumar, Rajesh; Pin, Isabelle; Scott, Robert A; Pietiläinen, Kirsi H; Surakka, Ida; Liu, Yongmei; Holliday, Elizabeth G; Schulz, Holger; Heinrich, Joachim; Davies, Gail; Vonk, Judith M; Wojczynski, Mary; Pouta, Anneli; Johansson, Asa; Wild, Sarah H; Ingelsson, Erik; Rivadeneira, Fernando; Völzke, Henry; Hysi, Pirro G; Eiriksdottir, Gudny; Morrison, Alanna C; Rotter, Jerome I; Gao, Wei; Postma, Dirkje S; White, Wendy B; Rich, Stephen S; Hofman, Albert; Aspelund, Thor; Couper, David; Smith, Lewis J; Psaty, Bruce M; Lohman, Kurt; Burchard, Esteban G; Uitterlinden, André G; Garcia, Melissa; Joubert, Bonnie R; McArdle, Wendy L; Musk, A Bill; Hansel, Nadia; Heckbert, Susan R; Zgaga, Lina; van Meurs, Joyce B J; Navarro, Pau; Rudan, Igor; Oh, Yeon-Mok; Redline, Susan; Jarvis, Deborah L; Zhao, Jing Hua; Rantanen, Taina; O'Connor, George T; Ripatti, Samuli; Scott, Rodney J; Karrasch, Stefan; Grallert, Harald; Gaddis, Nathan C; Starr, John M; Wijmenga, Cisca; Minster, Ryan L; Lederer, David J; Pekkanen, Juha; Gyllensten, Ulf; Campbell, Harry; Morris, Andrew P; Gläser, Sven; Hammond, Christopher J; Burkart, Kristin M; Beilby, John; Kritchevsky, Stephen B; Gudnason, Vilmundur; Hancock, Dana B; Williams, O Dale; Polasek, Ozren; Zemunik, Tatijana; Kolcic, Ivana; Petrini, Marcy F; Wjst, Matthias; Kim, Woo Jin; Porteous, David J; Scotland, Generation; Smith, Blair H; Viljanen, Anne; Heliövaara, Markku; Attia, John R; Sayers, Ian; Hampel, Regina; Gieger, Christian; Deary, Ian J; Boezen, H Marike; Newman, Anne; Jarvelin, Marjo-Riitta; Wilson, James F; Lind, Lars; Stricker, Bruno H; Teumer, Alexander; Spector, Timothy D; Melén, Erik; Peters, Marjolein J; Lange, Leslie A; Barr, R Graham; Bracke, Ken R; Verhamme, Fien M; Sung, Joohon; Hiemstra, Pieter S; Cassano, Patricia A; Sood, Akshay; Hayward, Caroline; Dupuis, Josée; Hall, Ian P; Brusselle, Guy G; Tobin, Martin D; London, Stephanie J

    2014-07-01

    Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease. PMID:24929828

  2. Current approaches of genome-wide association studies

    Institute of Scientific and Technical Information of China (English)

    Jianfeng Xu

    2008-01-01

    @@ With rapid advances in high-throughput genotyping technology and the great increase in information available on SNPs throughout the genuine, genuine-wide association(GWA) studies have now become feasible.

  3. A Genome-Wide Association Study of Depressive Symptoms

    NARCIS (Netherlands)

    Hek, Karin; Demirkan, Ayse; Lahti, Jari; Terracciano, Antonio; Teumer, Alexander; Cornelis, Marilyn C.; Amin, Najaf; Bakshis, Erin; Baumert, Jens; Ding, Jingzhong; Liu, Yongmei; Marciante, Kristin; Meirelles, Osorio; Nalls, Michael A.; Sun, Yan V.; Vogelzangs, Nicole; Yu, Lei; Bandinelli, Stefania; Benjamin, Emelia J.; Bennett, David A.; Boomsma, Dorret; Cannas, Alessandra; Coker, Laura H.; de Geus, Eco; De Jager, Philip L.; Diez-Roux, Ana V.; Purcell, Shaun; Hu, Frank B.; Rimm, Eric B.; Hunter, David J.; Jensen, Majken K.; Curhan, Gary; Rice, Kenneth; Penman, Alan D.; Rotter, Jerome I.; Sotoodehnia, Nona; Emeny, Rebecca; Eriksson, Johan G.; Evans, Denis A.; Ferrucci, Luigi; Fornage, Myriam; Gudnason, Vilmundur; Hofman, Albert; Illig, Thomas; Kardia, Sharon; Kelly-Hayes, Margaret; Koenen, Karestan; Kraft, Peter; Kuningas, Maris; Massaro, Joseph M.; Melzer, David; Mulas, Antonella; Mulder, Cornelis L.; Murray, Anna; Oostra, Ben A.; Palotie, Aarno; Penninx, Brenda; Petersmann, Astrid; Pilling, Luke C.; Psaty, Bruce; Rawal, Rajesh; Reiman, Eric M.; Schulz, Andrea; Shulman, Joshua M.; Singleton, Andrew B.; Smith, Albert V.; Sutin, Angelina R.; Uitterlinden, Andre G.; Voelzke, Henry; Widen, Elisabeth; Yaffe, Kristine; Zonderman, Alan B.; Cucca, Francesco; Harris, Tamara; Ladwig, Karl-Heinz; Llewellyn, David J.; Raikkonen, Katri; Tanaka, Toshiko; van Duijn, Cornelia M.; Grabe, Hans J.; Launer, Lenore J.; Lunetta, Kathryn L.; Mosley, Thomas H.; Newman, Anne B.; Tiemeier, Henning; Murabito, Joanne

    2013-01-01

    Background: Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. Methods: In t

  4. Enrichment of statistical power for genome-wide association studies

    OpenAIRE

    Li, Meng; Liu, Xiaolei; Bradbury, Peter; Yu, Jianming; Zhang, Yuan-Ming; Todhunter, Rory J.; Buckler, Edward S; Zhang, Zhiwu

    2014-01-01

    Background The inheritance of most human diseases and agriculturally important traits is controlled by many genes with small effects. Identifying these genes, while simultaneously controlling false positives, is challenging. Among available statistical methods, the mixed linear model (MLM) has been the most flexible and powerful for controlling population structure and individual unequal relatedness (kinship), the two common causes of spurious associations. The introduction of the compressed ...

  5. Automated quality control for genome wide association studies

    Science.gov (United States)

    Ellingson, Sally R.; Fardo, David W.

    2016-01-01

    This paper provides details on the necessary steps to assess and control data in genome wide association studies (GWAS) using genotype information on a large number of genetic markers for large number of individuals. Due to varied study designs and genotyping platforms between multiple sites/projects as well as potential genotyping errors, it is important to ensure high quality data. Scripts and directions are provided to facilitate others in this process.

  6. Genome-Wide Association Study Reveals Multiple Loci Associated with Primary Tooth Development during Infancy

    OpenAIRE

    Pillas, D.; Hoggart, C. J.; Evans, D. M.; O'Reilly, P. F.; Sipila, K.; Lahdesmaki, R.; Millwood, I. Y.; Kaakinen, M; Netuveli, G.; Blane, D; Charoen, P.; Sovio, U; Pouta, A.; Freimer, N; Hartikainen, A. L.

    2010-01-01

    Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,...

  7. Genetic Variants Associated with Increased Risk of Malignant Pleural Mesothelioma: A Genome-Wide Association Study

    OpenAIRE

    Matullo, Giuseppe; Guarrera, Simonetta; Betti, Marta; Fiorito, Giovanni; Ferrante, Daniela; Voglino, Floriana; Cadby, Gemma; Di Gaetano, Cornelia; De Rosa, Fabio; Russo, Alessia; Hirvonen, Ari; Casalone, Elisabetta; Tunesi, Sara; Padoan, Marina; Giordano, Mara

    2013-01-01

    Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5–17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complet...

  8. Epidemiological and genome-wide association study of gastritis or gastric ulcer in korean populations.

    Science.gov (United States)

    Oh, Sumin; Oh, Sejong

    2014-09-01

    Gastritis is a major disease that has the potential to grow as gastric cancer. Gastric cancer is a very common cancer, and it is related to a very high mortality rate in Korea. This disease is known to have various reasons, including infection with Helicobacter pylori, dietary habits, tobacco, and alcohol. The incidence rate of gastritis has reported to differ between age, population, and gender. However, unlike other factors, there has been no analysis based on gender. So, we examined the high risk factors of gastritis in each gender in the Korean population by focusing on sex. We performed an analysis of 120 clinical characteristics and genome-wide association studies (GWAS) using 349,184 single-nucleotide polymorphisms from the results of Anseong and Ansan cohort study in the Korea Association Resource (KARE) project. As the result, we could not prove a strong relation with these factors and gastritis or gastric ulcer in the GWAS. However, we confirmed several already-known risk factors and also found some differences of clinical characteristics in each gender using logistic regression. As a result of the logistic regression, a relation with hyperlipidemia, coronary artery disease, myocardial infarction, hyperlipidemia therapy, hypotensive or antihypotensive drug, diastolic blood pressure, and gastritis was seen in males; the results of this study suggest that vascular disease has a potential association with gastritis in males. PMID:25317112

  9. Genome wide association studies for body conformation traits in the Chinese Holstein cattle population

    DEFF Research Database (Denmark)

    Wu, Xiaoping; Fang, Ming; Liu, Lin;

    2013-01-01

    ,314 Chinese Holstein cattle and 52,166 SNPs. Totally, 59 genome-wide significant SNPs associated with 26 conformation traits were detected by genome-wide association analysis; five SNPs were within previously reported QTL regions (Animal Quantitative Trait Loci (QTL) database) and 11 were very close to the...... pairs of traits, and the genetic correlation between each pair of traits ranged from 0.35 to 0.86, suggesting that these SNPs may have a pleiotropic effect on each pair of traits.Conclusions: A total of 59 significant SNPs associated with 26 conformation traits were identified in the Chinese Holstein...

  10. A genome-wide association study identifies multiple loci for variation in human ear morphology

    OpenAIRE

    Adhikari, K.; Reales, G.; Smith, A. J.; Konka, E.; Palmen, J.; Quinto-Sanchez, M.; Acuña-Alonzo, V.; Jaramillo, C; Arias, W.; Fuentes, M; Pizarro, M.; Barquera Lozano, R.; Macín Pérez, G.; Gómez-Valdés, J.; Villamil-Ramírez, H.

    2015-01-01

    Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10(-8) to 3 × 10(-14)). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage devel...

  11. A genome-wide association study identifies multiple loci for variation in human ear morphology

    OpenAIRE

    Adhikari, Kaustubh; Reales, Guillermo; Smith, Andrew J. P.; Konka, Esra; Palmen, Jutta; Quinto-Sanchez, Mirsha; Acuña-Alonzo, Victor; Jaramillo, Claudia; Arias, William; Fuentes, Macarena; Pizarro, María; Barquera Lozano, Rodrigo; Macín Pérez, Gastón; Gómez-Valdés, Jorge; Villamil-Ramírez, Hugo

    2015-01-01

    Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10−8 to 3 × 10−14). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage developme...

  12. Genome-Wide Association Studies in Myocardial Infarction and Coronary Artery Disease

    Directory of Open Access Journals (Sweden)

    Luca A Lotta

    2010-08-01

    Full Text Available Myocardial infarction (MI and its major determinant, coronary artery disease (CAD, are complex diseases arising from the interaction between several genetic and environmental factors. Until recently, the genetic basis of these diseases was poorly understood. Genome-wide genetic association studies have afforded a comprehensive insight into the association between genetic variants and diseases. To date, seven genome-wide association studies have been conducted in CAD/MI,identifying thirteen genomic regions at which common genetic variants influence the predisposition to these diseases. This review article summarizes the progress achieved in the genetic basis of MI and CAD by means of genome-wide associationstudies and the potential clinical applications of these findings.

  13. Meta-analysis in genome-wide association datasets: strategies and application in Parkinson disease.

    Directory of Open Access Journals (Sweden)

    Evangelos Evangelou

    Full Text Available BACKGROUND: Genome-wide association studies hold substantial promise for identifying common genetic variants that regulate susceptibility to complex diseases. However, for the detection of small genetic effects, single studies may be underpowered. Power may be improved by combining genome-wide datasets with meta-analytic techniques. METHODOLOGY/PRINCIPAL FINDINGS: Both single and two-stage genome-wide data may be combined and there are several possible strategies. In the two-stage framework, we considered the options of (1 enhancement of replication data and (2 enhancement of first-stage data, and then, we also considered (3 joint meta-analyses including all first-stage and second-stage data. These strategies were examined empirically using data from two genome-wide association studies (three datasets on Parkinson disease. In the three strategies, we derived 12, 5, and 49 single nucleotide polymorphisms that show significant associations at conventional levels of statistical significance. None of these remained significant after conservative adjustment for the number of performed analyses in each strategy. However, some may warrant further consideration: 6 SNPs were identified with at least 2 of the 3 strategies and 3 SNPs [rs1000291 on chromosome 3, rs2241743 on chromosome 4 and rs3018626 on chromosome 11] were identified with all 3 strategies and had no or minimal between-dataset heterogeneity (I(2 = 0, 0 and 15%, respectively. Analyses were primarily limited by the suboptimal overlap of tested polymorphisms across different datasets (e.g., only 31,192 shared polymorphisms between the two tier 1 datasets. CONCLUSIONS/SIGNIFICANCE: Meta-analysis may be used to improve the power and examine the between-dataset heterogeneity of genome-wide association studies. Prospective designs may be most efficient, if they try to maximize the overlap of genotyping platforms and anticipate the combination of data across many genome-wide association studies.

  14. Genome-Wide Association Study Reveals Multiple Loci Influencing Normal Human Facial Morphology.

    Science.gov (United States)

    Shaffer, John R; Orlova, Ekaterina; Lee, Myoung Keun; Leslie, Elizabeth J; Raffensperger, Zachary D; Heike, Carrie L; Cunningham, Michael L; Hecht, Jacqueline T; Kau, Chung How; Nidey, Nichole L; Moreno, Lina M; Wehby, George L; Murray, Jeffrey C; Laurie, Cecelia A; Laurie, Cathy C; Cole, Joanne; Ferrara, Tracey; Santorico, Stephanie; Klein, Ophir; Mio, Washington; Feingold, Eleanor; Hallgrimsson, Benedikt; Spritz, Richard A; Marazita, Mary L; Weinberg, Seth M

    2016-08-01

    Numerous lines of evidence point to a genetic basis for facial morphology in humans, yet little is known about how specific genetic variants relate to the phenotypic expression of many common facial features. We conducted genome-wide association meta-analyses of 20 quantitative facial measurements derived from the 3D surface images of 3118 healthy individuals of European ancestry belonging to two US cohorts. Analyses were performed on just under one million genotyped SNPs (Illumina OmniExpress+Exome v1.2 array) imputed to the 1000 Genomes reference panel (Phase 3). We observed genome-wide significant associations (p mechanisms controlling normal and abnormal facial morphogenesis. PMID:27560520

  15. Genome-wide association studies in economics and entrepreneurship research: Promises and limitations

    NARCIS (Netherlands)

    Ph.D. Koellinger (Philipp); M.J.H.M. van der Loos (Matthijs); P.J.F. Groenen (Patrick); A.R. Thurik (Roy); F. Rivadeneira Ramirez (Fernando); F.J.A. van Rooij (Frank); A.G. Uitterlinden (André); A. Hofman (Albert)

    2010-01-01

    textabstractThe recently developed genome-wide association study (GWAS) design enables the identification of genes specifically associated with economic outcomes such as occupational and other choices. This is a promising new approach for economics research which we aim to apply to the choice for en

  16. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    NARCIS (Netherlands)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.; Duncan, Laramie; Parikshak, Neelroop N.; Newhouse, Stephen; Ripke, Stephan; Neale, Benjamin M.; Purcell, Shaun M.; Posthuma, Danielle; Nurnberger, John I.; Lee, S. Hong; Faraone, Stephen V.; Perlis, Roy H.; Mowry, Bryan J.; Thapar, Anita; Goddard, Michael E.; Witte, John S.; Absher, Devin; Agartz, Ingrid; Akil, Huda; Amin, Farooq; Andreassen, Ole A.; Anjorin, Adebayo; Anney, Richard; Anttila, Verneri; Arking, Dan E.; Asherson, Philip; Azevedo, Maria H.; Backlund, Lena; Badner, Judith A.; Bailey, Anthony J.; Banaschewski, Tobias; Barchas, Jack D.; Barnes, Michael R.; Barrett, Thomas B.; Bass, Nicholas; Battaglia, Agatino; Bauer, Michael; Bayes, Monica; Bellivier, Frank; Bergen, Sarah E.; Berrettini, Wade; Betancur, Catalina; Bettecken, Thomas; Biederman, Joseph; Binder, Elisabeth B.; Black, Donald W.; Blackwood, Douglas H. R.; Bloss, Cinnamon S.; Boehnke, Michael; Boomsma, Dorret I.; Breuer, Rene; Bruggeman, Richard; Cormican, Paul; Buccola, Nancy G.; Buitelaar, Jan K.; Bunney, William E.; Buxbaum, Joseph D.; Byerley, William F.; Byrne, Enda M.; Caesar, Sian; Cahn, Wiepke; Cantor, Rita M.; Casas, Miguel; Chakravarti, Aravinda; Chambert, Kimberly; Choudhury, Khalid; Cichon, Sven; Mattheisen, Manuel; Cloninger, C. Robert; Collier, David A.; Cook, Edwin H.; Coon, Hilary; Cormand, Bru; Corvin, Aiden; Coryell, William H.; Craig, David W.; Craig, Ian W.; Crosbie, Jennifer; Cuccaro, Michael L.; Curtis, David; Czamara, Darina; Datta, Susmita; Dawson, Geraldine; Day, Richard; De Geus, Eco J.; Degenhardt, Franziska; Djurovic, Srdjan; Donohoe, Gary J.; Doyle, Alysa E.; Duan, Jubao; Dudbridge, Frank; Duketis, Eftichia; Ebstein, Richard P.; Edenberg, Howard J.; Elia, Josephine; Ennis, Sean; Etain, Bruno; Fanous, Ayman; Farmer, Anne E.; Ferrier, I. Nicol; Flicldnger, Matthew; Fombonne, Eric; Foroud, Tatiana; Frank, Josef; Franke, Barbara; Fraser, Christine; Freedman, Robert; Freimer, Nelson B.; Freitag, Christine M.; Friedl, Marion; Frisen, Louise; Gailagher, Louise; Gejman, Pablo V.; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Gill, Michael; Gordon, Scott D.; Gordon-Smith, Katherine; Green, Elaine K.; Greenwood, Tiffany A.; Grice, Dorothy E.; Gross, Magdalena; Grozeva, Detelina; Guan, Weihua; Gurling, Hugh; De Haan, Lieuwe; Haines, Jonathan L.; Hakonarson, Hakon; Hallmayer, Joachim; Hamilton, Steven P.; Hamshere, Marian L.; Hansen, Thomas F.; Hartmann, Annette M.; Hautzinger, Martin; Heath, Andrew C.; Henders, Anjali K.; Herms, Stefan; Hickie, Ian B.; Hipolito, Maria; Hoefels, Susanne; Holsboer, Florian; Hoogendijk, Witte J.; Hottenga, Jouke-Jan; Hultman, Christina M.; Hus, Vanessa; Ingason, Andres; Ising, Marcus; Jamain, Stephane; Jones, Edward G.; Jones, Ian; Jones, Lisa; Tzeng, Jung-Ying; Kaehler, Anna K.; Kahn, Rene S.; Kandaswamy, Radhika; Keller, Matthew C.; Kennedy, James L.; Kenny, Elaine; Kent, Lindsey; Kim, Yunjung; Kirov, George K.; Klauck, Sabine M.; Klei, Lambertus; Knowles, James A.; Kohli, Martin A.; Koller, Daniel L.; Konte, Bettina; Korszun, Ania; Krabbendam, Lydia; Krasucki, Robert; Kuntsi, Jonna; Kwan, Phoenix; Landen, Mikael; Laengstroem, Niklas; Lathrop, Mark; Lawrence, Jacob; Lawson, William B.; Leboyer, Marion; Ledbetter, David H.; Lencz, Todd; Lesch, Klaus-Peter; Levinson, Douglas F.; Lewis, Cathryn M.; Li, Jun; Lichtenstein, Paul; Lieberman, Jeffrey A.; Lin, Dan-Yu; Linszen, Don H.; Liu, Chunyu; Lohoff, Falk W.; Loo, Sandra K.; Lord, Catherine; Lowe, Jennifer K.; Lucae, Susanne; MacIntyre, Donald J.; Madden, Pamela A. F.; Maestrini, Elena; Magnusson, Patrik K. E.; Mahon, Pamela B.; Maier, Wolfgang; Malhotra, Anil K.; Mane, Shrikant M.; Martin, Christa L.; Martin, Nicholas G.; Matthews, Keith; Mattingsdal, Morten; McCarroll, Steven A.; McGhee, Kevin A.; McGough, James J.; McGrath, Patrick J.; McGuffin, Peter; McInnis, Melvin G.; McIntosh, Andrew; McKinney, Rebecca; McLean, Alan W.; McMahon, Francis J.; McMahon, William M.; McQuillin, Andrew; Medeiros, Helena; Medland, Sarah E.; Meier, Sandra; Melle, Ingrid; Meng, Fan; Meyer, Jobst; Middeldorp, Christel M.; Middleton, Lefkos; Milanova, Vihra; Miranda, Ana; Monaco, Anthony P.; Montgomery, Grant W.; Moran, Jennifer L.; Moreno-De-Luca, Daniel; Morken, Gunnar; Morris, Derek W.; Morrow, Eric M.; Moskvina, Valentina; Muglia, Pierandrea; Muehleisen, Thomas W.; Muir, Walter J.; Mueller-Myhsok, Bertram; Murtha, Michael; Myers, Richard M.; Myin-Germeys, Inez; Neale, Michael C.; Nelson, Stan F.; Nievergelt, Caroline M.; Nikolov, Ivan; Nimgaonkar, Vishwajit; Nolen, Willem A.; Noethen, Markus M.; Nwulia, Evaristus A.; Nyholt, Dale R.; Oades, Robert D.; Olincy, Ann; Oliveira, Guiomar; Olsen, Line; Ophoff, Roel A.; Osby, Urban; Owen, Michael J.; Palotie, Aarno; Parr, Jeremy R.; Paterson, Andrew D.; Pato, Carlos N.; Pato, Michele T.; Penninx, Brenda W.; Pergadia, Michele L.; Pericak-Vance, Margaret A.; Pickard, Benjamin S.; Pimm, Jonathan; Piven, Joseph; Potash, James B.; Poustka, Fritz; Propping, Peter; Puri, Vinay; Quested, Digby J.; Quinn, Emma M.; Ramos-Quiroga, Josep Antoni; Rasmussen, Henrik B.; Raychaudhuri, Soumya; Rehnstroem, Karola; Reif, Andreas; Ribases, Marta; Rice, John P.; Rietschel, Marcella; Roeder, Kathryn; Roeyers, Herbert; Rothenberger, Aribert; Rouleau, Guy; Ruderfer, Douglas; Rujescu, Dan; Sanders, Alan R.; Sanders, Stephan J.; Santangelo, Susan L.; Sergeant, Joseph A.; Schachar, Russell; Schalling, Martin; Schatzberg, Alan F.; Scheftner, William A.; Schellenberg, Gerard D.; Scherer, Stephen W.; Schork, Nicholas J.; Schulze, Thomas G.; Schumacher, Johannes; Schwarz, Markus; Scolnick, Edward; Scott, Laura J.; Shi, Jianxin; Shilling, Paul D.; Shyn, Stanley I.; Silverman, Jeremy M.; Slager, Susan L.; Smalley, Susan L.; Smit, Johannes H.; Smith, Erin N.; Sonuga-Barke, Edmund J. S.; Cair, David St.; State, Matthew; Steffens, Michael; Steinhausen, Hans-Christoph; Strauss, John S.; Strohmaier, Jana; Stroup, T. Scott; Sutdiffe, James S.; Szatmari, Peter; Szelinger, Szabocls; Thirumalai, Srinivasa; Thompson, Robert C.; Todorov, Alexandre A.; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; Van den Oord, Edwin J. C. G.; Van Grootheest, Gerard; Van Os, Jim; Vicente, Astrid M.; Vieland, Veronica J.; Vincent, John B.; Visscher, Peter M.; Walsh, Christopher A.; Wassink, Thomas H.; Watson, Stanley J.; Weissman, Myrna M.; Werge, Thomas; Wienker, Thomas F.; Wijsman, Ellen M.; Willemsen, Gonneke; Williams, Nigel; Willsey, A. Jeremy; Witt, Stephanie H.; Xu, Wei; Young, Allan H.; Yu, Timothy W.; Zammit, Stanley; Zandi, Peter P.; Zhang, Peng; Zitman, Frans G.; Zoellner, Sebastian; Devlin, Bernie; Kelsoe, John R.; Sklar, Pamela; Daly, Mark J.; O'Donovan, Michael C.; Craddock, Nicholas; Kendler, Kenneth S.; Weiss, Lauren A.; Wray, Naomi R.; Zhao, Zhaoming; Geschwind, Daniel H.; Sullivan, Patrick F.; Smoller, Jordan W.; Holmans, Peter A.; Breen, Gerome

    2015-01-01

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from ove

  17. 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...

  18. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

    DEFF Research Database (Denmark)

    O'Dushlaine, Colm; Rossin, Lizzy; Lee, Phil H.;

    2015-01-01

    Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from ...

  19. Software engineering the mixed model for genome-wide association studies on large samples

    Science.gov (United States)

    Mixed models improve the ability to detect phenotype-genotype associations in the presence of population stratification and multiple levels of relatedness in genome-wide association studies (GWAS), but for large data sets the resource consumption becomes impractical. At the same time, the sample siz...

  20. A genome-wide association search for type 2 diabetes genes in African Americans

    DEFF Research Database (Denmark)

    Palmer, Nicholette D; McDonough, Caitrin W; Hicks, Pamela J;

    2012-01-01

    African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wid...

  1. Genome-Wide Association Study of Intelligence: Additive Effects of Novel Brain Expressed Genes

    Science.gov (United States)

    Loo, Sandra K.; Shtir, Corina; Doyle, Alysa E.; Mick, Eric; McGough, James J.; McCracken, James; Biederman, Joseph; Smalley, Susan L.; Cantor, Rita M.; Faraone, Stephen V.; Nelson, Stanley F.

    2012-01-01

    Objective: The purpose of the present study was to identify common genetic variants that are associated with human intelligence or general cognitive ability. Method: We performed a genome-wide association analysis with a dense set of 1 million single-nucleotide polymorphisms (SNPs) and quantitative intelligence scores within an ancestrally…

  2. Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci

    DEFF Research Database (Denmark)

    Børglum, A D; Demontis, D; Grove, J;

    2014-01-01

    Genetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all individuals...... born in Denmark since 1981 and diagnosed with schizophrenia as well as controls from the same birth cohort. Furthermore, we present the first genome-wide interaction survey of single nucleotide polymorphisms (SNPs) and maternal cytomegalovirus (CMV) infection. The GWA analysis included 888 cases and...... region-based analysis summarizing independent signals in segments of 100 kb identified a new region-based genome-wide significant locus overlapping the gene ZEB1 (P=7.0 × 10(-7)). This signal was replicated in the follow-up analysis (P=2.3 × 10(-2)). Significant interaction with maternal CMV infection...

  3. Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

    Science.gov (United States)

    Gottlieb, D J; Hek, K; Chen, T-H; Watson, N F; Eiriksdottir, G; Byrne, E M; Cornelis, M; Warby, S C; Bandinelli, S; Cherkas, L; Evans, D S; Grabe, H J; Lahti, J; Li, M; Lehtimäki, T; Lumley, T; Marciante, K D; Pérusse, L; Psaty, B M; Robbins, J; Tranah, G J; Vink, J M; Wilk, J B; Stafford, J M; Bellis, C; Biffar, R; Bouchard, C; Cade, B; Curhan, G C; Eriksson, J G; Ewert, R; Ferrucci, L; Fülöp, T; Gehrman, P R; Goodloe, R; Harris, T B; Heath, A C; Hernandez, D; Hofman, A; Hottenga, J-J; Hunter, D J; Jensen, M K; Johnson, A D; Kähönen, M; Kao, L; Kraft, P; Larkin, E K; Lauderdale, D S; Luik, A I; Medici, M; Montgomery, G W; Palotie, A; Patel, S R; Pistis, G; Porcu, E; Quaye, L; Raitakari, O; Redline, S; Rimm, E B; Rotter, J I; Smith, A V; Spector, T D; Teumer, A; Uitterlinden, A G; Vohl, M-C; Widen, E; Willemsen, G; Young, T; Zhang, X; Liu, Y; Blangero, J; Boomsma, D I; Gudnason, V; Hu, F; Mangino, M; Martin, N G; O'Connor, G T; Stone, K L; Tanaka, T; Viikari, J; Gharib, S A; Punjabi, N M; Räikkönen, K; Völzke, H; Mignot, E; Tiemeier, H

    2015-10-01

    Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease. PMID:25469926

  4. Genome-Wide Association Mapping in Arabidopsis Identifies Previously Known Flowering Time and Pathogen Resistance Genes.

    Directory of Open Access Journals (Sweden)

    2005-11-01

    Full Text Available There is currently tremendous interest in the possibility of using genome-wide association mapping to identify genes responsible for natural variation, particularly for human disease susceptibility. The model plant Arabidopsis thaliana is in many ways an ideal candidate for such studies, because it is a highly selfing hermaphrodite. As a result, the species largely exists as a collection of naturally occurring inbred lines, or accessions, which can be genotyped once and phenotyped repeatedly. Furthermore, linkage disequilibrium in such a species will be much more extensive than in a comparable outcrossing species. We tested the feasibility of genome-wide association mapping in A. thaliana by searching for associations with flowering time and pathogen resistance in a sample of 95 accessions for which genome-wide polymorphism data were available. In spite of an extremely high rate of false positives due to population structure, we were able to identify known major genes for all phenotypes tested, thus demonstrating the potential of genome-wide association mapping in A. thaliana and other species with similar patterns of variation. The rate of false positives differed strongly between traits, with more clinal traits showing the highest rate. However, the false positive rates were always substantial regardless of the trait, highlighting the necessity of an appropriate genomic control in association studies.

  5. Genome-wide association mapping in Arabidopsis identifies previously known flowering time and pathogen resistance genes.

    Directory of Open Access Journals (Sweden)

    María José Aranzana

    2005-11-01

    Full Text Available There is currently tremendous interest in the possibility of using genome-wide association mapping to identify genes responsible for natural variation, particularly for human disease susceptibility. The model plant Arabidopsis thaliana is in many ways an ideal candidate for such studies, because it is a highly selfing hermaphrodite. As a result, the species largely exists as a collection of naturally occurring inbred lines, or accessions, which can be genotyped once and phenotyped repeatedly. Furthermore, linkage disequilibrium in such a species will be much more extensive than in a comparable outcrossing species. We tested the feasibility of genome-wide association mapping in A. thaliana by searching for associations with flowering time and pathogen resistance in a sample of 95 accessions for which genome-wide polymorphism data were available. In spite of an extremely high rate of false positives due to population structure, we were able to identify known major genes for all phenotypes tested, thus demonstrating the potential of genome-wide association mapping in A. thaliana and other species with similar patterns of variation. The rate of false positives differed strongly between traits, with more clinal traits showing the highest rate. However, the false positive rates were always substantial regardless of the trait, highlighting the necessity of an appropriate genomic control in association studies.

  6. Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci

    NARCIS (Netherlands)

    E. Melum; A. Franke; C. Schramm; T.J. Weismüller; D.N. Gotthardt; F.A. Offner; B.D. Juran; J.K. Laerdahl; V. Labi; E. Björnsson; R.K. Weersma; L. Henckaerts; A. Teufel; C. Rust; E. Ellinghaus; T. Balschun; K.M. Boberg; D. Ellinghaus; A. Bergquist; P. Sauer; E. Ryu; J.R. Hov; J. Wedemeyer; B. Lindkvist; M. Wittig; R.J. Porte; K. Holm; C. Gieger; H.E. Wichmann; P. Stokkers; C.Y. Ponsioen; H. Runz; A. Stiehl; C. Wijmenga; M. Sterneck; S. Vermeire; U. Beuers; A. Villunger; E. Schrumpf; K.N. Lazaridis; M.P. Manns; S. Schreiber; T.H. Karlsen

    2011-01-01

    Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,17

  7. Genome-wide association study for claw disorders and trimming status in dairy cattle

    NARCIS (Netherlands)

    Spek, van der D.; Arendonk, van J.A.M.; Bovenhuis, H.

    2015-01-01

    Performing a genome-wide association study (GWAS) might add to a better understanding of the development of claw disorders and the need for trimming. Therefore, the aim of the current study was to perform a GWAS on claw disorders and trimming status and to validate the results for claw disorders bas

  8. A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study

    Science.gov (United States)

    Abstract Background: Blood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes. Metho...

  9. Genome-wide study of association and interaction with maternal cytomegalovirus infection suggests new schizophrenia loci

    NARCIS (Netherlands)

    A.D. Børglum; D. Demontis; J. Grove (Jakob); J. Pallesen (J.); M.V. Hollegaard (Mads V); C.B. Pedersen (C.); A. Hedemand (A.); M. Mattheisen (Manuel); A.G. Uitterlinden (André); M. Nyegaard (M.); T.F. Orntoft (Torben); C. Wiuf (Carsten); M. Didriksen (Michael); M. Nordentoft (M.); M.M. Nö then (M.); M. Rietschel (M.); R.A. Ophoff (Roel); S. Cichon (Sven); R.H. Yolken (Robert); D.M. Hougaard (David); P.B. Mortensen; O. Mors

    2014-01-01

    textabstractGenetic and environmental components as well as their interaction contribute to the risk of schizophrenia, making it highly relevant to include environmental factors in genetic studies of schizophrenia. This study comprises genome-wide association (GWA) and follow-up analyses of all indi

  10. Genome-wide association study of swine farrowing traits. Part II: Bayesian analysis of marker data

    Science.gov (United States)

    Reproductive efficiency has a great impact on the economic success of pork production. Number born alive (NBA) and average piglet birth weight (ABW) contribute greatly to reproductive efficiency. To better understand the underlying genetics of birth traits, a genome wide association study (GWAS) w...

  11. The Minnesota Center for Twin and Family Research Genome-Wide Association Study

    DEFF Research Database (Denmark)

    Miller, M. B.; Basu, S.; Cunningham, J.; Eskin, E.; Malone, S. M.; Oetting, W. S.; Schork, N.; Sul, J. H.; Iacono, W. G.; McGue, M.

    2012-01-01

    As part of the Genes, Environment and Development Initiative, the Minnesota Center for Twin and Family Research (MCTFR) undertook a genome-wide association study, which we describe here. A total of 8,405 research participants, clustered in four-member families, have been successfully genotyped on...

  12. Genome-wide association scan meta-analysis identifies three loci influencing adiposity and fat distribution

    NARCIS (Netherlands)

    C.M. Lindgren (Cecilia); I.M. Heid (Iris); J.C. Randall (Joshua); C. Lamina (Claudia); V. Steinthorsdottir (Valgerdur); L. Qi (Lu); E.K. Speliotes (Elizabeth); G. Thorleifsson (Gudmar); C.J. Willer (Cristen); B.M. Herrera (Blanca); A.U. Jackson (Anne); N. Lim (Noha); P. Scheet (Paul); N. Soranzo (Nicole); N. Amin (Najaf); Y.S. Aulchenko (Yurii); J.C. Chambers (John); A. Drong (Alexander); J. Luan; H.N. Lyon (Helen); F. Rivadeneira Ramirez (Fernando); S. Sanna (Serena); N. Timpson (Nicholas); M.C. Zillikens (Carola); H.Z. Jing; P. Almgren (Peter); S. Bandinelli (Stefania); A.J. Bennett (Amanda); R.N. Bergman (Richard); L.L. Bonnycastle (Lori); S. Bumpstead (Suzannah); S.J. Chanock (Stephen); L. Cherkas (Lynn); P.S. Chines (Peter); L. Coin (Lachlan); C. Cooper (Charles); G. Crawford (Gabe); A. Doering (Angela); A. Dominiczak (Anna); A.S.F. Doney (Alex); S. Ebrahim (Shanil); P. Elliott (Paul); M.R. Erdos (Michael); K. Estrada Gil (Karol); L. Ferrucci (Luigi); G. Fischer (Guido); N.G. Forouhi (Nita); C. Gieger (Christian); H. Grallert (Harald); C.J. Groves (Christopher); S.M. Grundy (Scott); C. Guiducci (Candace); D. Hadley (David); A. Hamsten (Anders); A.S. Havulinna (Aki); A. Hofman (Albert); R. Holle (Rolf); J.W. Holloway (John); T. Illig (Thomas); B. Isomaa (Bo); L.C. Jacobs (Leonie); K. Jameson (Karen); P. Jousilahti (Pekka); F. Karpe (Fredrik); J. Kuusisto (Johanna); J. Laitinen (Jaana); G.M. Lathrop (Mark); D.A. Lawlor (Debbie); M. Mangino (Massimo); W.L. McArdle (Wendy); T. Meitinger (Thomas); M.A. Morken (Mario); A.P. Morris (Andrew); P. Munroe (Patricia); N. Narisu (Narisu); A. Nordström (Anna); B.A. Oostra (Ben); C.N.A. Palmer (Colin); F. Payne (Felicity); J. Peden (John); I. Prokopenko (Inga); F. Renström (Frida); A. Ruokonen (Aimo); V. Salomaa (Veikko); M.S. Sandhu (Manjinder); L.J. Scott (Laura); A. Scuteri (Angelo); K. Silander (Kaisa); K. Song (Kijoung); X. Yuan (Xin); H.M. Stringham (Heather); A.J. Swift (Amy); T. Tuomi (Tiinamaija); M. Uda (Manuela); P. Vollenweider (Peter); G. Waeber (Gérard); C. Wallace (Chris); G.B. Walters (Bragi); M.N. Weedon (Michael); J.C.M. Witteman (Jacqueline); C. Zhang (Cuilin); M. Caulfield (Mark); F.S. Collins (Francis); G.D. Smith; I.N.M. Day (Ian); P.W. Franks (Paul); A.T. Hattersley (Andrew); F.B. Hu (Frank); M.R. Jarvelin; A. Kong (Augustine); J.S. Kooner (Jaspal); M. Laakso (Markku); E. Lakatta (Edward); V. Mooser (Vincent); L. Peltonen (Leena Johanna); N.J. Samani (Nilesh); T.D. Spector (Timothy); D.P. Strachan (David); T. Tanaka (Toshiko); J. Tuomilehto (Jaakko); A.G. Uitterlinden (André); P. Tikka-Kleemola (Päivi); N.J. Wareham (Nick); H. Watkins (Hugh); D. Waterworth (Dawn); M. Boehnke (Michael); P. Deloukas (Panagiotis); L. Groop (Leif); D.J. Hunter (David); U. Thorsteinsdottir (Unnur); D. Schlessinger (David); H.E. Wichmann (Erich); T.M. Frayling (Timothy); G.R. Abecasis (Gonçalo); J.N. Hirschhorn (Joel); R.J.F. Loos (Ruth); J-A. Zwart (John-Anker); K.L. Mohlke (Karen); I. Barroso (Inês); M.I. McCarthy (Mark)

    2009-01-01

    textabstractTo identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evid

  13. Genome-Wide Association Study of Receptive Language Ability of 12-Year-Olds

    Science.gov (United States)

    Harlaar, Nicole; Meaburn, Emma L.; Hayiou-Thomas, Marianna E.; Davis, Oliver S. P.; Docherty, Sophia; Hanscombe, Ken B.; Haworth, Claire M. A.; Price, Thomas S.; Trzaskowski, Maciej; Dale, Philip S.; Plomin, Robert

    2014-01-01

    Purpose: Researchers have previously shown that individual differences in measures of receptive language ability at age 12 are highly heritable. In the current study, the authors attempted to identify some of the genes responsible for the heritability of receptive language ability using a "genome-wide association" approach. Method: The…

  14. Genome-wide association study of biochemical traits in Korcula Island, Croatia

    OpenAIRE

    Zemunik, Tatijana; Boban, Mladen; Lauc, Gordan; Janković, Stipan; Rotim, Kresimir; Vatavuk, Zoran; Bencić, Goran; Dogas, Zoran; Boraska, Vesna; Torlak, Vesela; Susac, Jelena; Zobić, Ivana; Rudan, Diana; Pulanić, Drazen; Modun, Darko

    2009-01-01

    To identify genetic variants underlying biochemical traits--total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, uric acid, albumin, and fibrinogen, in a genome-wide association study in an isolated population where rare variants of larger effect may be more easily identified.

  15. Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations

    DEFF Research Database (Denmark)

    Demirkan, Ayşe; van Duijn, Cornelia M; Ugocsai, Peter; Isaacs, Aaron; Pramstaller, Peter P; Liebisch, Gerhard; Wilson, James F; Johansson, Åsa; Rudan, Igor; Aulchenko, Yurii S; Kirichenko, Anatoly V; Janssens, A Cecile J W; Jansen, Ritsert C; Gnewuch, Carsten; Domingues, Francisco S; Pattaro, Cristian; Wild, Sarah H; Jonasson, Inger; Polasek, Ozren; Zorkoltseva, Irina V; Hofman, Albert; Karssen, Lennart C; Struchalin, Maksim; Floyd, James; Igl, Wilmar; Biloglav, Zrinka; Broer, Linda; Pfeufer, Arne; Pichler, Irene; Campbell, Susan; Zaboli, Ghazal; Kolcic, Ivana; Rivadeneira, Fernando; Huffman, Jennifer; Hastie, Nicholas D; Uitterlinden, Andre; Franke, Lude; Franklin, Christopher S; Vitart, Veronique; Nelson, Christopher P; Preuss, Michael; Bis, Joshua C; O'Donnell, Christopher J; Franceschini, Nora; Witteman, Jacqueline C M; Axenovich, Tatiana; Oostra, Ben A; Meitinger, Thomas; Hicks, Andrew A; Hayward, Caroline; Wright, Alan F; Gyllensten, Ulf; Campbell, Harry; Schmitz, Gerd; Jørgensen, Torben

    2012-01-01

    Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric......, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57...

  16. Genome-wide association study identifies 74 loci associated with educational attainment.

    Science.gov (United States)

    Okbay, Aysu; Beauchamp, Jonathan P; Fontana, Mark Alan; Lee, James J; Pers, Tune H; Rietveld, Cornelius A; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S Fleur W; Oskarsson, Sven; Pickrell, Joseph K; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H; Pina Concas, Maria; Derringer, Jaime; Furlotte, Nicholas A; Galesloot, Tessel E; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M; Harris, Sarah E; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E; Kaasik, Kadri; Kalafati, Ioanna P; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J; deLeeuw, Christiaan; Lind, Penelope A; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B; van der Most, Peter J; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E; Shi, Jianxin; Smith, Albert V; Poot, Raymond A; St Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A; Campbell, Harry; Cappuccio, Francesco P; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans, David M; Faul, Jessica D; Feitosa, Mary F; Forstner, Andreas J; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V; Harris, Tamara B; Heath, Andrew C; Hocking, Lynne J; Holliday, Elizabeth G; Homuth, Georg; Horan, Michael A; Hottenga, Jouke-Jan; de Jager, Philip L; Joshi, Peter K; Jugessur, Astanand; Kaakinen, Marika A; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A L M; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J; Lebreton, Maël P; Levinson, Douglas F; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C M; Loukola, Anu; Madden, Pamela A; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E; Marques-Vidal, Pedro; Meddens, Gerardus A; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W; Myhre, Ronny; Nelson, Christopher P; Nyholt, Dale R; Ollier, William E R; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L; Petrovic, Katja E; Porteous, David J; Räikkönen, Katri; Ring, Susan M; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J; Smith, Blair H; Smith, Jennifer A; Staessen, Jan A; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J A; Venturini, Cristina; Vinkhuyzen, Anna A E; Völker, Uwe; Völzke, Henry; Vonk, Judith M; Vozzi, Diego; Waage, Johannes; Ware, Erin B; Willemsen, Gonneke; Attia, John R; Bennett, David A; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I; Borecki, Ingrid B; Bültmann, Ute; Chabris, Christopher F; Cucca, Francesco; Cusi, Daniele; Deary, Ian J; Dedoussis, George V; van Duijn, Cornelia M; Eriksson, Johan G; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J F; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L R; Lehtimäki, Terho; Lehrer, Steven F; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W J H; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A; Samani, Nilesh J; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I A; Spector, Tim D; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A Roy; Timpson, Nicholas J; Tiemeier, Henning; Tung, Joyce Y; Uitterlinden, André G; Vitart, Veronique; Vollenweider, Peter; Weir, David R; Wilson, James F; Wright, Alan F; Conley, Dalton C; Krueger, Robert F; Davey Smith, George; Hofman, Albert; Laibson, David I; Medland, Sarah E; Meyer, Michelle N; Yang, Jian; Johannesson, Magnus; Visscher, Peter M; Esko, Tõnu; Koellinger, Philipp D; Cesarini, David; Benjamin, Daniel J

    2016-05-26

    Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases. PMID:27225129

  17. A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

    DEFF Research Database (Denmark)

    Evangelou, Evangelos; Kerkhof, Hanneke J; Styrkarsdottir, Unnur;

    2014-01-01

    Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects....

  18. Annotation of loci from genome-wide association studies using tissue-specific quantitative interaction proteomics

    DEFF Research Database (Denmark)

    Lundby, Alicia; Rossin, Elizabeth J.; Steffensen, Annette B.;

    2014-01-01

    Genome-wide association studies (GWAS) have identified thousands of loci associated with complex traits, but it is challenging to pinpoint causal genes in these loci and to exploit subtle association signals. We used tissue-specific quantitative interaction proteomics to map a network of five genes...... propose candidates in GWAS loci for functional studies and to systematically filter subtle association signals using tissue-specific quantitative interaction proteomics....

  19. Imputation Aware Meta-Analysis of Genome-Wide Association Studies

    OpenAIRE

    Zaitlen, Noah; Eskin, Eleazar

    2010-01-01

    Genome-wide association studies have recently identified many new loci associated with human complex diseases. These newly discovered variants typically have weak effects requiring studies with large numbers of individuals to achieve the statistical power necessary to identify them. Likely, there exist even more associated variants, which remain to be found if even larger association studies can be assembled. Meta-analysis provides a straightforward means of increasing study sample sizes with...

  20. Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures.

    Science.gov (United States)

    Wang, Xinchen; Tucker, Nathan R; Rizki, Gizem; Mills, Robert; Krijger, Peter Hl; de Wit, Elzo; Subramanian, Vidya; Bartell, Eric; Nguyen, Xinh-Xinh; Ye, Jiangchuan; Leyton-Mange, Jordan; Dolmatova, Elena V; van der Harst, Pim; de Laat, Wouter; Ellinor, Patrick T; Newton-Cheh, Christopher; Milan, David J; Kellis, Manolis; Boyer, Laurie A

    2016-01-01

    Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits. PMID:27162171

  1. Genome wide association study identifies KCNMA1 contributing to human obesity

    DEFF Research Database (Denmark)

    Jiao, Hong; Arner, Peter; Hoffstedt, Johan;

    2011-01-01

    Recent genome-wide association (GWA) analyses have identified common single nucleotide polymorphisms (SNPs) that are associated with obesity. However, the reported genetic variation in obesity explains only a minor fraction of the total genetic variation expected to be present in the population....... Thus many genetic variants controlling obesity remain to be identified. The aim of this study was to use GWA followed by multiple stepwise validations to identify additional genes associated with obesity....

  2. Joint Analysis of Functional Genomic Data and Genome-wide Association Studies of 18 Human Traits

    OpenAIRE

    Pickrell, Joseph K.

    2014-01-01

    Annotations of gene structures and regulatory elements can inform genome-wide association studies (GWASs). However, choosing the relevant annotations for interpreting an association study of a given trait remains challenging. I describe a statistical model that uses association statistics computed across the genome to identify classes of genomic elements that are enriched with or depleted of loci influencing a trait. The model naturally incorporates multiple types of annotations. I applied th...

  3. Is Replication the Gold Standard for Validating Genome-Wide Association Findings?

    OpenAIRE

    Liu, Yong-Jun; Papasian, Christopher J.; Liu, Jian-Feng; Hamilton, James; Deng, Hong-Wen

    2008-01-01

    With the advent of genome-wide association (GWA) studies, researchers are hoping that reliable genetic association of common human complex diseases/traits can be detected. Currently, there is an increasing enthusiasm about GWA and a number of GWA studies have been published. In the field a common practice is that replication should be used as the gold standard to validate an association finding. In this article, based on empirical and theoretical data, we emphasize that replication of GWA fin...

  4. Incorporating group correlations in genome-wide association studies using smoothed group Lasso

    OpenAIRE

    Liu, Jin; Huang, Jian; Ma, Shuangge; Wang, Kai

    2012-01-01

    In genome-wide association studies, penalization is an important approach for identifying genetic markers associated with disease. Motivated by the fact that there exists natural grouping structure in single nucleotide polymorphisms and, more importantly, such groups are correlated, we propose a new penalization method for group variable selection which can properly accommodate the correlation between adjacent groups. This method is based on a combination of the group Lasso penalty and a quad...

  5. A Genome-Wide Association Study of Neuroticism in a Population-Based Sample

    OpenAIRE

    Calboli, F. C. F.; Tozzi, F.; Galwey, N. W.; Antoniades, A.; Mooser, V.; Preisig, M.; Vollenweider, P; Waterworth, D.; Waeber, G.; Johnson, M. R.; Muglia, P; Balding, D. J.

    2010-01-01

    Neuroticism is a moderately heritable personality trait considered to be a risk factor for developing major depression, anxiety disorders and dementia. We performed a genome-wide association study in 2,235 participants drawn from a population-based study of neuroticism, making this the largest association study for neuroticism to date. Neuroticism was measured by the Eysenck Personality Questionnaire. After Quality Control, we analysed 430,000 autosomal SNPs together with an additional 1.2 mi...

  6. Multiple SNP-sets Analysis for Genome-wide Association Studies through Bayesian Latent Variable Selection

    OpenAIRE

    Lu, Zhaohua; Zhu, Hongtu; Knickmeyer, Rebecca C.; Sullivan, Patrick F.; Stephanie, Williams N.; Zou, Fei

    2015-01-01

    The power of genome-wide association studies (GWAS) for mapping complex traits with single SNP analysis may be undermined by modest SNP effect sizes, unobserved causal SNPs, correlation among adjacent SNPs, and SNP-SNP interactions. Alternative approaches for testing the association between a single SNP-set and individual phenotypes have been shown to be promising for improving the power of GWAS. We propose a Bayesian latent variable selection (BLVS) method to simultaneously model the joint a...

  7. A genome-wide association study of body mass index across early life and childhood

    OpenAIRE

    Nicole M Warrington; Howe, Laura D; Paternoster, Lavinia; Kaakinen, Marika; Herrala, Sauli; Huikari, Ville; Wu, Yan Yan; Kemp, John P.; Timpson, Nicholas J.; Pourcain, Beate St; Davey Smith, George; Tilling, Kate; Jarvelin, Marjo-Riitta; Pennell, Craig E.; Evans, David M.

    2015-01-01

    Background: Several studies have investigated the effect of known adult body mass index (BMI) associated single nucleotide polymorphisms (SNPs) on BMI in childhood. There has been no genome-wide association study (GWAS) of BMI trajectories over childhood. Methods: We conducted a GWAS meta-analysis of BMI trajectories from 1 to 17 years of age in 9377 children (77 967 measurements) from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Western Australian Pregnancy Cohort (Ra...

  8. A genome-wide association study of body mass index across early life and childhood

    OpenAIRE

    Warrington, N.; Howe, L; Paternoster, L.; Kaakinen, M.; Herrala, S. (Sauli); Huikari, V.; Wu, Y.; Kemp, J.; Timpson, N.; St Pourcain, B.; Smith, G.; Tilling, K; Jarvelin, M; Pennell, C; Evans, D

    2015-01-01

    Background: Several studies have investigated the effect of known adult body mass index (BMI) associated single nucleotide polymorphisms (SNPs) on BMI in childhood. There has been no genome-wide association study (GWAS) of BMI trajectories over childhood. Methods: We conducted a GWAS meta-analysis of BMI trajectories from 1 to 17 years of age in 9377 children (77 967 measurements) from the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Western Australian Pregnancy Cohort (Ra...

  9. Genome-wide association scan for five major dimensions of personality

    OpenAIRE

    Terracciano, Antonio; Sanna, Serena; Uda, Manuela; Deiana, Barbara; Usala, Gianluca; Busonero, Fabio; Maschio, Andrea; Scally, Matthew; Patriciu, Nicholas; Chen, Wei-Min; Distel, Marijn A.; Slagboom, Eline P.; Boomsma, Dorret I.; Villafuerte, Sandra; Śliwerska, Elżbieta

    2008-01-01

    Personality traits are summarized by five broad dimensions with pervasive influences on major life outcomes, strong links to psychiatric disorders, and clear heritable components. To identify genetic variants associated with each of the five dimensions of personality we performed a genome wide association (GWA) scan of 3,972 individuals from a genetically isolated population within Sardinia, Italy. Based on analyses of 362,129 single nucleotide polymorphisms (SNPs) we found several strong sig...

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

    OpenAIRE

    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

    2010-01-01

    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 < 10−800), we found associa...

  11. ParallABEL: An R library for generalized parallelization of genome-wide association studies

    OpenAIRE

    Sangket, Unitsa; Mahasirimongkol, Surakameth; Chantratita, Wasun; Tandayya, Pichaya; Aulchenko, Yurii

    2010-01-01

    textabstractBackground: Genome-Wide Association (GWA) analysis is a powerful method for identifying loci associated with complex traits and drug response. Parts of GWA analyses, especially those involving thousands of individuals and consuming hours to months, will benefit from parallel computation. It is arduous acquiring the necessary programming skills to correctly partition and distribute data, control and monitor tasks on clustered computers, and merge output files.Results: Most componen...

  12. ParallABEL: an R library for generalized parallelization of genome-wide association studies

    OpenAIRE

    Tandayya Pichaya; Chantratita Wasun; Mahasirimongkol Surakameth; Sangket Unitsa; Aulchenko Yurii S

    2010-01-01

    Abstract Background Genome-Wide Association (GWA) analysis is a powerful method for identifying loci associated with complex traits and drug response. Parts of GWA analyses, especially those involving thousands of individuals and consuming hours to months, will benefit from parallel computation. It is arduous acquiring the necessary programming skills to correctly partition and distribute data, control and monitor tasks on clustered computers, and merge output files. Results Most components o...

  13. Genome-Wide Association of Body Fat Distribution in African Ancestry Populations Suggests New Loci

    OpenAIRE

    Liu, Ching-Ti; Keri L Monda; Taylor, Kira C.; Lange, Leslie; Demerath, Ellen W; Palmas, Walter; Wojczynski, Mary K.; Jaclyn C Ellis; Mara Z Vitolins; Liu, Simin; Papanicolaou, George J.; Irvin, Marguerite R.; Xue, Luting; Griffin, Paula J.; Michael A Nalls

    2013-01-01

    Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in...

  14. Glutamate Networks Implicate Cognitive Impairments in Schizophrenia: Genome-Wide Association Studies of 52 Cognitive Phenotypes

    OpenAIRE

    Ohi, Kazutaka; Hashimoto, Ryota; Ikeda, Masashi; Yamamori, Hidenaga; Yasuda, Yuka; Fujimoto, Michiko; Umeda-Yano, Satomi; Fukunaga, Masaki; Fujino, Haruo; Watanabe, Yoshiyuki; Iwase, Masao; Kazui, Hiroaki; Iwata, Nakao; Weinberger, Daniel R.; Takeda, Masatoshi

    2014-01-01

    Cognitive impairments are a core feature in patients with schizophrenia. These deficits could serve as effective tools for understanding the genetic architecture of schizophrenia. This study investigated whether genetic variants associated with cognitive impairments aggregate in functional gene networks related to the pathogenesis of schizophrenia. Here, genome-wide association studies (GWAS) of a range of cognitive phenotypes relevant to schizophrenia were performed in 411 healthy subjects. ...

  15. Genome-wide association study of sleep duration in the Finnish population.

    Science.gov (United States)

    Ollila, Hanna M; Kettunen, Johannes; Pietiläinen, Olli; Aho, Vilma; Silander, Kaisa; Kronholm, Erkki; Perola, Markus; Lahti, Jari; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Eriksson, Johan G; Partonen, Timo; Kaprio, Jaakko; Salomaa, Veikko; Raitakari, Olli; Lehtimäki, Terho; Sallinen, Mikael; Härmä, Mikko; Porkka-Heiskanen, Tarja; Paunio, Tiina

    2014-12-01

    Sleep duration is genetically regulated, but the genetic variants are largely unknown. We aimed to identify such genes using a genome-wide association study (GWAS) combined with RNA expression at the population level, and with experimental verification. A GWAS was performed in a Finnish sample (n = 1941), and variants with suggestive association (P sleep physiology. However, additional studies are needed in order to understand the roles of KLF6 and PCDH7 in sleep regulation. PMID:25109461

  16. A genome-wide association scan in pig identifies novel regions associated with feed efficiency trait

    DEFF Research Database (Denmark)

    Sahana, Goutam; Kadlecová, Veronika; Hornshøj, Henrik;

    2013-01-01

    Feed conversion ratio (FCR) is an economically important trait in pigs and feed accounts for a significant proportion of the costs involved in pig production. In this study we used a high density SNP chip panel, Porcine SNP60 BeadChip, to identify association between FCR and SNP markers and to......,071 Duroc pigs had both FCR data and genotype data. The linkage disequilibrium (r2) between adjacent markers was 0.56. Two association mapping approaches were used: linear mixed model (LMM) based on single locus regression analysis and a Bayesian variable selection approach (BVS). A total of 79 significant...... (p < 0.0001) SNP associations on six chromosomes were identified by LMM analyses. Out of these, ten SNPs crossed the genome-wide significance threshold. These ten SNPs were all located on the chromosomes 4 and 14. In the BVS analysis, a total of 44 SNPs located on 12 chromosomes had posterior...

  17. Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs.

    Science.gov (United States)

    Ooyama, Akio; Okayama, Yoshihiro; Takechi, Teiji; Sugimoto, Yoshikazu; Oka, Toshinori; Fukushima, Masakazu

    2007-04-01

    Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5'-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nucleotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response. PMID:17425594

  18. Genome-wide association and fine mapping of genetic loci predisposing to colon carcinogenesis in mice.

    Science.gov (United States)

    Liu, Pengyuan; Lu, Yan; Liu, Hongbo; Wen, Weidong; Jia, Dongmei; Wang, Yian; You, Ming

    2012-01-01

    To identify the genetic determinants of colon tumorigenesis, 268 male mice from 33 inbred strains derived from different genealogies were treated with azoxymethane (AOM; 10 mg/kg) once a week for six weeks to induce colon tumors. Tumors were localized exclusively within the distal colon in each of the strains examined. Inbred mouse strains exhibit a large variability in genetic susceptibility to AOM-induced colon tumorigenesis. The mean colon tumor multiplicity ranged from 0 to 38.6 (mean = 6.5 ± 8.6) and tumor volume ranged from 0 to 706.5 mm(3) (mean = 87.4 ± 181.9) at 24 weeks after the first dose of AOM. AOM-induced colon tumor phenotypes are highly heritable in inbred mice, and 68.8% and 71.3% of total phenotypic variation in colon tumor multiplicity and tumor volume, respectively, are attributable to strain-dependent genetic background. Using 97,854 single-nucleotide polymorphisms, we carried out a genome-wide association study (GWAS) of AOM-induced colon tumorigenesis and identified a novel susceptibility locus on chromosome 15 (rs32359607, P = 6.31 × 10(-6)). Subsequent fine mapping confirmed five (Scc3, Scc2, Scc12, Scc8, and Ccs1) of 16 linkage regions previously found to be associated with colon tumor susceptibility. These five loci were refined to less than 1 Mb genomic regions of interest. Major candidates in these loci are Sema5a, Fmn2, Grem2, Fap, Gsg1l, Xpo6, Rabep2, Eif3c, Unc5d, and Gpr65. In particular, the refined Scc3 locus shows high concordance with the human GWAS locus that underlies hereditary mixed polyposis syndrome. These findings increase our understanding of the complex genetics of colon tumorigenesis, and provide important insights into the pathways of colorectal cancer development and might ultimately lead to more effective individually targeted cancer prevention strategies. PMID:22127497

  19. Privacy-Preserving Data Sharing for Genome-Wide Association Studies

    CERN Document Server

    Uhler, Caroline; Fienberg, Stephen E

    2012-01-01

    Traditional statistical methods for confidentiality protection of statistical databases do not scale well to deal with GWAS (genome-wide association studies) databases especially in terms of guarantees regarding protection from linkage to external information. The more recent concept of differential privacy, introduced by the cryptographic community, is an approach which provides a rigorous definition of privacy with meaningful privacy guarantees in the presence of arbitrary external information, although the guarantees come at a serious price in terms of data utility. Building on such notions, we propose new methods to release aggregate GWAS data without compromising an individual's privacy. We present methods for releasing differentially private minor allele frequencies, chi-square statistics and p-values. We compare these approaches on simulated data and on a GWAS study of canine hair length involving 685 dogs. We also propose a privacy-preserving method for finding genome-wide associations based on a diff...

  20. Genome-Wide Association Study Identifies Novel Pharmacogenomic Loci For Therapeutic Response to Montelukast in Asthma.

    Directory of Open Access Journals (Sweden)

    Amber Dahlin

    Full Text Available Genome-wide association study (GWAS is a powerful tool to identify novel pharmacogenetic single nucleotide polymorphisms (SNPs. Leukotriene receptor antagonists (LTRAs are a major class of asthma medications, and genetic factors contribute to variable responses to these drugs. We used GWAS to identify novel SNPs associated with the response to the LTRA, montelukast, in asthmatics.Using genome-wide genotype and phenotypic data available from American Lung Association - Asthma Clinical Research Center (ALA-ACRC cohorts, we evaluated 8-week change in FEV1 related to montelukast administration in a discovery population of 133 asthmatics. The top 200 SNPs from the discovery GWAS were then tested in 184 additional samples from two independent cohorts.Twenty-eight SNP associations from the discovery GWAS were replicated. Of these, rs6475448 achieved genome-wide significance (combined P = 1.97 x 10-09, and subjects from all four studies who were homozygous for rs6475448 showed increased ΔFEV1 from baseline in response to montelukast.Through GWAS, we identified a novel pharmacogenomic locus related to improved montelukast response in asthmatics.

  1. Data Mining Approaches for Genome-Wide Association of Mood Disorders

    OpenAIRE

    Pirooznia, Mehdi; Seifuddin, Fayaz; Judy, Jennifer; Mahon, Pamela B; James B Potash; Zandi, Peter P.

    2012-01-01

    Mood disorders are highly heritable forms of major mental illness. A major breakthrough in elucidating the genetic architecture of mood disorders was anticipated with the advent of genome-wide association studies (GWAS). However, to date few susceptibility loci have been conclusively identified. The genetic etiology of mood disorders appears to be quite complex, and as a result, alternative approaches for analyzing GWAS data are needed. Recently, a polygenic scoring approach that captures the...

  2. A Genome-Wide Association Study of the Metabolic Syndrome in Indian Asian Men

    OpenAIRE

    Zabaneh, Delilah; Balding, David J.

    2010-01-01

    We conducted a two-stage genome-wide association study to identify common genetic variation altering risk of the metabolic syndrome and related phenotypes in Indian Asian men, who have a high prevalence of these conditions. In Stage 1, approximately 317,000 single nucleotide polymorphisms were genotyped in 2700 individuals, from which 1500 SNPs were selected to be genotyped in a further 2300 individuals. Selection for inclusion in Stage 1 was based on four metabolic syndrome component traits:...

  3. Genome-wide association mapping to candidate polymorphism resolution in the unsequenced barley genome

    OpenAIRE

    Cockram, James; White, Jon; Zuluaga, Diana L.; Smith, David; Comadran, Jordi; Macaulay, Malcolm; Luo, Zewei; Kearsey, Mike J.; Werner, Peter; Harrap, David; Tapsell, Chris; LIU, HUI; Hedley, Peter E; Stein, Nils; Schulte, Daniela

    2010-01-01

    Although commonplace in human disease genetics, genome-wide association (GWA) studies have only relatively recently been applied to plants. Using 32 phenotypes in the inbreeding crop barley, we report GWA mapping of 15 morphological traits across ∼500 cultivars genotyped with 1,536 SNPs. In contrast to the majority of human GWA studies, we observe high levels of linkage disequilibrium within and between chromosomes. Despite this, GWA analysis readily detected common alleles of high penetrance...

  4. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies

    DEFF Research Database (Denmark)

    Bulik-Sullivan, Brendan K; Loh, Po-Ru; Finucane, Hilary K; Ripke, Stephan; Yang, Jian; Patterson, Nick; Daly, Mark J; Price, Alkes L; Neale, Benjamin M; Hansen, Thomas; Werge, Thomas Mears; Olsen, Line; Rasmussen, Henrik Berg

    2015-01-01

    Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a...... correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size....

  5. Case-control genome-wide association study of attention-deficit/hyperactivity disorder

    OpenAIRE

    Neale, Benjamin M.; Medland, Sarah; Ripke, Stephan; Anney, Richard JL; Asherson, Philip; Buitelaar, Jan; Franke, Barbara; Gill, Michael; Kent, Lindsey; Holmans, Peter; Middleton, Frank; Thapar, Anita; Lesch, Klaus-Peter; Faraone, Stephen V.; Daly, Mark

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus additional genomewide association studies (GWAS) are needed. Method: We used case-control analyses of 896 cases with DSM-IV ADHD genotvped using the Affymetrix 5.0 array and 2,455 repository controls screened for psychotic and bipolar symptoms genotyped using Affy...

  6. Genome-Wide Association Study of Retinopathy in Individuals Without Diabetes

    OpenAIRE

    Richard A. Jensen; Sim, Xueling; Li, Xiaohui; Cotch, Mary Frances; Ikram, M. Kamran; Holliday, Elizabeth G.; Eiriksdottir, Gudny; Harris, Tamara B; Jonasson, Fridbert; Klein, Barbara E. K.; Launer, Lenore J; Smith, Albert Vernon; Boerwinkle, Eric; Cheung, Ning; Hewitt, Alex W

    2013-01-01

    Background: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. Methods: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results fro...

  7. Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

    OpenAIRE

    Richard A. Jensen; Sim, Xueling; Li, Xiaohui; Cotch, Mary Frances; Ikram, M. Kamran; Holliday, Elizabeth G.; Eiriksdottir, Gudny; Harris, Tamara B; Jonasson, Fridbert; Klein, Barbara E. K.; Launer, Lenore J; Smith, Albert Vernon; Boerwinkle, Eric; Cheung, Ning; Hewitt, Alex W

    2013-01-01

    Background Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. Methods A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from ...

  8. A genome-wide association study for age-related hearing impairment in the Saami

    OpenAIRE

    Van Camp, Guy; Van Laer, Lut; Huyghe, Jeroen; Hannula, Samuli; Van Eyken, Els; Stephan, Dietrich; Mäki-Torkko, Elina; Aikio, Pekka; Lysholm-Bernacchi, Alana; Sorri, Martti; Huentelman, Matthew J; Fransen, Erik

    2010-01-01

    International audience This study aimed to contribute to the elucidation of the genetic basis of age-related hearing impairment (ARHI), a common multifactorial disease with an important genetic contribution as demonstrated by heritability studies. We conducted a genome-wide association study (GWAS) in the Finnish Saami, a small ancient genetically isolated population without evidence of demographic expansion. The choice of this study population was motivated by its anticipated higher exten...

  9. A genome-wide association study for age-related hearing impairment in the Saami

    OpenAIRE

    Van Laer, Lut; Huyghe, Jeroen R; Hannula, Samuli; Van Eyken, Els; Stephan, Dietrich A.; Mäki-Torkko, Elina; Aikio, Pekka; Fransen, Erik; Lysholm-Bernacchi, Alana; Sorri, Martti; Huentelman, Matthew J; Van Camp, Guy

    2010-01-01

    This study aimed at contributing to the elucidation of the genetic basis of age-related hearing impairment (ARHI), a common multifactorial disease with an important genetic contribution as demonstrated by heritability studies. We conducted a genome-wide association study (GWAS) in the Finnish Saami, a small, ancient, genetically isolated population without evidence of demographic expansion. The choice of this study population was motivated by its anticipated higher extent of LD, potentially o...

  10. Meta-analysis of genome-wide association studies for personality

    OpenAIRE

    Moor, M.H.M.; Costa, P. T.; Terracciano, A; Krueger, R.F.; de Geus, E.J.C.; Toshiko, T.; Penninx, B W J H; Esko, T.; Madden, P.A.F.; Derringer, J; Amin, N; Willemsen, G.; Hottenga, J-J; Distel, M A; Uda, M

    2012-01-01

    Abstract Personality can be thought of as a set of characteristics that influence people's thoughts, feelings, and behaviour across a variety of settings. Variation in personality is predictive of many outcomes in life, including mental health. Here we report on a meta-analysis of genome-wide association (GWA) data for personality in ten discovery samples (17 375 adults) and five in-silico replication samples (3 294 adults). All participants were of European ancestry. Personality s...

  11. Genome-Wide Association Analysis of Eating Disorder-Related Symptoms, Behaviors, and Personality Traits

    OpenAIRE

    Boraska, Vesna; Davis, Oliver SP; Cherkas, Lynn F; Helder, Sietske G; Harris, Juliette; Krug, Isabel; Pei-Chi Liao, Thomas; Treasure, Janet; Ntalla, Ioanna; Karhunen, Leila; Keski-Rahkonen, Anna; Christakopoulou, Danai; Raevuori, Anu; Shin, So-Youn; Dedoussis, George V.

    2012-01-01

    Eating disorders (EDs) are common, complex psychiatric disorders thought to be caused by both genetic and environmental factors. They share many symptoms, behaviors, and personality traits, which may have overlapping heritability. The aim of the present study is to perform a genome-wide association scan (GWAS) of six ED phenotypes comprising three symptom traits from the Eating Disorders Inventory 2 [Drive for Thinness (DT), Body Dissatisfaction (BD), and Bulimia], Weight Fluctuation symptom,...

  12. Meta-Analyses of Genome-Wide Association Data Hold New Promise for Addiction Genetics.

    Science.gov (United States)

    Agrawal, Arpana; Edenberg, Howard J; Gelernter, Joel

    2016-09-01

    Meta-analyses of genome-wide association study data have begun to lead to promising new discoveries for behavioral and psychiatrically relevant phenotypes (e.g., schizophrenia, educational attainment). We outline how this methodology can similarly lead to novel discoveries in genomic studies of substance use disorders, and discuss challenges that will need to be overcome to accomplish this goal. We illustrate our approach with the work of the newly established Substance Use Disorders workgroup of the Psychiatric Genomics Consortium. PMID:27588522

  13. LASSO model selection with post-processing for a genome-wide association study data set

    OpenAIRE

    Motyer Allan J; McKendry Chris; Galbraith Sally; Wilson Susan R

    2011-01-01

    Abstract Model selection procedures for simultaneous analysis of all single-nucleotide polymorphisms in genome-wide association studies are most suitable for making full use of the data for a complex disease study. In this paper we consider a penalized regression using the LASSO procedure and show that post-processing of the penalized-regression results with subsequent stepwise selection may lead to improved identification of causal single-nucleotide polymorphisms.

  14. Analysis of genome-wide association data by large-scale Bayesian logistic regression

    OpenAIRE

    Wang Yuanjia; Sha Nanshi; Fang Yixin

    2009-01-01

    Abstract Single-locus analysis is often used to analyze genome-wide association (GWA) data, but such analysis is subject to severe multiple comparisons adjustment. Multivariate logistic regression is proposed to fit a multi-locus model for case-control data. However, when the sample size is much smaller than the number of single-nucleotide polymorphisms (SNPs) or when correlation among SNPs is high, traditional multivariate logistic regression breaks down. To accommodate the scale of data fro...

  15. Genome-Wide Association Study of Plasma Polyunsaturated Fatty Acids in the InCHIANTI Study

    OpenAIRE

    Tanaka, Toshiko; Shen, Jian; Abecasis, Gonçalo R.; Kisialiou, Aliaksei; Ordovas, Jose M; Guralnik, Jack M.; Singleton, Andrew; Bandinelli, Stefania; Cherubini, Antonio; Arnett, Donna; Tsai, Michael Y.; Ferrucci, Luigi

    2009-01-01

    Polyunsaturated fatty acids (PUFA) have a role in many physiological processes, including energy production, modulation of inflammation, and maintenance of cell membrane integrity. High plasma PUFA concentrations have been shown to have beneficial effects on cardiovascular disease and mortality. To identify genetic contributors of plasma PUFA concentrations, we conducted a genome-wide association study of plasma levels of six omega-3 and omega-6 fatty acids in 1,075 participants in the InCHIA...

  16. New Approaches to Identify Gene-by-Gene Interactions in Genome Wide Association Studies

    OpenAIRE

    LU, CHEN

    2016-01-01

    Genetic variants identified to date by genome-wide association studies only explain a small fraction of total heritability. Gene-by-gene interaction is one important potential source of unexplained heritability. In the first part of this dissertation, a novel approach to detect such interactions is proposed. This approach utilizes penalized regression and sparse estimation principles, and incorporates outside biological knowledge through a network-based penalty. The method is tested on simula...

  17. Genome-Wide Association of the Laboratory-Based Nicotine Metabolite Ratio in Three Ancestries

    Science.gov (United States)

    Baurley, James W.; Edlund, Christopher K.; Pardamean, Carissa I.; Conti, David V.; Krasnow, Ruth; Javitz, Harold S.; Hops, Hyman; Swan, Gary E.; Benowitz, Neal L.

    2016-01-01

    Introduction: Metabolic enzyme variation and other patient and environmental characteristics influence smoking behaviors, treatment success, and risk of related disease. Population-specific variation in metabolic genes contributes to challenges in developing and optimizing pharmacogenetic interventions. We applied a custom genome-wide genotyping array for addiction research (Smokescreen), to three laboratory-based studies of nicotine metabolism with oral or venous administration of labeled nicotine and cotinine, to model nicotine metabolism in multiple populations. The trans-3′-hydroxycotinine/cotinine ratio, the nicotine metabolite ratio (NMR), was the nicotine metabolism measure analyzed. Methods: Three hundred twelve individuals of self-identified European, African, and Asian American ancestry were genotyped and included in ancestry-specific genome-wide association scans (GWAS) and a meta-GWAS analysis of the NMR. We modeled natural-log transformed NMR with covariates: principal components of genetic ancestry, age, sex, body mass index, and smoking status. Results: African and Asian American NMRs were statistically significantly (P values ≤ 5E-5) lower than European American NMRs. Meta-GWAS analysis identified 36 genome-wide significant variants over a 43 kilobase pair region at CYP2A6 with minimum P = 2.46E-18 at rs12459249, proximal to CYP2A6. Additional minima were located in intron 4 (rs56113850, P = 6.61E-18) and in the CYP2A6-CYP2A7 intergenic region (rs34226463, P = 1.45E-12). Most (34/36) genome-wide significant variants suggested reduced CYP2A6 activity; functional mechanisms were identified and tested in knowledge-bases. Conditional analysis resulted in intergenic variants of possible interest (P values genome-wide association of CYP2A6 single nucleotide and insertion–deletion polymorphisms. We identify three regions of genome-wide significance: proximal, intronic, and distal to CYP2A6. We replicate the top-ranking single nucleotide polymorphism

  18. Identification of Promising Mutants Associated with Egg Production Traits Revealed by Genome-Wide Association Study.

    Directory of Open Access Journals (Sweden)

    Jingwei Yuan

    Full Text Available Egg number (EN, egg laying rate (LR and age at first egg (AFE are important production traits related to egg production in poultry industry. To better understand the knowledge of genetic architecture of dynamic EN during the whole laying cycle and provide the precise positions of associated variants for EN, LR and AFE, laying records from 21 to 72 weeks of age were collected individually for 1,534 F2 hens produced by reciprocal crosses between White Leghorn and Dongxiang Blue-shelled chicken, and their genotypes were assayed by chicken 600 K Affymetrix high density genotyping arrays. Subsequently, pedigree and SNP-based genetic parameters were estimated and a genome-wide association study (GWAS was conducted on EN, LR and AFE. The heritability estimates were similar between pedigree and SNP-based estimates varying from 0.17 to 0.36. In the GWA analysis, we identified nine genome-wide significant loci associated with EN of the laying periods from 21 to 26 weeks, 27 to 36 weeks and 37 to 72 weeks. Analysis of GTF2A1 and CLSPN suggested that they influenced the function of ovary and uterus, and may be considered as relevant candidates. The identified SNP rs314448799 for accumulative EN from 21 to 40 weeks on chromosome 5 created phenotypic differences of 6.86 eggs between two homozygous genotypes, which could be potentially applied to the molecular breeding for EN selection. Moreover, our finding showed that LR was a moderate polygenic trait. The suggestive significant region on chromosome 16 for AFE suggested the relationship between sex maturity and immune in the current population. The present study comprehensively evaluates the role of genetic variants in the development of egg laying. The findings will be helpful to investigation of causative genes function and future marker-assisted selection and genomic selection in chickens.

  19. Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study.

    Science.gov (United States)

    Matullo, Giuseppe; Guarrera, Simonetta; Betti, Marta; Fiorito, Giovanni; Ferrante, Daniela; Voglino, Floriana; Cadby, Gemma; Di Gaetano, Cornelia; Rosa, Fabio; Russo, Alessia; Hirvonen, Ari; Casalone, Elisabetta; Tunesi, Sara; Padoan, Marina; Giordano, Mara; Aspesi, Anna; Casadio, Caterina; Ardissone, Francesco; Ruffini, Enrico; Betta, Pier Giacomo; Libener, Roberta; Guaschino, Roberto; Piccolini, Ezio; Neri, Monica; Musk, Arthur W B; de Klerk, Nicholas H; Hui, Jennie; Beilby, John; James, Alan L; Creaney, Jenette; Robinson, Bruce W; Mukherjee, Sutapa; Palmer, Lyle J; Mirabelli, Dario; Ugolini, Donatella; Bonassi, Stefano; Magnani, Corrado; Dianzani, Irma

    2013-01-01

    Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs) in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes), causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14). Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC) of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28). These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos. PMID:23626673

  20. Genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study.

    Directory of Open Access Journals (Sweden)

    Giuseppe Matullo

    Full Text Available Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM, a rare aggressive tumor. Nevertheless, only 5-17% of those exposed to asbestos develop MPM, suggesting the involvement of other environmental and genetic risk factors. To identify the genetic risk factors that may contribute to the development of MPM, we conducted a genome-wide association study (GWAS; 370,000 genotyped SNPs, 5 million imputed SNPs in Italy, among 407 MPM cases and 389 controls with a complete history of asbestos exposure. A replication study was also undertaken and included 428 MPM cases and 1269 controls from Australia. Although no single marker reached the genome-wide significance threshold, several associations were supported by haplotype-, chromosomal region-, gene- and gene-ontology process-based analyses. Most of these SNPs were located in regions reported to harbor aberrant alterations in mesothelioma (SLC7A14, THRB, CEBP350, ADAMTS2, ETV1, PVT1 and MMP14 genes, causing at most a 2-3-fold increase in MPM risk. The Australian replication study showed significant associations in five of these chromosomal regions (3q26.2, 4q32.1, 7p22.2, 14q11.2, 15q14. Multivariate analysis suggested an independent contribution of 10 genetic variants, with an Area Under the ROC Curve (AUC of 0.76 when only exposure and covariates were included in the model, and of 0.86 when the genetic component was also included, with a substantial increase of asbestos exposure risk estimation (odds ratio, OR: 45.28, 95% confidence interval, CI: 21.52-95.28. These results showed that genetic risk factors may play an additional role in the development of MPM, and that these should be taken into account to better estimate individual MPM risk in individuals who have been exposed to asbestos.

  1. Integrated analysis of genome-wide genetic and epigenetic association data for identification of disease mechanisms.

    Science.gov (United States)

    Ke, Xiayi; Cortina-Borja, Mario; Silva, Bruno Cesar; Lowe, Robert; Rakyan, Vardhman; Balding, David

    2013-11-01

    Many human diseases are multifactorial, involving multiple genetic and environmental factors impacting on one or more biological pathways. Much of the environmental effect is believed to be mediated through epigenetic changes. Although many genome-wide genetic and epigenetic association studies have been conducted for different diseases and traits, it is still far from clear to what extent the genomic loci and biological pathways identified in the genetic and epigenetic studies are shared. There is also a lack of statistical tools to assess these important aspects of disease mechanisms. In the present study, we describe a protocol for the integrated analysis of genome-wide genetic and epigenetic data based on permutation of a sum statistic for the combined effects in a locus or pathway. The method was then applied to published type 1 diabetes (T1D) genome-wide- and epigenome-wide-association studies data to identify genomic loci and biological pathways that are associated with T1D genetically and epigenetically. Through combined analysis, novel loci and pathways were also identified, which could add to our understanding of disease mechanisms of T1D as well as complex diseases in general. PMID:24071862

  2. Meta-analysis of genome-wide association studies of attention deficit/hyperactivity disorder

    Science.gov (United States)

    Neale, Benjamin M; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; Franke, Barbara; Lesch, Klaus-Peter; Faraone, Stephen V.; Nguyen, Thuy Trang; Schäfer, Helmut; Holmans, Peter; Daly, Mark; Steinhausen, Hans-Christoph; Freitag, Christine; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Walitza, Susanne; Warnke, Andreas; Meyer, Jobst; Palmason, Haukur; Buitelaar, Jan; Vasquez, Alejandro Arias; Lambregts-Rommelse, Nanda; Gill, Michael; Anney, Richard J.L.; Langely, Kate; O’Donovan, Michael; Williams, Nigel; Owen, Michael; Thapar, Anita; Kent, Lindsey; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph; Doyle, Alysa; Smalley, Susan; Loo, Sandra; Hakonarson, Hakon; Elia, Josephine; Todorov, Alexandre; Miranda, Ana; Mulas, Fernando; Ebstein, Richard P.; Rothenberger, Aribert; Banaschewski, Tobias; Oades, Robert D.; Sonuga-Barke, Edmund; McGough, James; Nisenbaum, Laura; Middleton, Frank; Hu, Xiaolan; Nelson, Stan

    2010-01-01

    Objective Although twin and family studies have shown Attention Deficit/Hyperactivity Disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association scans (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children’s Hospital of Philadelphia (CHOP), b) phase I of the International Multicenter ADHD Genetics project (IMAGE), c) phase II of IMAGE (IMAGE II), and d) the Pfizer funded study from the University of California, Los Angeles, Washington University and the Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases and 2,455 controls. For each study, we imputed HapMap SNPs, computed association test statistics and transformed them to Z-scores, and then combined weighted Z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g. rare ones, account for much of the disorder’s heritability. PMID:20732625

  3. Population substructure and control selection in genome-wide association studies.

    Science.gov (United States)

    Yu, Kai; Wang, Zhaoming; Li, Qizhai; Wacholder, Sholom; Hunter, David J; Hoover, Robert N; Chanock, Stephen; Thomas, Gilles

    2008-01-01

    Determination of the relevance of both demanding classical epidemiologic criteria for control selection and robust handling of population stratification (PS) represents a major challenge in the design and analysis of genome-wide association studies (GWAS). Empirical data from two GWAS in European Americans of the Cancer Genetic Markers of Susceptibility (CGEMS) project were used to evaluate the impact of PS in studies with different control selection strategies. In each of the two original case-control studies nested in corresponding prospective cohorts, a minor confounding effect due to PS (inflation factor lambda of 1.025 and 1.005) was observed. In contrast, when the control groups were exchanged to mimic a cost-effective but theoretically less desirable control selection strategy, the confounding effects were larger (lambda of 1.090 and 1.062). A panel of 12,898 autosomal SNPs common to both the Illumina and Affymetrix commercial platforms and with low local background linkage disequilibrium (pair-wise r(2)<0.004) was selected to infer population substructure with principal component analysis. A novel permutation procedure was developed for the correction of PS that identified a smaller set of principal components and achieved a better control of type I error (to lambda of 1.032 and 1.006, respectively) than currently used methods. The overlap between sets of SNPs in the bottom 5% of p-values based on the new test and the test without PS correction was about 80%, with the majority of discordant SNPs having both ranks close to the threshold. Thus, for the CGEMS GWAS of prostate and breast cancer conducted in European Americans, PS does not appear to be a major problem in well-designed studies. A study using suboptimal controls can have acceptable type I error when an effective strategy for the correction of PS is employed. PMID:18596976

  4. Genome-wide association analyses for growth and feed efficiency traits in beef cattle.

    Science.gov (United States)

    Lu, D; Miller, S; Sargolzaei, M; Kelly, M; Vander Voort, G; Caldwell, T; Wang, Z; Plastow, G; Moore, S

    2013-08-01

    A genome-wide association study using the Illumina 50K BeadChip included 38,745 SNP on 29 BTA analyzed on 751 animals, including 33 purebreds and 718 crossbred cattle. Genotypes and 6 production traits: birth weight (BWT), weaning weight (WWT), ADG, DMI, midtest metabolic BW (MMWT), and residual feed intake (RFI), were used to estimate effects of individual SNP on the traits. At the genome-wide level false discovery rate (FDR impact them in same direction. In terms of the size of SNP effect, the significant SNP (P information to further assist the identification of chromosome regions and subsequently genes affecting growth and feed efficiency traits in beef cattle. PMID:23851991

  5. Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat

    Science.gov (United States)

    Sung, Yun Ju; Pérusse, Louis; Sarzynski, Mark A.; Fornage, Myriam; Sidney, Steve; Sternfeld, Barbara; Rice, Treva; Terry, Gregg; Jacobs, David R.; Katzmarzyk, Peter; Curran, Joanne E; Carr, John Jeffrey; Blangero, John; Ghosh, Sujoy; Després, Jean-Pierre; Rankinen, Tuomo; Rao, D.C.; Bouchard, Claude

    2015-01-01

    Background To identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR). Subjects and Methods Sex-combined and sex-stratified analyses were performed on each trait with (TRAIT-BMI) or without (TRAIT) adjustment for BMI, and cohort-specific results were combined via a fixed effects meta-analysis. A total of 2,513 subjects of European descent were available for the discovery phase. For replication, 2,171 European Americans and 772 African Americans were available. Results A total of 52 SNPs encompassing 7 loci showed suggestive evidence of association (p < 1.0 × 10−6) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; p= 1.10 × 10−7), an association that was replicated (p = 0.02). For the BMI-adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT-BMI (rs10506943; p= 2.42 × 10−7). Our sex-specific analyses identified one genome-wide significant (p < 5.0 × 10−8) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (p = 3.97 × 10−8 to 1.13 × 10−8). The THNSL2 gene previously associated with VAT in women was also replicated (p= 0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively. Conclusions Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2

  6. Impact of phenotype definition on genome-wide association signals: empirical evaluation in human immunodeficiency virus type 1 infection

    DEFF Research Database (Denmark)

    Evangelou, Evangelos; Fellay, Jacques; Colombo, Sara; Martinez-Picado, Javier; Obel, Niels; Goldstein, David B; Telenti, Amalio; Ioannidis, John P A

    2011-01-01

    Discussion on improving the power of genome-wide association studies to identify candidate variants and genes is generally centered on issues of maximizing sample size; less attention is given to the role of phenotype definition and ascertainment. The authors used genome-wide data from patients i...

  7. Simultaneous analysis of all SNPs in genome-wide and re-sequencing association studies.

    Directory of Open Access Journals (Sweden)

    Clive J Hoggart

    Full Text Available Testing one SNP at a time does not fully realise the potential of genome-wide association studies to identify multiple causal variants, which is a plausible scenario for many complex diseases. We show that simultaneous analysis of the entire set of SNPs from a genome-wide study to identify the subset that best predicts disease outcome is now feasible, thanks to developments in stochastic search methods. We used a Bayesian-inspired penalised maximum likelihood approach in which every SNP can be considered for additive, dominant, and recessive contributions to disease risk. Posterior mode estimates were obtained for regression coefficients that were each assigned a prior with a sharp mode at zero. A non-zero coefficient estimate was interpreted as corresponding to a significant SNP. We investigated two prior distributions and show that the normal-exponential-gamma prior leads to improved SNP selection in comparison with single-SNP tests. We also derived an explicit approximation for type-I error that avoids the need to use permutation procedures. As well as genome-wide analyses, our method is well-suited to fine mapping with very dense SNP sets obtained from re-sequencing and/or imputation. It can accommodate quantitative as well as case-control phenotypes, covariate adjustment, and can be extended to search for interactions. Here, we demonstrate the power and empirical type-I error of our approach using simulated case-control data sets of up to 500 K SNPs, a real genome-wide data set of 300 K SNPs, and a sequence-based dataset, each of which can be analysed in a few hours on a desktop workstation.

  8. 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".

  9. An efficient weighted tag SNP-set analytical method in genome-wide association studies

    OpenAIRE

    Yan, Bin; Wang, Shudong; Jia, Huaqian; Liu, Xing; Wang, Xinzeng

    2015-01-01

    Background Single-nucleotide polymorphism (SNP)-set analysis in Genome-wide association studies (GWAS) has emerged as a research hotspot for identifying genetic variants associated with disease susceptibility. But most existing methods of SNP-set analysis are affected by the quality of SNP-set, and poor quality of SNP-set can lead to low power in GWAS. Results In this research, we propose an efficient weighted tag-SNP-set analytical method to detect the disease associations. In our method, we...

  10. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis

    OpenAIRE

    Liu, Xiangdong; Invernizzi, Pietro; Lu, Yue,; Kosoy, Roman; Lu, Yan; Bianchi, Ilaria; Podda, Mauro; Chun XU; Xie, Gang; Macciardi, Fabio; Selmi, Carlo; Lupoli, Sara; Shigeta, Russell; Ransom, Michael; Lleo, Ana

    2010-01-01

    A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10–11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10–10, OR = 1.63) and 17q12-21 (P = 1.7 × 10–10, OR = 1.38).

  11. Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis

    Science.gov (United States)

    Liu, Xiangdong; Invernizzi, Pietro; Lu, Yue; Kosoy, Roman; Lu, Yan; Bianchi, Ilaria; Podda, Mauro; Xu, Chun; Xie, Gang; Macciardi, Fabio; Selmi, Carlo; Lupoli, Sara; Shigeta, Russell; Ransom, Michael; Lleo, Ana; Lee, Annette T; Mason, Andrew L; Myers, Robert P; Peltekian, Kevork M; Ghent, Cameron N; Bernuzzi, Francesca; Zuin, Massimo; Rosina, Floriano; Borghesio, Elisabetta; Floreani, Annarosa; Lazzari, Roberta; Niro, Grazia; Andriulli, Angelo; Muratori, Luigi; Muratori, Paolo; Almasio, Piero L; Andreone, Pietro; Margotti, Marzia; Brunetto, Maurizia; Coco, Barbara; Alvaro, Domenico; Bragazzi, Maria C; Marra, Fabio; Pisano, Alessandro; Rigamonti, Cristina; Colombo, Massimo; Marzioni, Marco; Benedetti, Antonio; Fabris, Luca; Strazzabosco, Mario; Portincasa, Piero; Palmieri, Vincenzo O; Tiribelli, Claudio; Croce, Lory; Bruno, Savino; Rossi, Sonia; Vinci, Maria; Prisco, Cleofe; Mattalia, Alberto; Toniutto, Pierluigi; Picciotto, Antonio; Galli, Andrea; Ferrari, Carlo; Colombo, Silvia; Casella, Giovanni; Morini, Lorenzo; Caporaso, Nicola; Colli, Agostino; Spinzi, Giancarlo; Montanari, Renzo; Gregersen, Peter K; Heathcote, E Jenny; Hirschfield, Gideon M; Siminovitch, Katherine A; Amos, Christopher I; Gershwin, M Eric; Seldin, Michael F

    2011-01-01

    A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 × 10–11, odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 × 10–10, OR = 1.63) and 17q12-21 (P = 1.7 × 10–10, OR = 1.38). PMID:20639880

  12. Genome-wide Association Study of Personality Traits in the Long Life Family Study

    Directory of Open Access Journals (Sweden)

    Harold T Bae

    2013-05-01

    Full Text Available Personality traits have been shown to be associated with longevity and healthy aging. In order to discover novel genetic modifiers associated with personality traits as related with longevity, we performed a genome-wide association study (GWAS on personality factors assessed by NEO-FFI in individuals enrolled in the Long Life Family Study (LLFS, a study of 583 families (N up to 4595 with clustering for longevity in the United States and Denmark. Three SNPs, in almost perfect LD, associated with agreeableness reached genome-wide significance (p<10-8 and replicated in an additional sample of 1279 LLFS subjects, although one (rs9650241 failed to replicate and the other two were not available in two independent replication cohorts, the Baltimore Longitudinal Study of Aging and the New England Centenarian Study. Based on 10,000,000 permutations, the empirical p-value of 2X10-7 was observed for the genome-wide significant SNPs. Seventeen SNPs that reached marginal statistical significance in the two previous GWASs (p-value < 10-4 and 10-5, were also marginally significantly associated in this study (p-value < 0.05, although none of the associations passed the Bonferroni correction. In addition, we tested age-by-SNP interactions and found some significant associations. Since scores of personality traits in LLFS subjects change in the oldest ages, and genetic factors outweigh environmental factors to achieve extreme ages, these age-by-SNP interactions could be a proxy for complex gene-gene interactions affecting personality traits and longevity.

  13. Genome-Wide Association Study Identifies Candidate Loci Associated with Platelet Count in Koreans

    Science.gov (United States)

    Oh, Ji Hee; Kim, Yun Kyoung; Moon, Sanghoon; Kim, Young Jin

    2014-01-01

    Platelets are derived from the fragments that are formed from the cytoplasm of bone marrow megakaryocytes-small irregularly shaped anuclear cells. Platelets respond to vascular damage, contracts blood vessels, and attaches to the damaged region, thereby stopping bleeding, together with the action of blood coagulation factors. Platelet activation is known to affect genes associated with vascular risk factors, as well as with arteriosclerosis and myocardial infarction. Here, we performed a genome-wide association study with 352,228 single-nucleotide polymorphisms typed in 8,842 subjects of the Korea Association Resource (KARE) project and replicated the results in 7,861 subjects from an independent population. We identified genetic associations between platelet count and common variants nearby chromosome 4p16.1 (p = 1.46 × 10-10, in the KIAA0232 gene), 6p21 (p = 1.36 × 10-7, in the BAK1 gene), and 12q24.12 (p = 1.11 × 10-15, in the SH2B3 gene). Our results illustrate the value of large-scale discovery and a focus for several novel research avenues. PMID:25705162

  14. Genome-wide association of anthropometric traits in African- and African-derived populations.

    Science.gov (United States)

    Kang, Sun J; Chiang, Charleston W K; Palmer, Cameron D; Tayo, Bamidele O; Lettre, Guillaume; Butler, Johannah L; Hackett, Rachel; Adeyemo, Adebowale A; Guiducci, Candace; Berzins, Ilze; Nguyen, Thutrang T; Feng, Tao; Luke, Amy; Shriner, Daniel; Ardlie, Kristin; Rotimi, Charles; Wilks, Rainford; Forrester, Terrence; McKenzie, Colin A; Lyon, Helen N; Cooper, Richard S; Zhu, Xiaofeng; Hirschhorn, Joel N

    2010-07-01

    Genome-wide association (GWA) studies have identified common variants that are associated with a variety of traits and diseases, but most studies have been performed in European-derived populations. Here, we describe the first genome-wide analyses of imputed genotype and copy number variants (CNVs) for anthropometric measures in African-derived populations: 1188 Nigerians from Igbo-Ora and Ibadan, Nigeria, and 743 African-Americans from Maywood, IL. To improve the reach of our study, we used imputation to estimate genotypes at approximately 2.1 million single-nucleotide polymorphisms (SNPs) and also tested CNVs for association. No SNPs or common CNVs reached a genome-wide significance level for association with height or body mass index (BMI), and the best signals from a meta-analysis of the two cohorts did not replicate in approximately 3700 African-Americans and Jamaicans. However, several loci previously confirmed in European populations showed evidence of replication in our GWA panel of African-derived populations, including variants near IHH and DLEU7 for height and MC4R for BMI. Analysis of global burden of rare CNVs suggested that lean individuals possess greater total burden of CNVs, but this finding was not supported in an independent European population. Our results suggest that there are not multiple loci with strong effects on anthropometric traits in African-derived populations and that sample sizes comparable to those needed in European GWA studies will be required to identify replicable associations. Meta-analysis of this data set with additional studies in African-ancestry populations will be helpful to improve power to detect novel associations. PMID:20400458

  15. Genome-wide linkage scan for colorectal cancer susceptibility genes supports linkage to chromosome 3q

    Directory of Open Access Journals (Sweden)

    Velculescu Victor E

    2008-04-01

    Full Text Available Abstract Background Colorectal cancer is one of the most common causes of cancer-related mortality. The disease is clinically and genetically heterogeneous though a strong hereditary component has been identified. However, only a small proportion of the inherited susceptibility can be ascribed to dominant syndromes, such as Hereditary Non-Polyposis Colorectal Cancer (HNPCC or Familial Adenomatous Polyposis (FAP. In an attempt to identify novel colorectal cancer predisposing genes, we have performed a genome-wide linkage analysis in 30 Swedish non-FAP/non-HNPCC families with a strong family history of colorectal cancer. Methods Statistical analysis was performed using multipoint parametric and nonparametric linkage. Results Parametric analysis under the assumption of locus homogeneity excluded any common susceptibility regions harbouring a predisposing gene for colorectal cancer. However, several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected in the parametric analysis under the assumption of locus heterogeneity as well as in the nonparametric analysis. Among these loci, the locus on chromosome 3q21.1-q26.2 was the most consistent finding providing positive results in both parametric and nonparametric analyses Heterogeneity LOD score (HLOD = 1.90, alpha = 0.45, Non-Parametric LOD score (NPL = 2.1. Conclusion The strongest evidence of linkage was seen for the region on chromosome 3. Interestingly, the same region has recently been reported as the most significant finding in a genome-wide analysis performed with SNP arrays; thus our results independently support the finding on chromosome 3q.

  16. Genome-wide Association Scan for Childhood Caries Implicates Novel Genes

    OpenAIRE

    Shaffer, J.R.; Wang, X.; Feingold, E.; M. Lee; Begum, F.; Weeks, D. E.; Cuenco, K.T.; Barmada, M M; Wendell, S.K.; Crosslin, D R; Laurie, C. C.; Doheny, K F; Pugh, E W; Zhang, Q.; Feenstra, B

    2011-01-01

    Dental caries is the most common chronic disease in children and a major public health concern due to its increasing incidence, serious health and social co-morbidities, and socio-demographic disparities in disease burden. We performed the first genome-wide association scan for dental caries to identify associated genetic loci and nominate candidate genes affecting tooth decay in 1305 US children ages 3-12 yrs. Affection status was defined as 1 or more primary teeth with evidence of decay bas...

  17. Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci

    Science.gov (United States)

    Melum, Espen; Franke, Andre; Schramm, Christoph; Weismüller, Tobias J; Gotthardt, Daniel Nils; Offner, Felix A; Juran, Brian D; Laerdahl, Jon K; Labi, Verena; Björnsson, Einar; Weersma, Rinse K; Henckaerts, Liesbet; Teufel, Andreas; Rust, Christian; Ellinghaus, Eva; Balschun, Tobias; Boberg, Kirsten Muri; Ellinghaus, David; Bergquist, Annika; Sauer, Peter; Ryu, Euijung; Hov, Johannes Roksund; Wedemeyer, Jochen; Lindkvist, Björn; Wittig, Michael; Porte, Robert J; Holm, Kristian; Gieger, Christian; Wichmann, H-Erich; Stokkers, Pieter; Ponsioen, Cyriel Y; Runz, Heiko; Stiehl, Adolf; Wijmenga, Cisca; Sterneck, Martina; Vermeire, Severine; Beuers, Ulrich; Villunger, Andreas; Schrumpf, Erik; Lazaridis, Konstantinos N; Manns, Michael P; Schreiber, Stefan; Karlsen, Tom H

    2015-01-01

    Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4–7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10−16 and P = 4.1 × 10−8, respectively). PMID:21151127

  18. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

    OpenAIRE

    Kouri, Naomi; Ross, Owen A.; Dombroski, Beth; Younkin, Curtis S.; Serie, Daniel J.; Soto-Ortolaza, Alexandra; Baker, Matthew; Finch, Ni Cole A.; Yoon, Hyejin; Kim, Jungsu; Fujioka, Shinsuke; McLean, Catriona A.; Ghetti, Bernardino; Spina, Salvatore; Cantwell, Laura B.

    2015-01-01

    Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10−8), and 2p22 at SOS1 (rs963731; P=1.76 × 10−7). Testing for associat...

  19. A Genome Wide Association Study Links Glutamate Receptor Pathway to Sporadic Creutzfeldt-Jakob Disease Risk

    OpenAIRE

    Sanchez-Juan, Pascual; Bishop, Matthew T.; Kovacs, Gabor G.; Calero, Miguel; Aulchenko, Yurii S; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J; Ströbel, Thomas; Rivadeneira, Fernando

    2015-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction ...

  20. A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk

    OpenAIRE

    Sanchez-Juan, Pascual; Bishop, Matthew; Kovacs, Gabor; Calero, Miguel; Aulchenko, Yurii; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, C. (Claudia); Calero, O. (Olga); Poleggi, Anna; Carracedo, Angel; van der Lee, S. J.; Ströbel, Thomas; Rivadeneira Ramirez, Fernando

    2015-01-01

    textabstractWe performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after...

  1. A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.

    OpenAIRE

    Sanchez-Juan, Pascual; Bishop, Matthew T.; Kovacs, Gabor G.; Calero, Miguel; Aulchenko, Yurii S; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J; Ströbel, Thomas; Rivadeneira, Fernando

    2014-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction ...

  2. A genome wide association study links glutamate receptor pathway to Sporadic Creutzfeldt-Jakob disease risk.

    OpenAIRE

    Sanchez-Juan, Pascual; Bishop, Matthew; Kovacs, Gabor; Calero, Miguel; Aulchenko, Yuri; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Angel; van der Lee, Sven; Strobel, Thomas; Rivadeneira, Fernando

    2015-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction f...

  3. A data-driven weighting scheme for family-based genome-wide association studies

    OpenAIRE

    Qin, Huaizhen; FENG, Tao; Zhang, Shuanglin; Sha, Qiuying

    2009-01-01

    Recently, Steen et al proposed a novel two-stage approach for family-based genome-wide association studies. In the first stage, a test based on between-family information is used to rank SNPs according to their P-values or conditional power of the test. In the second stage, the R most promising SNPs are tested using a family-based association test. We call this two-stage approach top R method. Ionita-Laza et al proposed an exponential weighting method within a two-stage framework. In the seco...

  4. Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci.

    Science.gov (United States)

    Melum, Espen; Franke, Andre; Schramm, Christoph; Weismüller, Tobias J; Gotthardt, Daniel Nils; Offner, Felix A; Juran, Brian D; Laerdahl, Jon K; Labi, Verena; Björnsson, Einar; Weersma, Rinse K; Henckaerts, Liesbet; Teufel, Andreas; Rust, Christian; Ellinghaus, Eva; Balschun, Tobias; Boberg, Kirsten Muri; Ellinghaus, David; Bergquist, Annika; Sauer, Peter; Ryu, Euijung; Hov, Johannes Roksund; Wedemeyer, Jochen; Lindkvist, Björn; Wittig, Michael; Porte, Robert J; Holm, Kristian; Gieger, Christian; Wichmann, H-Erich; Stokkers, Pieter; Ponsioen, Cyriel Y; Runz, Heiko; Stiehl, Adolf; Wijmenga, Cisca; Sterneck, Martina; Vermeire, Severine; Beuers, Ulrich; Villunger, Andreas; Schrumpf, Erik; Lazaridis, Konstantinos N; Manns, Michael P; Schreiber, Stefan; Karlsen, Tom H

    2011-01-01

    Primary sclerosing cholangitis (PSC) is a chronic bile duct disease affecting 2.4-7.5% of individuals with inflammatory bowel disease. We performed a genome-wide association analysis of 2,466,182 SNPs in 715 individuals with PSC and 2,962 controls, followed by replication in 1,025 PSC cases and 2,174 controls. We detected non-HLA associations at rs3197999 in MST1 and rs6720394 near BCL2L11 (combined P = 1.1 × 10⁻¹⁶ and P = 4.1 × 10⁻⁸, respectively). PMID:21151127

  5. Genome-wide linkage and association scans for pulse pressure in Chinese twins

    DEFF Research Database (Denmark)

    Zhang, Dongfeng; Pang, Zengchang; Li, Shuxia; Jiang, Wenjie; Wang, Shaojie; Thomassen, Mads; von Bornemann Hjelmborg, Jacob; Kruse, Torben A; Ohm Kyvik, Kirsten; Christensen, Kaare; Zhu, Gu; Tan, Qihua

    2012-01-01

    report the results of our gene mapping studies conducted in the Chinese population in mainland China. The genome-wide linkage and association scans were carried out on 63 middle-aged dizygotic twin pairs using high-density markers. The linkage analysis identified three significant linkage peaks (all with......Elevated pulse pressure (PP) is associated with cardiovascular disorders and mortality in various populations. The genetic influence on PP has been confirmed by heritability estimates using related individuals. Recently, efforts have been made by mapping genes that are linked to the phenotype. We...

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

    OpenAIRE

    Khor, CC; Do, T.; Jia, H; Nakano, M; George, R.; Abu-Amero, K; Duvesh, R; Chen, LJ; Z. Li; Nongpiur, ME; Perera, SA; Qiao, C.; Wong, H-T; Sakai, H.; de Melo, MB

    2016-01-01

    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 = ...

  7. Genetic determinants of cardiovascular events among women with migraine: a genome-wide association study.

    Directory of Open Access Journals (Sweden)

    Markus Schürks

    Full Text Available BACKGROUND: Migraine is associated with an increased risk for cardiovascular disease (CVD. Both migraine and CVD are highly heritable. However, the genetic liability for CVD among migraineurs is unclear. METHODS: We performed a genome-wide association study for incident CVD events during 12 years of follow-up among 5,122 migraineurs participating in the population-based Women's Genome Health Study. Migraine was self-reported and CVD events were confirmed after medical records review. We calculated odds ratios (OR and 95% confidence intervals (CI and considered a genome-wide p-value <5×10(-8 as significant. RESULTS: Among the 5,122 women with migraine 164 incident CVD events occurred during follow-up. No SNP was associated with major CVD, ischemic stroke, myocardial infarction, or CVD death at the genome-wide level; however, five SNPs showed association with p<5×10(-6. Among migraineurs with aura rs7698623 in MEPE (OR = 6.37; 95% CI 3.15-12.90; p = 2.7×10(-7 and rs4975709 in IRX4 (OR = 5.06; 95% CI 2.66-9.62; p = 7.7×10(-7 appeared to be associated with ischemic stroke, rs2143678 located close to MDF1 with major CVD (OR = 3.05; 95% CI 1.98-4.69; p = 4.3×10(-7, and the intergenic rs1406961 with CVD death (OR = 12.33; 95% CI 4.62-32.87; p = 5.2×10(-7. Further, rs1047964 in BACE1 appeared to be associated with CVD death among women with any migraine (OR = 4.67; 95% CI 2.53-8.62; p = 8.0×10(-7. CONCLUSION: Our results provide some suggestion for an association of five SNPs with CVD events among women with migraine; none of the results was genome-wide significant. Four associations appeared among migraineurs with aura, two of those with ischemic stroke. Although our population is among the largest with migraine and incident CVD information, these results must be treated with caution, given the limited number of CVD events among women with migraine and the low minor allele frequencies for three of the SNPs

  8. Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations.

    Directory of Open Access Journals (Sweden)

    Ayşe Demirkan

    Full Text Available Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034 on plasma levels of 24 sphingomyelins (SPM, 9 ceramides (CER, 57 phosphatidylcholines (PC, 20 lysophosphatidylcholines (LPC, 27 phosphatidylethanolamines (PE, and 16 PE-based plasmalogens (PLPE, as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10(-204 and 10 loci for sphingolipids (smallest P-value = 3.10×10(-57. After a correction for multiple comparisons (P-value<2.2×10(-9, we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1 and two with sphingolipids (PLD2 and APOE explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3 suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2 to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our

  9. A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity

    International Nuclear Information System (INIS)

    Background and purpose: This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity 2 years after radiotherapy. Materials and methods: A genome wide association study was performed in 1850 patients from the RAPPER study: 1217 received adjuvant breast radiotherapy and 633 had radical prostate radiotherapy. Genotype associations with both overall and individual endpoints of toxicity were tested via univariable and multivariable regression. Replication of potentially associated SNPs was carried out in three independent patient cohorts who had radiotherapy for prostate (516 RADIOGEN and 862 Gene-PARE) or breast (355 LeND) cancer. Results: Quantile–quantile plots show more associations at the P < 5 × 10−7 level than expected by chance (164 vs. 9 for the prostate cases and 29 vs. 4 for breast cases), providing evidence that common genetic variants are associated with risk of toxicity. Strongest associations were for individual endpoints rather than an overall measure of toxicity in all patients. However, in general, significant associations were not validated at a nominal 0.05 level in the replication cohorts. Conclusions: This largest GWAS to date provides evidence of true association between common genetic variants and toxicity. Associations with toxicity appeared to be tumour site-specific. Future GWAS require higher statistical power, in particular in the validation stage, to test clinically relevant effect sizes of SNP associations with individual endpoints, but the required sample sizes are achievable

  10. FVGWAS: Fast voxelwise genome wide association analysis of large-scale imaging genetic data.

    Science.gov (United States)

    Huang, Meiyan; Nichols, Thomas; Huang, Chao; Yu, Yang; Lu, Zhaohua; Knickmeyer, Rebecca C; Feng, Qianjin; Zhu, Hongtu

    2015-09-01

    More and more large-scale imaging genetic studies are being widely conducted to collect a rich set of imaging, genetic, and clinical data to detect putative genes for complexly inherited neuropsychiatric and neurodegenerative disorders. Several major big-data challenges arise from testing genome-wide (NC>12 million known variants) associations with signals at millions of locations (NV~10(6)) in the brain from thousands of subjects (n~10(3)). The aim of this paper is to develop a Fast Voxelwise Genome Wide Association analysiS (FVGWAS) framework to efficiently carry out whole-genome analyses of whole-brain data. FVGWAS consists of three components including a heteroscedastic linear model, a global sure independence screening (GSIS) procedure, and a detection procedure based on wild bootstrap methods. Specifically, for standard linear association, the computational complexity is O (nNVNC) for voxelwise genome wide association analysis (VGWAS) method compared with O ((NC+NV)n(2)) for FVGWAS. Simulation studies show that FVGWAS is an efficient method of searching sparse signals in an extremely large search space, while controlling for the family-wise error rate. Finally, we have successfully applied FVGWAS to a large-scale imaging genetic data analysis of ADNI data with 708 subjects, 193,275voxels in RAVENS maps, and 501,584 SNPs, and the total processing time was 203,645s for a single CPU. Our FVGWAS may be a valuable statistical toolbox for large-scale imaging genetic analysis as the field is rapidly advancing with ultra-high-resolution imaging and whole-genome sequencing. PMID:26025292

  11. Genome-wide association studies in an isolated founder population from the Pacific Island of Kosrae.

    Directory of Open Access Journals (Sweden)

    Jennifer K Lowe

    2009-02-01

    Full Text Available It has been argued that the limited genetic diversity and reduced allelic heterogeneity observed in isolated founder populations facilitates discovery of loci contributing to both Mendelian and complex disease. A strong founder effect, severe isolation, and substantial inbreeding have dramatically reduced genetic diversity in natives from the island of Kosrae, Federated States of Micronesia, who exhibit a high prevalence of obesity and other metabolic disorders. We hypothesized that genetic drift and possibly natural selection on Kosrae might have increased the frequency of previously rare genetic variants with relatively large effects, making these alleles readily detectable in genome-wide association analysis. However, mapping in large, inbred cohorts introduces analytic challenges, as extensive relatedness between subjects violates the assumptions of independence upon which traditional association test statistics are based. We performed genome-wide association analysis for 15 quantitative traits in 2,906 members of the Kosrae population, using novel approaches to manage the extreme relatedness in the sample. As positive controls, we observe association to known loci for plasma cholesterol, triglycerides, and C-reactive protein and to a compelling candidate loci for thyroid stimulating hormone and fasting plasma glucose. We show that our study is well powered to detect common alleles explaining >/=5% phenotypic variance. However, no such large effects were observed with genome-wide significance, arguing that even in such a severely inbred population, common alleles typically have modest effects. Finally, we show that a majority of common variants discovered in Caucasians have indistinguishable effect sizes on Kosrae, despite the major differences in population genetics and environment.

  12. Kernel Machine SNP-set Analysis for Censored Survival Outcomes in Genome-wide Association Studies

    OpenAIRE

    Lin, Xinyi; Cai, Tianxi; Wu, Michael C.; ZHOU, Qian; Liu, Geoffrey; Christiani, David C.; Lin, Xihong

    2011-01-01

    In this paper, we develop a powerful test for identifying SNP-sets that are predictive of survival with data from genome-wide association studies (GWAS). We first group typed SNPs into SNP-sets based on genomic features and then apply a score test to assess the overall effect of each SNP-set on the survival outcome through a kernel machine Cox regression framework. This approach uses genetic information from all SNPs in the SNP-set simultaneously and accounts for linkage disequilibrium (LD), ...

  13. Genome-wide association study and biological pathway analysis for response to Eimeria maxima in broilers

    DEFF Research Database (Denmark)

    Hamzic, Edin; Buitenhuis, Albert Johannes; Hérault, Frédéric;

    2015-01-01

    costs for development of efficient vaccines, respectively. Therefore, the present control programs must be expanded with complementary approaches such as the use of genetics for improvement of the host’s response to Eimeria infections. Recently, we have performed a large-scale challenge study on Cobb500...... broilers using E. maxima where we investigated variability among animals in response to the challenge. Taking advantage of size and structure of the large-scale challenge study, we performed a genome-wide association study (GWAS) with the aim to identify genomic regions underlying variability of the...

  14. Genome-wide association analysis identifies 13 new risk loci for schizophrenia

    OpenAIRE

    Ripke, Stephan; O'Dushlaine, Colm; Chambert, Kimberly; Moran, Jennifer L; Kähler, Anna K.; Akterin, Susanne; Bergen, Sarah E.; Collins, Ann L.; Crowley, James J.; Fromer, Menachem; Kim, Yunjung; Lee, Sang Hong; Magnusson, Patrik K E; Sanchez, Nick; Stahl, Eli A

    2013-01-01

    Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offsprin...

  15. Genome-wide association analysis identifies 13 new risk loci for schizophrenia.

    OpenAIRE

    Ripke, Stephan; O'Dushlaine, Colm; Chambert, Kimberly; Moran, Jennifer L; Kähler, Anna K.; Akterin, Susanne; Bergen, Sarah E.; Collins, Ann L.; Crowley, James J.; Fromer, Menachem; Kim, Yunjung; Bender, Stephan; Collier, David; Crespo-Facorro, Benedicto; Hall, Jeremy

    2013-01-01

    Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offsprin...

  16. Prediction of disease and phenotype associations from genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Stephanie N Lewis

    Full Text Available BACKGROUND: Genome wide association studies (GWAS have proven useful as a method for identifying genetic variations associated with diseases. In this study, we analyzed GWAS data for 61 diseases and phenotypes to elucidate common associations based on single nucleotide polymorphisms (SNP. The study was an expansion on a previous study on identifying disease associations via data from a single GWAS on seven diseases. METHODOLOGY/PRINCIPAL FINDINGS: Adjustments to the originally reported study included expansion of the SNP dataset using Linkage Disequilibrium (LD and refinement of the four levels of analysis to encompass SNP, SNP block, gene, and pathway level comparisons. A pair-wise comparison between diseases and phenotypes was performed at each level and the Jaccard similarity index was used to measure the degree of association between two diseases/phenotypes. Disease relatedness networks (DRNs were used to visualize our results. We saw predominant relatedness between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis for the first three levels of analysis. Expected relatedness was also seen between lipid- and blood-related traits. CONCLUSIONS/SIGNIFICANCE: The predominant associations between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis can be validated by clinical studies. The diseases have been proposed to share a systemic inflammation phenotype that can result in progression of additional diseases in patients with one of these three diseases. We also noticed unexpected relationships between metabolic and neurological diseases at the pathway comparison level. The less significant relationships found between diseases require a more detailed literature review to determine validity of the predictions. The results from this study serve as a first step towards a better understanding of seemingly unrelated diseases and phenotypes with similar symptoms or modes of treatment.

  17. Genome-Wide Association Study of Behavioral Disinhibition in a Selected Adolescent Sample.

    Science.gov (United States)

    Derringer, Jaime; Corley, Robin P; Haberstick, Brett C; Young, Susan E; Demmitt, Brittany A; Howrigan, Daniel P; Kirkpatrick, Robert M; Iacono, William G; McGue, Matt; Keller, Matthew C; Brown, Sandra; Tapert, Susan; Hopfer, Christian J; Stallings, Michael C; Crowley, Thomas J; Rhee, Soo Hyun; Krauter, Ken; Hewitt, John K; McQueen, Matthew B

    2015-07-01

    Behavioral disinhibition (BD) is a quantitative measure designed to capture the heritable variation encompassing risky and impulsive behaviors. As a result, BD represents an ideal target for discovering genetic loci that predispose individuals to a wide range of antisocial behaviors and substance misuse that together represent a large cost to society as a whole. Published genome-wide association studies (GWAS) have examined specific phenotypes that fall under the umbrella of BD (e.g. alcohol dependence, conduct disorder); however no GWAS has specifically examined the overall BD construct. We conducted a GWAS of BD using a sample of 1,901 adolescents over-selected for characteristics that define high BD, such as substance and antisocial behavior problems, finding no individual locus that surpassed genome-wide significance. Although no single SNP was significantly associated with BD, restricted maximum likelihood analysis estimated that 49.3 % of the variance in BD within the Caucasian sub-sample was accounted for by the genotyped SNPs (p = 0.06). Gene-based tests identified seven genes associated with BD (p ≤ 2.0 × 10(-6)). Although the current study was unable to identify specific SNPs or pathways with replicable effects on BD, the substantial sample variance that could be explained by all genotyped SNPs suggests that larger studies could successfully identify common variants associated with BD. PMID:25637581

  18. Meta-analysis of genome-wide association studies identifies 10 loci influencing allergic sensitization

    Science.gov (United States)

    Granell, Raquel; Strachan, David P; Alves, Alexessander Couto; Linneberg, Allan; Curtin, John A; Warrington, Nicole M; Standl, Marie; Kerkhof, Marjan; Jonsdottir, Ingileif; Bukvic, Blazenka K; Kaakinen, Marika; Sleimann, Patrick; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Schramm, Katharina; Baltic, Svetlana; Kreiner-Møller, Eskil; Simpson, Angela; St Pourcain, Beate; Coin, Lachlan; Hui, Jennie; Walters, Eugene H; Tiesler, Carla M T; Duffy, David L; Jones, Graham; Ring, Susan M; McArdle, Wendy L; Price, Loren; Robertson, Colin F; Pekkanen, Juha; Tang, Clara S; Thiering, Elisabeth; Montgomery, Grant W; Hartikainen, Anna-Liisa; Dharmage, Shyamali C; Husemoen, Lise L; Herder, Christian; Kemp, John P; Elliot, Paul; James, Alan; Waldenberger, Melanie; Abramson, Michael J; Fairfax, Benjamin P; Knight, Julian C; Gupta, Ramneek; Thompson, Philip J; Holt, Patrick; Sly, Peter; Hirschhorn, Joel N; Blekic, Mario; Weidinger, Stephan; Hakonarsson, Hakon; Stefansson, Kari; Heinrich, Joachim; Postma, Dirkje S; Custovic, Adnan; Pennell, Craig E; Jarvelin, Marjo-Riitta; Koppelman, Gerard H; Timpson, Nicholas; Ferreira, Manuel A; Bisgaard, Hans; Henderson, A John

    2016-01-01

    Allergen-specific IgE (allergic sensitization) plays a central role in the pathogenesis of allergic disease. We performed the first large-scale genome wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP from 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association to allergic sensitization from three to 10, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top-SNPs were associated with allergic symptoms in an independent study. Risk variants at these 10 loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide novel insight into the etiology of allergic disease. PMID:23817571

  19. Genome-wide investigation of schizophrenia associated plasma Ndel1 enzyme activity.

    Science.gov (United States)

    Gadelha, Ary; Coleman, Jonathan; Breen, Gerome; Mazzoti, Diego Robles; Yonamine, Camila M; Pellegrino, Renata; Ota, Vanessa Kiyomi; Belangero, Sintia Iole; Glessner, Joseph; Sleiman, Patrick; Hakonarson, Hakon; Hayashi, Mirian A F; Bressan, Rodrigo A

    2016-04-01

    Ndel1 is a DISC1-interacting oligopeptidase that cleaves in vitro neuropeptides as neurotensin and bradykinin, and which has been associated with both neuronal migration and neurite outgrowth. We previously reported that plasma Ndel1 enzyme activity is lower in patients with schizophrenia (SCZ) compared to healthy controls (HCs). To our knowledge, no previous study has investigated the genetic factors associated with the plasma Ndel1 enzyme activity. In the current analyses, samples from 83 SCZ patients and 92 control subjects that were assayed for plasma Ndel1 enzyme activity were genotyped on Illumina Omni Express arrays. A genetic relationship matrix using genome-wide information was then used for ancestry correction, and association statistics were calculated genome-wide. Ndel1 enzyme activity was significantly lower in patients with SCZ (t=4.9; p<0.001) and was found to be associated with CAMK1D, MAGI2, CCDC25, and GABGR3, at a level of suggestive significance (p<10(-6)), independent of the clinical status. Then, we performed a model to investigate the observed differences for case/control measures. 2 SNPs at region 1p22.2 reached the p<10(-7) level. ZFPM2 and MAD1L1 were the only two genes with more than one hit at 10(-6) order of p value. Therefore, Ndel1 enzyme activity is a complex trait influenced by many different genetic variants that may contribute to SCZ physiopathology. PMID:26851141

  20. 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

  1. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region.

    OpenAIRE

    CORVIN, AIDEN PETER

    2009-01-01

    PUBLISHED Ulcerative colitis (UC) is a common form of inflammatory bowel disease with a complex aetiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome- wide association scan for UC in 2361 cases and 5417 controls. Loci showing evidence of association at P < 1 ? 10 ?5 were followed up by genotyping in an independent set of 2321 cases and 4818 controls. We find genome-wide significant evidence of association at three new loci, each cont...

  2. Genome-wide association study on antipsychotic-induced weight gain in the CATIE sample.

    Science.gov (United States)

    Brandl, E J; Tiwari, A K; Zai, C C; Nurmi, E L; Chowdhury, N I; Arenovich, T; Sanches, M; Goncalves, V F; Shen, J J; Lieberman, J A; Meltzer, H Y; Kennedy, J L; Müller, D J

    2016-08-01

    Antipsychotic-induced weight gain (AIWG) is a common side effect with a high genetic contribution. We reanalyzed genome-wide association study (GWAS) data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) selecting a refined subset of patients most suitable for AIWG studies. The final GWAS was conducted in N=189 individuals. The top polymorphisms were analyzed in a second cohort of N=86 patients. None of the single-nucleotide polymorphisms was significant at the genome-wide threshold of 5x10(-8). We observed interesting trends for rs9346455 (P=6.49x10(-6)) upstream of OGFRL1, the intergenic variants rs7336345 (P=1.31 × 10(-5)) and rs1012650 (P=1.47 × 10(-5)), and rs1059778 (P=1.49x10(-5)) in IBA57. In the second cohort, rs9346455 showed significant association with AIWG (P=0.005). The combined meta-analysis P-value for rs9346455 was 1.09 × 10(-7). Our reanalysis of the CATIE GWAS data revealed interesting new variants associated with AIWG. As the functional relevance of these polymorphisms is yet to be determined, further studies are needed.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.59. PMID:26323598

  3. Genome-wide association scan suggests basis for microtia in Awassi sheep.

    Science.gov (United States)

    Jawasreh, K; Boettcher, P J; Stella, A

    2016-08-01

    Hereditary underdevelopment of the ear, a condition also known as microtia, has been observed in several sheep breeds as well as in humans and other species. Its genetic basis in sheep is unknown. The Awassi sheep, a breed native to southwest Asia, carries this phenotype and was targeted for molecular characterization via a genome-wide association study. DNA samples were collected from sheep in Jordan. Eight affected and 12 normal individuals were genotyped with the Illumina OvineSNP50(®) chip. Multilocus analyses failed to identify any genotypic association. In contrast, a single-locus analysis revealed a statistically significant association (P = 0.012, genome-wide) with a SNP at basepair 34 647 499 on OAR23. This marker is adjacent to the gene encoding transcription factor GATA-6, which has been shown to play a role in many developmental processes, including chondrogenesis. The lack of extended homozygosity in this region suggests a fairly ancient mutation, and the time of occurrence was estimated to be approximately 3000 years ago. Many of the earless sheep breeds may thus share the causative mutation, especially within the subgroup of fat-tailed, wool sheep. PMID:26990958

  4. Genome-wide association studies in preterm birth: implications for the practicing obstetrician-gynaecologist

    Directory of Open Access Journals (Sweden)

    Dolan Siobhan M

    2013-01-01

    Full Text Available Abstract Preterm birth has the highest mortality and morbidity of all pregnancy complications. The burden of preterm birth on public health worldwide is enormous, yet there are few effective means to prevent a preterm delivery. To date, much of its etiology is unexplained, but genetic predisposition is thought to play a major role. In the upcoming year, the international Preterm Birth Genome Project (PGP consortium plans to publish a large genome wide association study in early preterm birth. Genome-wide association studies (GWAS are designed to identify common genetic variants that influence health and disease. Despite the many challenges that are involved, GWAS can be an important discovery tool, revealing genetic variations that are associated with preterm birth. It is highly unlikely that findings of a GWAS can be directly translated into clinical practice in the short run. Nonetheless, it will help us to better understand the etiology of preterm birth and the GWAS results will generate new hypotheses for further research, thus enhancing our understanding of preterm birth and informing prevention efforts in the long run.

  5. phenosim - A software to simulate phenotypes for testing in genome-wide association studies

    Directory of Open Access Journals (Sweden)

    Gawenda Inka

    2011-06-01

    Full Text Available Abstract Background There is a great interest in understanding the genetic architecture of complex traits in natural populations. Genome-wide association studies (GWAS are becoming routine in human, animal and plant genetics to understand the connection between naturally occurring genotypic and phenotypic variation. Coalescent simulations are commonly used in population genetics to simulate genotypes under different parameters and demographic models. Results Here, we present phenosim, a software to add a phenotype to genotypes generated in time-efficient coalescent simulations. Both qualitative and quantitative phenotypes can be generated and it is possible to partition phenotypic variation between additive effects and epistatic interactions between causal variants. The output formats of phenosim are directly usable as input for different GWAS tools. The applicability of phenosim is shown by simulating a genome-wide association study in Arabidopsis thaliana. Conclusions By using the coalescent approach to generate genotypes and phenosim to add phenotypes, the data sets can be used to assess the influence of various factors such as demography, genetic architecture or selection on the statistical power of association methods to detect causal genetic variants under a wide variety of population genetic scenarios. phenosim is freely available from the authors' website http://evoplant.uni-hohenheim.de

  6. On the genetics of sleep disorders: genome-wide association studies and beyond

    Directory of Open Access Journals (Sweden)

    Parsons MJ

    2015-08-01

    Full Text Available Michael J ParsonsMammalian Genetics Unit, MRC Harwell, Harwell, Oxfordshire, UKAbstract: Sleep is an essential behavior, yet much of its underlying functions are still unknown. The disruption of sleep can led to a variety of health consequences. Family and twin studies have together shown that genetic factors underlie variation in sleep characteristics and sleep disorders. Given the importance of sleep to our well-being, understanding its underlying genetic factors is essential to both the prevention and treatment of these disorders. Recently, genome-wide association studies (GWAS have helped to provide evidence of associations of both known and novel genetic variants with sleep disorders. This review outlines the findings from GWAS for a number of sleep disorders, including insomnia, restless leg syndrome, obstructive sleep apnea, and narcolepsy, and discusses these findings in the context of supporting evidence from independent methodologies. Finally, the limitations of GWAS approaches are outlined, along with the future directions of the genetics of sleep in the post-GWAS era.Keywords: genome-wide association studies, sleep, sleep disorder, insomnia, restless leg syndrome, obstructive sleep apnea, narcolepsy

  7. phenosim - A software to simulate phenotypes for testing in genome-wide association studies

    Science.gov (United States)

    2011-01-01

    Background There is a great interest in understanding the genetic architecture of complex traits in natural populations. Genome-wide association studies (GWAS) are becoming routine in human, animal and plant genetics to understand the connection between naturally occurring genotypic and phenotypic variation. Coalescent simulations are commonly used in population genetics to simulate genotypes under different parameters and demographic models. Results Here, we present phenosim, a software to add a phenotype to genotypes generated in time-efficient coalescent simulations. Both qualitative and quantitative phenotypes can be generated and it is possible to partition phenotypic variation between additive effects and epistatic interactions between causal variants. The output formats of phenosim are directly usable as input for different GWAS tools. The applicability of phenosim is shown by simulating a genome-wide association study in Arabidopsis thaliana. Conclusions By using the coalescent approach to generate genotypes and phenosim to add phenotypes, the data sets can be used to assess the influence of various factors such as demography, genetic architecture or selection on the statistical power of association methods to detect causal genetic variants under a wide variety of population genetic scenarios. phenosim is freely available from the authors' website http://evoplant.uni-hohenheim.de PMID:21714868

  8. Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women

    DEFF Research Database (Denmark)

    Fox, Caroline S; Liu, Yongmei; White, Charles C;

    2012-01-01

    Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants...... of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous...... previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large...

  9. A Review of Genome-Wide Association Studies of Stimulant and Opioid Use Disorders.

    Science.gov (United States)

    Jensen, Kevin P

    2016-05-01

    Substance use disorders (SUD) are a major contributor to disability and disease burden worldwide. Risk for developing SUDs is influenced by variation in the genome. Identifying the genetic variants that influence SUD risk may help us to understand the biological mechanisms for the disorders and improve treatments. Genome-wide association studies (GWAS) have been successful in identifying many regions of the genome associated with common human disorders. Here, findings from recent GWAS of SUDs that involve illicit substances will be reviewed. Several GWAS have been reported, including studies on opioid and stimulant use disorder (cocaine and methamphetamine). Several of these GWAS report associations that are biologically interesting and statistically robust. Replication of the associations in independent samples and functional studies to understand the basis for the statistical associations will be important next steps. PMID:27606319

  10. Comparative analysis of genome-wide divergence, domestication footprints and genome-wide association study of root traits for Gossypium hirsutum and Gossypium barbadense

    Science.gov (United States)

    Use of 10,129 singleton SNPs of known genomic location in tetraploid cotton provided unique opportunities to characterize genome-wide diversity among 440 Gossypium hirsutum and 219 G. barbadense cultivars and landrace accessions of widespread origin. Using genome-wide distributed SNPs, we examined ...

  11. Genome-wide Association Study of Biochemical Traits in Korčula Island, Croatia

    Science.gov (United States)

    Zemunik, Tatijana; Boban, Mladen; Lauc, Gordan; Janković, Stipan; Rotim, Krešimir; Vatavuk, Zoran; Benčić, Goran; Đogaš, Zoran; Boraska, Vesna; Torlak, Vesela; Sušac, Jelena; Zobić, Ivana; Rudan, Diana; Pulanić, Dražen; Modun, Darko; Mudnić, Ivana; Gunjača, Grgo; Budimir, Danijela; Hayward, Caroline; Vitart, Veronique; Wright, Alan F.; Campbell, Harry; Rudan, Igor

    2009-01-01

    Aim To identify genetic variants underlying biochemical traits – total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, uric acid, albumin, and fibrinogen, in a genome-wide association study in an isolated population where rare variants of larger effect may be more easily identified. Methods The study included 944 adult inhabitants of the island of Korčula, as a part of a larger DNA-based genetic epidemiological study in 2007. Biochemical measurements were performed in a single laboratory with stringent internal and external quality control procedures. Examinees were genotyped using Human Hap370CNV chip by Illumina, with a genome-wide scan containing 346 027 single nucleotide polymorphisms (SNP). Results A total of 31 SNPs were associated with 7 investigated traits at the level of P < 1.00 × 10−5. Nine of SNPs implicated the role of SLC2A9 in uric acid regulation (P = 4.10 × 10−6-2.58 × 10−12), as previously found in other populations. All 22 remaining associations fell into the P = 1.00 × 10−5-1.00 × 10−6 significance range. One of them replicated the association between cholesteryl ester transfer protein (CETP) and HDL, and 7 associations were more than 100 kilobases away from the closest known gene. Nearby SNPs, rs4767631 and rs10444502, in gene kinase suppressor of ras 2 (KSR2) on chromosome 12 were associated with LDL cholesterol levels, and rs10444502 in the same gene with total cholesterol levels. Similarly, rs2839619 in gene PBX/knotted 1 homeobox 1 (PKNOX1) on chromosome 21 was associated with total and LDL cholesterol levels. The remaining 9 findings implied possible associations between phosphatidylethanolamine N-methyltransferase (PEMT) gene and total cholesterol; USP46, RAP1GDS1, and ZCCHC16 genes and triglycerides; BCAT1 and SLC14A2 genes and albumin; and NR3C2, GRIK2, and PCSK2 genes and fibrinogen. Conclusion Although this study was

  12. Neuregulin-1 and schizophrenia in the genome-wide association study era.

    Science.gov (United States)

    Mostaid, Md Shaki; Lloyd, David; Liberg, Benny; Sundram, Suresh; Pereira, Avril; Pantelis, Christos; Karl, Tim; Weickert, Cynthia Shannon; Everall, Ian P; Bousman, Chad A

    2016-09-01

    Clinical and pre-clinical evidence has implicated neuregulin 1 (NRG1) as a critical component in the pathophysiology of schizophrenia. However, the arrival of the genome-wide association study (GWAS) era has yielded results that challenge the relevance of NRG1 in schizophrenia due to the absence of a genome-wide significant NRG1 variant associated with schizophrenia. To assess NRG1's relevance to schizophrenia in the GWAS era, we provide a targeted review of recent preclinical evidence on NRG1's role in regulating several aspects of excitatory/inhibitory neurotransmission and in turn schizophrenia risk. We also present a systematic review of the last decade of clinical research examining NRG1 in the context of schizophrenia. We include concise summaries of genotypic variation, gene-expression, protein expression, structural and functional neuroimaging as well as cognitive studies conducted during this time period. We conclude with recommendations for future clinical and preclinical work that we hope will help prioritize a strategy forward to further advance our understanding of the relationship between NRG1 and schizophrenia. PMID:27283360

  13. Case-Control Genome-Wide Association of Attention-Deficit / Hyperactivity Disorder

    Science.gov (United States)

    Neale, Benjamin M.; Medland, Sarah; Ripke, Stephan; Anney, Richard J.L.; Asherson, Philip; Buitelaar, Jan; Franke, Barbara; Gill, Michael; Kent, Lindsey; Holmans, Peter; Middleton, Frank; Thapar, Anita; Lesch, Klaus-Peter; Faraone, Stephen V.; Daly, Mark; Nguyen, Thuy Trang; Schäfer, Helmut; Steinhausen, Hans-Christoph; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Warnke, Andreas; Walitza, Susanne; Freitag, Christine; Meyer, Jobst; Palmason, Haukur; Rothenberger, Aribert; Hawi, Ziarih; Sergeant, Joseph; Roeyers, Herbert; Biederman, Joseph

    2010-01-01

    Objective Although twin and family studies have shown attention deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus, additional genomewide association studies (GWAS) are needed. Method We used case-control analyses of 896 cases with DSM-IV ADHD genotyped using the Affymetrix 5.0 array and 2,455 repository controls screened for psychotic and bipolar symptoms genotyped using Affymetrix 6.0 arrays. A consensus SNP set was imputed using BEAGLE 3.0, resulting in an analysis dataset of 1,033,244 SNPs. The data were analyzed using a generalized linear model. Results No genome-wide significant associations were found. The most significant results implicated the following genes: PRKG1, FLNC, TCERG1L, PPM1H, NXPH1, PPM1H, CDH13, HK1 and HKDC1. Conclusions The current analyses are a useful addition to the present literature and will make a valuable contribution to future meta-analyses. The candidate gene findings are consistent with a prior meta-analysis in suggesting that the effects of ADHD risk variants must, individually, be very small and/or include multiple rare alleles. PMID:20732627

  14. Genome-wide association studies for fatty acid metabolic traits in five divergent pig populations

    Science.gov (United States)

    Zhang, Wanchang; Bin Yang; Zhang, Junjie; Cui, Leilei; Ma, Junwu; Chen, Congying; Ai, Huashui; Xiao, Shijun; Ren, Jun; Huang, Lusheng

    2016-01-01

    Fatty acid composition profiles are important indicators of meat quality and tasting flavor. Metabolic indices of fatty acids are more authentic to reflect meat nutrition and public acceptance. To investigate the genetic mechanism of fatty acid metabolic indices in pork, we conducted genome-wide association studies (GWAS) for 33 fatty acid metabolic traits in five pig populations. We identified a total of 865 single nucleotide polymorphisms (SNPs), corresponding to 11 genome-wide significant loci on nine chromosomes and 12 suggestive loci on nine chromosomes. Our findings not only confirmed seven previously reported QTL with stronger association strength, but also revealed four novel population-specific loci, showing that investigations on intermediate phenotypes like the metabolic traits of fatty acids can increase the statistical power of GWAS for end-point phenotypes. We proposed a list of candidate genes at the identified loci, including three novel genes (FADS2, SREBF1 and PLA2G7). Further, we constructed the functional networks involving these candidate genes and deduced the potential fatty acid metabolic pathway. These findings advance our understanding of the genetic basis of fatty acid composition in pigs. The results from European hybrid commercial pigs can be immediately transited into breeding practice for beneficial fatty acid composition. PMID:27097669

  15. Genome-wide association of lipid-lowering response to statins in combined study populations.

    Directory of Open Access Journals (Sweden)

    Mathew J Barber

    Full Text Available BACKGROUND: Statins effectively lower total and plasma LDL-cholesterol, but the magnitude of decrease varies among individuals. To identify single nucleotide polymorphisms (SNPs contributing to this variation, we performed a combined analysis of genome-wide association (GWA results from three trials of statin efficacy. METHODS AND PRINCIPAL FINDINGS: Bayesian and standard frequentist association analyses were performed on untreated and statin-mediated changes in LDL-cholesterol, total cholesterol, HDL-cholesterol, and triglyceride on a total of 3932 subjects using data from three studies: Cholesterol and Pharmacogenetics (40 mg/day simvastatin, 6 weeks, Pravastatin/Inflammation CRP Evaluation (40 mg/day pravastatin, 24 weeks, and Treating to New Targets (10 mg/day atorvastatin, 8 weeks. Genotype imputation was used to maximize genomic coverage and to combine information across studies. Phenotypes were normalized within each study to account for systematic differences among studies, and fixed-effects combined analysis of the combined sample were performed to detect consistent effects across studies. Two SNP associations were assessed as having posterior probability greater than 50%, indicating that they were more likely than not to be genuinely associated with statin-mediated lipid response. SNP rs8014194, located within the CLMN gene on chromosome 14, was strongly associated with statin-mediated change in total cholesterol with an 84% probability by Bayesian analysis, and a p-value exceeding conventional levels of genome-wide significance by frequentist analysis (P = 1.8 x 10(-8. This SNP was less significantly associated with change in LDL-cholesterol (posterior probability = 0.16, P = 4.0 x 10(-6. Bayesian analysis also assigned a 51% probability that rs4420638, located in APOC1 and near APOE, was associated with change in LDL-cholesterol. CONCLUSIONS AND SIGNIFICANCE: Using combined GWA analysis from three clinical trials involving nearly 4

  16. An Integrated Genome-Wide Systems Genetics Screen for Breast Cancer Metastasis Susceptibility Genes.

    Science.gov (United States)

    Bai, Ling; Yang, Howard H; Hu, Ying; Shukla, Anjali; Ha, Ngoc-Han; Doran, Anthony; Faraji, Farhoud; Goldberger, Natalie; Lee, Maxwell P; Keane, Thomas; Hunter, Kent W

    2016-04-01

    Metastasis remains the primary cause of patient morbidity and mortality in solid tumors and is due to the action of a large number of tumor-autonomous and non-autonomous factors. Here we report the results of a genome-wide integrated strategy to identify novel metastasis susceptibility candidate genes and molecular pathways in breast cancer metastasis. This analysis implicates a number of transcriptional regulators and suggests cell-mediated immunity is an important determinant. Moreover, the analysis identified novel or FDA-approved drugs as potentially useful for anti-metastatic therapy. Further explorations implementing this strategy may therefore provide a variety of information for clinical applications in the control and treatment of advanced neoplastic disease. PMID:27074153

  17. Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization

    DEFF Research Database (Denmark)

    Bønnelykke, Klaus; Matheson, Melanie C; Pers, Tune Hannes;

    2013-01-01

    top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2...... and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may...

  18. Genome-wide association study identified a narrow chromosome 1 region associated with chicken growth traits.

    Directory of Open Access Journals (Sweden)

    Liang Xie

    Full Text Available Chicken growth traits are important economic traits in broilers. A large number of studies are available on finding genetic factors affecting chicken growth. However, most of these studies identified chromosome regions containing putative quantitative trait loci and finding causal mutations is still a challenge. In this genome-wide association study (GWAS, we identified a narrow 1.5 Mb region (173.5-175 Mb of chicken (Gallus gallus chromosome (GGA 1 to be strongly associated with chicken growth using 47,678 SNPs and 489 F2 chickens. The growth traits included aggregate body weight (BW at 0-90 d of age measured weekly, biweekly average daily gains (ADG derived from weekly body weight, and breast muscle weight (BMW, leg muscle weight (LMW and wing weight (WW at 90 d of age. Five SNPs in the 1.5 Mb KPNA3-FOXO1A region at GGA1 had the highest significant effects for all growth traits in this study, including a SNP at 8.9 Kb upstream of FOXO1A for BW at 22-48 d and 70 d, a SNP at 1.9 Kb downstream of FOXO1A for WW, a SNP at 20.9 Kb downstream of ENSGALG00000022732 for ADG at 29-42 d, a SNP in INTS6 for BW at 90 d, and a SNP in KPNA3 for BMW and LMW. The 1.5 Mb KPNA3-FOXO1A region contained two microRNA genes that could bind to messenger ribonucleic acid (mRNA of IGF1, FOXO1A and KPNA3. It was further indicated that the 1.5 Mb GGA1 region had the strongest effects on chicken growth during 22-42 d.

  19. Genome Wide Association Identifies PPFIA1 as a Candidate Gene for Acute Lung Injury Risk Following Major Trauma

    OpenAIRE

    Christie, Jason D.; Wurfel, Mark M.; Feng, Rui; O'Keefe, Grant E; Bradfield, Jonathan; Ware, Lorraine B.; Calfee, Carolyn S.; Matthay, Michael; Meyer, Nuala J.; Kim, Cecilia; Li, Mingyao; Akey, Joshua; Barnes, Kathleen C.; Sevransky, Jonathan; Lanken, Paul N

    2012-01-01

    Acute Lung Injury (ALI) is a syndrome with high associated mortality characterized by severe hypoxemia and pulmonary infiltrates in patients with critical illness. We conducted the first investigation to use the genome wide association (GWA) approach to identify putative risk variants for ALI. Genome wide genotyping was performed using the Illumina Human Quad 610 BeadChip. We performed a two-stage GWA study followed by a third stage of functional characterization. In the discovery phase (Phas...

  20. Genome-wide association analyses of child genotype effects and parent-of-origin effects in specific language impairment

    OpenAIRE

    Nudel, R; Simpson, N.; Baird, G; O’Hare, A; Conti-Ramsden, G; Bolton, P.; Hennessy, E.; The SLli consortium,; Ring, S; G. Smith; Francks, C.; Paracchini, S.; Monaco, A.; Fisher, S.; Newbury, D.

    2014-01-01

    Specific language impairment (SLI) is a neurodevelopmental disorder that affects linguistic abilities when development is otherwise normal. We report the results of a genome-wide association study of SLI which included parent-of-origin effects and child genotype effects and used 278 families of language-impaired children. The child genotype effects analysis did not identify significant associations. We found genome-wide significant paternal parent-of-origin effects on chromosome 14q12 (P = 3....

  1. Genome-wide association study of retinopathy in individuals without diabetes.

    Directory of Open Access Journals (Sweden)

    Richard A Jensen

    Full Text Available BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS of mild retinopathy in persons without diabetes. METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9 on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error, p = 6.6×10(-9. Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%, the quality of the imputation was moderate (r(2 ∼0.7, and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

  2. A genome-wide association study of serum uric acid in African Americans

    Directory of Open Access Journals (Sweden)

    Gerry Norman P

    2011-02-01

    Full Text Available Abstract Background Uric acid is the primary byproduct of purine metabolism. Hyperuricemia is associated with body mass index (BMI, sex, and multiple complex diseases including gout, hypertension (HTN, renal disease, and type 2 diabetes (T2D. Multiple genome-wide association studies (GWAS in individuals of European ancestry (EA have reported associations between serum uric acid levels (SUAL and specific genomic loci. The purposes of this study were: 1 to replicate major signals reported in EA populations; and 2 to use the weak LD pattern in African ancestry population to better localize (fine-map reported loci and 3 to explore the identification of novel findings cognizant of the moderate sample size. Methods African American (AA participants (n = 1,017 from the Howard University Family Study were included in this study. Genotyping was performed using the Affymetrix® Genome-wide Human SNP Array 6.0. Imputation was performed using MACH and the HapMap reference panels for CEU and YRI. A total of 2,400,542 single nucleotide polymorphisms (SNPs were assessed for association with serum uric acid under the additive genetic model with adjustment for age, sex, BMI, glomerular filtration rate, HTN, T2D, and the top two principal components identified in the assessment of admixture and population stratification. Results Four variants in the gene SLC2A9 achieved genome-wide significance for association with SUAL (p-values ranging from 8.88 × 10-9 to 1.38 × 10-9. Fine-mapping of the SLC2A9 signals identified a 263 kb interval of linkage disequilibrium in the HapMap CEU sample. This interval was reduced to 37 kb in our AA and the HapMap YRI samples. Conclusions The most strongly associated locus for SUAL in EA populations was also the most strongly associated locus in this AA sample. This finding provides evidence for the role of SLC2A9 in uric acid metabolism across human populations. Additionally, our findings demonstrate the utility of following-up EA

  3. A genome-wide association search for type 2 diabetes genes in African Americans.

    Directory of Open Access Journals (Sweden)

    Nicholette D Palmer

    Full Text Available African Americans are disproportionately affected by type 2 diabetes (T2DM yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD and 1029 population-based controls. The most significant SNPs (n = 550 independent loci were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071, were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05. Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8. SNP rs7560163 (P = 7.0×10(-9, OR (95% CI = 0.75 (0.67-0.84 is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217 were associated with T2DM (P<0.05 and reached more nominal levels of significance (P<2.5×10(-5 in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.

  4. The role of height-associated loci identified in genome wide association studies in the determination of pediatric stature

    Directory of Open Access Journals (Sweden)

    Frackelton Edward C

    2010-06-01

    Full Text Available Abstract Background Human height is considered highly heritable and correlated with certain disorders, such as type 2 diabetes and cancer. Despite environmental influences, genetic factors are known to play an important role in stature determination. A number of genetic determinants of adult height have already been established through genome wide association studies. Methods To examine 51 single nucleotide polymorphisms (SNPs corresponding to the 46 previously reported genomic loci for height in 8,184 European American children with height measurements. We leveraged genotyping data from our ongoing GWA study of height variation in children in order to query the 51 SNPs in this pediatric cohort. Results Sixteen of these SNPs yielded at least nominally significant association to height, representing fifteen different loci including EFEMP1-PNPT1, GPR126, C6orf173, SPAG17, Histone class 1, HLA class III and GDF5-UQCC. Other loci revealed no evidence for association, including HMGA1 and HMGA2. For the 16 associated variants, the genotype score explained 1.64% of the total variation for height z-score. Conclusion Among 46 loci that have been reported to associate with adult height to date, at least 15 also contribute to the determination of height in childhood.

  5. A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice.

    Science.gov (United States)

    McIntyre, Rebecca E; Nicod, Jérôme; Robles-Espinoza, Carla Daniela; Maciejowski, John; Cai, Na; Hill, Jennifer; Verstraten, Ruth; Iyer, Vivek; Rust, Alistair G; Balmus, Gabriel; Mott, Richard; Flint, Jonathan; Adams, David J

    2016-01-01

    In mammals the regulation of genomic instability plays a key role in tumor suppression and also controls genome plasticity, which is important for recombination during the processes of immunity and meiosis. Most studies to identify regulators of genomic instability have been performed in cells in culture or in systems that report on gross rearrangements of the genome, yet subtle differences in the level of genomic instability can contribute to whole organism phenotypes such as tumor predisposition. Here we performed a genome-wide association study in a population of 1379 outbred Crl:CFW(SW)-US_P08 mice to dissect the genetic landscape of micronucleus formation, a biomarker of chromosomal breaks, whole chromosome loss, and extranuclear DNA. Variation in micronucleus levels is a complex trait with a genome-wide heritability of 53.1%. We identify seven loci influencing micronucleus formation (false discovery rate locus. Intriguingly at several loci we find evidence for sexual dimorphism in micronucleus formation, with a locus on chromosome 11 being specific to males. PMID:27233670

  6. Brain expression genome-wide association study (eGWAS identifies human disease-associated variants.

    Directory of Open Access Journals (Sweden)

    Fanggeng Zou

    Full Text Available Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202 and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197. We conducted an expression genome-wide association study (eGWAS using 213,528 cisSNPs within ± 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs significant in both ADs and non-ADs (q<0.05, p=7.70 × 10(-5-1.67 × 10(-82. Of these, 2,089 were also significant in the temporal cortex (p=1.85 × 10(-5-1.70 × 10(-141. The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6. We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6 of significant cisSNPs with suggestive AD-risk association (p<10(-3 in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings

  7. Genome-wide association of implantable cardioverter-defibrillator activation with life-threatening arrhythmias.

    Directory of Open Access Journals (Sweden)

    Sarah S Murray

    Full Text Available OBJECTIVES: To identify genetic factors that would be predictive of individuals who require an implantable cardioverter-defibrillator (ICD, we conducted a genome-wide association study among individuals with an ICD who experienced a life-threatening arrhythmia (LTA; cases vs. those who did not over at least a 3-year period (controls. BACKGROUND: Most individuals that receive implantable cardioverter-defibrillators never experience a life-threatening arrhythmia. Genetic factors may help identify who is most at risk. METHODS: Patients with an ICD and extended follow-up were recruited from 34 clinical sites with the goal of oversampling those who had experienced LTA, with a cumulative 607 cases and 297 controls included in the analysis. A total of 1,006 Caucasian patients were enrolled during a time period of 13 months. Arrhythmia status of 904 patients could be confirmed and their genomic data were included in the analysis. In this cohort, there were 704 males, 200 females, and the average age was 73.3 years. We genotyped DNA samples using the Illumina Human660 W Genotyping BeadChip and tested for association between genotype at common variants and the phenotype of having an LTA. RESULTS AND CONCLUSIONS: We did not find any associations reaching genome-wide significance, with the strongest association at chromosome 13, rs11856574 at P = 5×10⁻⁶. Loci previously implicated in phenotypes such as QT interval (measure of the time between the start of the Q wave and the end of the T wave as measured by electrocardiogram were not found to be significantly associated with having an LTA. Although powered to detect such associations, we did not find common genetic variants of large effect associated with having a LTA in those of European descent. This indicates that common gene variants cannot be used at this time to guide ICD risk-stratification. TRIAL REGISTRATION: ClinicalTrials.gov NCT00664807.

  8. Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

    Science.gov (United States)

    Mattheisen, M; Samuels, J F; Wang, Y; Greenberg, B D; Fyer, A J; McCracken, J T; Geller, D A; Murphy, D L; Knowles, J A; Grados, M A; Riddle, M A; Rasmussen, S A; McLaughlin, N C; Nurmi, E L; Askland, K D; Qin, H-D; Cullen, B A; Piacentini, J; Pauls, D L; Bienvenu, O J; Stewart, S E; Liang, K-Y; Goes, F S; Maher, B; Pulver, A E; Shugart, Y Y; Valle, D; Lange, C; Nestadt, G

    2015-03-01

    Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples. PMID:24821223

  9. A genome-wide association study reveals variants in ARL15 that influence adiponectin levels.

    Directory of Open Access Journals (Sweden)

    J Brent Richards

    2009-12-01

    Full Text Available The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D and coronary heart disease (CHD. We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531 and sought validation of the lead single nucleotide polymorphisms (SNPs in 5 additional cohorts (n = 6,202. Five SNPs were genome-wide significant in their relationship with adiponectin (P< or =5x10(-8. We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P< or =0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2x10(-19 for lead SNP, rs266717, n = 14,733. A novel variant in the ARL15 (ADP-ribosylation factor-like 15 gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9x10(-8, n = 14,733. This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5x10(-6, n = 22,421 more nominally, an increased risk of T2D (OR = 1.11, P = 3.2x10(-3, n = 10,128, and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.

  10. SYSTEMS BIOLOGY ANALYSES OF GENE EXPRESSION AND GENOME WIDE ASSOCIATION STUDY DATA IN OBSTRUCTIVE SLEEP APNEA

    Science.gov (United States)

    LIU, YU; PATEL, SANJAY; NIBBE, ROD; MAXWELL, SEAN; CHOWDHURY, SALIM A.; KOYUTURK, MEHMET; ZHU, XIAOFENG; LARKIN, EMMA K.; BUXBAUM, SARAH G; PUNJABI, NARESH M.; GHARIB, SINA A.; REDLINE, SUSAN; CHANCE, MARK R.

    2015-01-01

    The precise molecular etiology of obstructive sleep apnea (OSA) is unknown; however recent research indicates that several interconnected aberrant pathways and molecular abnormalities are contributors to OSA. Identifying the genes and pathways associated with OSA can help to expand our understanding of the risk factors for the disease as well as provide new avenues for potential treatment. Towards these goals, we have integrated relevant high dimensional data from various sources, such as genome-wide expression data (microarray), protein-protein interaction (PPI) data and results from genome-wide association studies (GWAS) in order to define sub-network elements that connect some of the known pathways related to the disease as well as define novel regulatory modules related to OSA. Two distinct approaches are applied to identify sub-networks significantly associated with OSA. In the first case we used a biased approach based on sixty genes/proteins with known associations with sleep disorders and/or metabolic disease to seed a search using commercial software to discover networks associated with disease followed by information theoretic (mutual information) scoring of the sub-networks. In the second case we used an unbiased approach and generated an interactome constructed from publicly available gene expression profiles and PPI databases, followed by scoring of the network with p-values from GWAS data derived from OSA patients to uncover sub-networks significant for the disease phenotype. A comparison of the approaches reveals a number of proteins that have been previously known to be associated with OSA or sleep. In addition, our results indicate a novel association of Phosphoinositide 3-kinase, the STAT family of proteins and its related pathways with OSA. PMID:21121029

  11. An enhanced version of Cochran-Armitage trend test for genome-wide association studies.

    Science.gov (United States)

    Ghodsi, Mansi; Amiri, Saeid; Hassani, Hossein; Ghodsi, Zara

    2016-09-01

    Genome-wide association studies the evaluation of association between candidate gene and disease status is widely carried out using Cochran-Armitage trend test. However, only a small number of research papers have evaluated the distribution of p-values for the Cochran-Armitage trend test. In this paper, an enhanced version of Cochran-Armitage trend test based on bootstrap approach is introduced. The achieved results confirm that the distribution of p-values of the proposed approach fits better to the uniform distribution, and it is thus concluded that the proposed method, which needs less assumptions in comparison with the conventional method, can be successfully used to test the genetic association. PMID:27617223

  12. Lessons and Implications from Genome-Wide Association Studies (GWAS Findings of Blood Cell Phenotypes

    Directory of Open Access Journals (Sweden)

    Nathalie Chami

    2014-01-01

    Full Text Available Genome-wide association studies (GWAS have identified reproducible genetic associations with hundreds of human diseases and traits. The vast majority of these associated single nucleotide polymorphisms (SNPs are non-coding, highlighting the challenge in moving from genetic findings to mechanistic and functional insights. Nevertheless, large-scale (epigenomic studies and bioinformatic analyses strongly suggest that GWAS hits are not randomly distributed in the genome but rather pinpoint specific biological pathways important for disease development or phenotypic variation. In this review, we focus on GWAS discoveries for the three main blood cell types: red blood cells, white blood cells and platelets. We summarize the knowledge gained from GWAS of these phenotypes and discuss their possible clinical implications for common (e.g., anemia and rare (e.g., myeloproliferative neoplasms human blood-related diseases. Finally, we argue that blood phenotypes are ideal to study the genetics of complex human traits because they are fully amenable to experimental testing.

  13. Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease

    Science.gov (United States)

    Kahali, Bratati; Halligan, Brian; Speliotes, Elizabeth K.

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future. PMID:26676813

  14. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy

    DEFF Research Database (Denmark)

    Hor, Hyun; Kutalik, Zoltán; Dauvilliers, Yves; Valsesia, Armand; Lammers, Gert J; Donjacour, Claire E H M; Iranzo, Alex; Santamaria, Joan; Peraita Adrados, Rosa; Vicario, José L; Overeem, Sebastiaan; Arnulf, Isabelle; Theodorou, Ioannis; Jennum, Poul; Knudsen, Stine; Bassetti, Claudio; Mathis, Johannes; Lecendreux, Michel; Mayer, Geert; Geisler, Peter; Benetó, Antonio; Petit, Brice; Pfister, Corinne; Bürki, Julie Vienne; Didelot, Gérard; Billiard, Michel; Ercilla, Guadalupe; Verduijn, Willem; Claas, Frans H J; Vollenweider, Peter; Vollenwider, Peter; Waeber, Gerard; Waterworth, Dawn M; Mooser, Vincent; Heinzer, Raphaël; Beckmann, Jacques S; Bergmann, Sven; Tafti, Mehdi

    2010-01-01

    Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing...... narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1...... ratio = 0.02; P <6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility....

  15. Genome-wide association study of periweaning failure-to-thrive syndrome (PFTS) in pigs.

    Science.gov (United States)

    Zanella, R; Morés, N; Morés, M A Z; Peixoto, J O; Zanella, E L; Ciacci-Zanella, J R; Ibelli, A M G; Gava, D; Cantão, M E; Ledur, M C

    2016-06-25

    Porcine periweaning-failure-to-thrive syndrome (PFTS) is a condition that affects newly weaned piglets. It is characterised by a progressive debilitation leading to death, in the absence of infectious, nutritional, management or environmental factors. In this study, we present the first report of PFTS in South America and the results of a genome-wide association study to identify the genetic markers associated with the appearance of this condition in a crossbred swine population. Four chromosomal regions were associated with PFTS predisposition, one located on SSCX, one on SSC8, and the two other regions on SSC14. Regions on SSC8 and SSC14 harbour important functional candidate genes involved in human depression and might have an important role in PFTS. Our findings contribute to the increasing knowledge about this syndrome, which has been investigated since 2007, and to the identification of the aetiology of this disease. PMID:27162284

  16. A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.

    Science.gov (United States)

    Sanchez-Juan, Pascual; Bishop, Matthew T; Kovacs, Gabor G; Calero, Miguel; Aulchenko, Yurii S; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J; Ströbel, Thomas; Rivadeneira, Fernando; Hofman, Albert; Haïk, Stéphane; Combarros, Onofre; Berciano, José; Uitterlinden, Andre G; Collins, Steven J; Budka, Herbert; Brandel, Jean-Philippe; Laplanche, Jean Louis; Pocchiari, Maurizio; Zerr, Inga; Knight, Richard S G; Will, Robert G; van Duijn, Cornelia M

    2014-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis. PMID:25918841

  17. A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough

    DEFF Research Database (Denmark)

    Mosley, J D; Shaffer, C M; Van Driest, S L;

    2016-01-01

    The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects...

  18. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits

    DEFF Research Database (Denmark)

    Speliotes, Elizabeth K; Yerges-Armstrong, Laura M; Wu, Jun;

    2011-01-01

    Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic...

  19. Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits

    NARCIS (Netherlands)

    Speliotes, Elizabeth K.; Yerges-Armstrong, Laura M.; Wu, Jun; Hernaez, Ruben; Kim, Lauren J.; Palmer, Cameron D.; Gudnason, Vilmundur; Eiriksdottir, Gudny; Garcia, Melissa E.; Launer, Lenore J.; Nalls, Michael A.; Clark, Jeanne M.; Mitchell, Braxton D.; Shuldiner, Alan R.; Butler, Johannah L.; Tomas, Marta; Hoffmann, Udo; Hwang, Shih-Jen; Massaro, Joseph M.; O'Donnell, Christopher J.; Sahani, Dushyant V.; Salomaa, Veikko; Schadt, Eric E.; Schwartz, Stephen M.; Siscovick, David S.; Voight, Benjamin F.; Carr, J. Jeffrey; Feitosa, Mary F.; Harris, Tamara B.; Fox, Caroline S.; Smith, Albert V.; Kao, W. H. Linda; Hirschhorn, Joel N.; Borecki, Ingrid B.

    2011-01-01

    Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic st

  20. 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. PMID:27169231

  1. ParallABEL: an R library for generalized parallelization of genome-wide association studies

    Directory of Open Access Journals (Sweden)

    Tandayya Pichaya

    2010-04-01

    Full Text Available Abstract Background Genome-Wide Association (GWA analysis is a powerful method for identifying loci associated with complex traits and drug response. Parts of GWA analyses, especially those involving thousands of individuals and consuming hours to months, will benefit from parallel computation. It is arduous acquiring the necessary programming skills to correctly partition and distribute data, control and monitor tasks on clustered computers, and merge output files. Results Most components of GWA analysis can be divided into four groups based on the types of input data and statistical outputs. The first group contains statistics computed for a particular Single Nucleotide Polymorphism (SNP, or trait, such as SNP characterization statistics or association test statistics. The input data of this group includes the SNPs/traits. The second group concerns statistics characterizing an individual in a study, for example, the summary statistics of genotype quality for each sample. The input data of this group includes individuals. The third group consists of pair-wise statistics derived from analyses between each pair of individuals in the study, for example genome-wide identity-by-state or genomic kinship analyses. The input data of this group includes pairs of SNPs/traits. The final group concerns pair-wise statistics derived for pairs of SNPs, such as the linkage disequilibrium characterisation. The input data of this group includes pairs of individuals. We developed the ParallABEL library, which utilizes the Rmpi library, to parallelize these four types of computations. ParallABEL library is not only aimed at GenABEL, but may also be employed to parallelize various GWA packages in R. The data set from the North American Rheumatoid Arthritis Consortium (NARAC includes 2,062 individuals with 545,080, SNPs' genotyping, was used to measure ParallABEL performance. Almost perfect speed-up was achieved for many types of analyses. For example, the computing

  2. A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.

    Science.gov (United States)

    Chiò, Adriano; Schymick, Jennifer C; Restagno, Gabriella; Scholz, Sonja W; Lombardo, Federica; Lai, Shiao-Lin; Mora, Gabriele; Fung, Hon-Chung; Britton, Angela; Arepalli, Sampath; Gibbs, J Raphael; Nalls, Michael; Berger, Stephen; Kwee, Lydia Coulter; Oddone, Eugene Z; Ding, Jinhui; Crews, Cynthia; Rafferty, Ian; Washecka, Nicole; Hernandez, Dena; Ferrucci, Luigi; Bandinelli, Stefania; Guralnik, Jack; Macciardi, Fabio; Torri, Federica; Lupoli, Sara; Chanock, Stephen J; Thomas, Gilles; Hunter, David J; Gieger, Christian; Wichmann, H Erich; Calvo, Andrea; Mutani, Roberto; Battistini, Stefania; Giannini, Fabio; Caponnetto, Claudia; Mancardi, Giovanni Luigi; La Bella, Vincenzo; Valentino, Francesca; Monsurrò, Maria Rosaria; Tedeschi, Gioacchino; Marinou, Kalliopi; Sabatelli, Mario; Conte, Amelia; Mandrioli, Jessica; Sola, Patrizia; Salvi, Fabrizio; Bartolomei, Ilaria; Siciliano, Gabriele; Carlesi, Cecilia; Orrell, Richard W; Talbot, Kevin; Simmons, Zachary; Connor, James; Pioro, Erik P; Dunkley, Travis; Stephan, Dietrich A; Kasperaviciute, Dalia; Fisher, Elizabeth M; Jabonka, Sibylle; Sendtner, Michael; Beck, Marcus; Bruijn, Lucie; Rothstein, Jeffrey; Schmidt, Silke; Singleton, Andrew; Hardy, John; Traynor, Bryan J

    2009-04-15

    The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors. PMID:19193627

  3. A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing.

    Science.gov (United States)

    Davies, G; Harris, S E; Reynolds, C A; Payton, A; Knight, H M; Liewald, D C; Lopez, L M; Luciano, M; Gow, A J; Corley, J; Henderson, R; Murray, C; Pattie, A; Fox, H C; Redmond, P; Lutz, M W; Chiba-Falek, O; Linnertz, C; Saith, S; Haggarty, P; McNeill, G; Ke, X; Ollier, W; Horan, M; Roses, A D; Ponting, C P; Porteous, D J; Tenesa, A; Pickles, A; Starr, J M; Whalley, L J; Pedersen, N L; Pendleton, N; Visscher, P M; Deary, I J

    2014-01-01

    Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549 692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual's cognitive changes were constructed. One SNP--rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)--had a genome-wide significant association with cognitive ageing (P=2.5 × 10(-8)). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10(-6)). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10(-8); females, P=1.66 × 10(-11); males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10(-11)) and TOMM40 (rs11556505; P=2.45 × 10(-8)) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear. PMID:23207651

  4. Genome-wide Association Study of Autism Spectrum Disorder in the East Asian Populations.

    Science.gov (United States)

    Liu, Xiaoxi; Shimada, Takafumi; Otowa, Takeshi; Wu, Yu-Yu; Kawamura, Yoshiya; Tochigi, Mamoru; Iwata, Yasuhide; Umekage, Tadashi; Toyota, Tomoko; Maekawa, Motoko; Iwayama, Yoshimi; Suzuki, Katsuaki; Kakiuchi, Chihiro; Kuwabara, Hitoshi; Kano, Yukiko; Nishida, Hisami; Sugiyama, Toshiro; Kato, Nobumasa; Chen, Chia-Hsiang; Mori, Norio; Yamada, Kazuo; Yoshikawa, Takeo; Kasai, Kiyoto; Tokunaga, Katsushi; Sasaki, Tsukasa; Gau, Susan Shur-Fen

    2016-03-01

    Autism spectrum disorder is a heterogeneous neurodevelopmental disorder with strong genetic basis. To identify common genetic variations conferring the risk of ASD, we performed a two-stage genome-wide association study using ASD family and healthy control samples obtained from East Asian populations. A total of 166 ASD families (n = 500) and 642 healthy controls from the Japanese population were used as the discovery cohort. Approximately 900,000 single nucleotide polymorphisms (SNPs) were genotyped using Affymetrix Genome-Wide Human SNP array 6.0 chips. In the replication stage, 205 Japanese ASD cases and 184 healthy controls, as well as 418 Chinese Han trios (n = 1,254), were genotyped by TaqMan platform. Case-control analysis, family based association test, and transmission/disequilibrium test (TDT) were then conducted to test the association. In the discovery stage, significant associations were suggested for 14 loci, including 5 known ASD candidate genes: GPC6, JARID2, YTHDC2, CNTN4, and CSMD1. In addition, significant associations were identified for several novel genes with intriguing functions, such as JPH3, PTPRD, CUX1, and RIT2. After a meta-analysis combining the Japanese replication samples, the strongest signal was found at rs16976358 (P = 6.04 × 10(-7) ), which is located near the RIT2 gene. In summary, our results provide independent support to known ASD candidate genes and highlight a number of novel genes warranted to be further investigated in a larger sample set in an effort to improve our understanding of the genetic basis of ASD. Autism Res 2016, 9: 340-349. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. PMID:26314684

  5. Genome-wide association and functional follow-up reveals new loci for kidney function.

    Directory of Open Access Journals (Sweden)

    Cristian Pattaro

    Full Text Available Chronic kidney disease (CKD is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR, the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.

  6. Genome-Wide Association Study in Dachshund: Identification of a Major Locus Affecting Intervertebral Disc Calcification

    DEFF Research Database (Denmark)

    Mogensen, Mette Sloth; Karlskov-Mortensen, Peter; Proschowsky, Helle Friis;

    2011-01-01

    Intervertebral disc calcification and herniation commonly affects Dachshund where the predisposition is caused by an early onset degenerative process resulting in disc calcification. A continuous spectrum of disc degeneration is seen within and among clog breeds, suggesting a multifactorial...... etiology. The number of calcified discs at 2 years of age determined by a radiographic evaluation is a good indicator of the severity of disc degeneration and thus serves as a measure for the risk of developing intervertebral disc herniation. The aim of the study was to identify genetic variants associated...... with intervertebral disc calcification in Dachshund through a genome-wide association (GWA) study. Based on thorough radiographic examinations, 48 cases with >= 6 disc calcifications or surgically treated for disc herniation and 46 controls with 0-1 disc calcifications were identified. GWA using the...

  7. The effect of measurement error of phenotypes on genome wide association studies

    Directory of Open Access Journals (Sweden)

    Barendse William

    2011-05-01

    Full Text Available Abstract Background There is an unspoken assumption that imprecision of measurement of phenotypes will not have large systematic effects on the location of significant associations in a genome wide association study (GWAS. In this report, the effects of two independent measurements of the same trait, subcutaneous fat thickness, were examined in GWAS of 940 individuals. Results The trait values obtained by two independent groups working to the same trait definition were correlated with r = 0.72. The allele effects obtained from the two analyses were only moderately correlated, with r = 0.53, and there was one significant (P Conclusions It is recommended that trait values in GWAS experiments be examined for repeatability before the experiment is performed. For traits that do not have high repeatability (r

  8. Genome-wide association study of tick resistance in South African Nguni cattle.

    Science.gov (United States)

    Mapholi, N O; Maiwashe, A; Matika, O; Riggio, V; Bishop, S C; MacNeil, M D; Banga, C; Taylor, J F; Dzama, K

    2016-04-01

    Ticks and tick-borne diseases are among the main causes of economic loss in the South African cattle industry through high morbidity and mortality rates. Concerns of the general public regarding chemical residues may tarnish their perceptions of food safety and environmental health when the husbandry of cattle includes frequent use of acaricides to manage ticks. The primary objective of this study was to identify single nucleotide polymorphism (SNP) markers associated with host resistance to ticks in South African Nguni cattle. Tick count data were collected monthly from 586 Nguni cattle reared in four herds under natural grazing conditions over a period of two years. The counts were recorded for six species of ticks attached in eight anatomical locations on the animals and were summed by species and anatomical location. This gave rise to 63 measured phenotypes or traits, with results for 12 of these traits being reported here. Tick count (x) data were transformed using log10(x+1) and the resulting values were examined for normality. DNA was extracted from hair and blood samples and was genotyped using the Illumina BovineSNP50 assay. After quality control (call rate >90%, minor allele frequency >0.02), 40,436 SNPs were retained for analysis. Genetic parameters were estimated and association analysis for tick resistance was carried out using two approaches: a genome-wide association (GWA) analysis using the GenABEL package and a regional heritability mapping (RHM) analysis. The Bonferroni genome-wide (Psire models ranged from 0.02±0.00 to 0.17±0.04 for the transformed tick count data. Several genomic regions harbouring quantitative trait loci (QTL) were identified for different tick count traits by both the GWA and RHM approaches. Three genome-wide significant regions on chromosomes 7, 10 and 19 were identified for total tick count on the head, total body A. hebraeum tick count and total A. hebraeum on the perineum region, respectively. Additional regions

  9. A "candidate-interactome" aggregate analysis of genome-wide association data in multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Rosella Mechelli

    Full Text Available Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms.

  10. Genome-wide meta-analyses identify multiple loci associated with smoking behavior.

    LENUS (Irish Health Repository)

    2010-05-01

    Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], beta = 1.03, standard error (s.e.) = 0.053, P = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], beta = 0.367, s.e. = 0.059, P = 5.7 x 10(-10); and rs1028936[A], beta = 0.446, s.e. = 0.074, P = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], beta = 0.333, s.e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.

  11. A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Castanos-Velez Esmeralda

    2006-09-01

    Full Text Available Abstract Background Cancer development is accompanied by genetic phenomena like deletion and amplification of chromosome parts or alterations of chromatin structure. It is expected that these mechanisms have a strong effect on regional gene expression. Results We investigated genome-wide gene expression in colorectal carcinoma (CRC and normal epithelial tissues from 25 patients using oligonucleotide arrays. This allowed us to identify 81 distinct chromosomal islands with aberrant gene expression. Of these, 38 islands show a gain in expression and 43 a loss of expression. In total, 7.892 genes (25.3% of all human genes are located in aberrantly expressed islands. Many chromosomal regions that are linked to hereditary colorectal cancer show deregulated expression. Also, many known tumor genes localize to chromosomal islands of misregulated expression in CRC. Conclusion An extensive comparison with published CGH data suggests that chromosomal regions known for frequent deletions in colon cancer tend to show reduced expression. In contrast, regions that are often amplified in colorectal tumors exhibit heterogeneous expression patterns: even show a decrease of mRNA expression. Because for several islands of deregulated expression chromosomal aberrations have never been observed, we speculate that additional mechanisms (like abnormal states of regional chromatin also have a substantial impact on the formation of co-expression islands in colorectal carcinoma.

  12. A genome-wide association study points to multiple loci predicting antidepressant treatment outcome in depression

    Science.gov (United States)

    Binder, Elisabeth B.; Bettecken, Thomas; Uhr, Manfred; Ripke, Stephan; Kohli, Martin A.; Hennings, Johannes M.; Horstmann, Sonja; Kloiber, Stefan; Menke, Andreas; Bondy, Brigitta; Rupprecht, Rainer; Domschke, Katharina; Baune, Bernhard T.; Arolt, Volker; Rush, A. John; Holsboer, Florian; Müller-Myhsok, Bertram

    2015-01-01

    Context Efficacy of antidepressant treatment in depression is unsatisfactory as one in three patients does not fully recover even after several treatment trials. Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome. Objective To identify genetic and clinical determinants of antidepressant treatment outcome in depression. Design Genome-wide pharmacogenetic association study with two independent replication samples. Setting We performed a genome-wide association (GWA) study in patients from the Munich-Antidepressant-Response-Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single nucleotide polymorphisms (SNPs) highly related to outcome in both GWA studies was genotyped in a sample of the Sequenced-Treatment-Alternatives-to-Relieve-Depression (STAR*D) study. Participants 339 inpatients suffering from a depressive episode (MARS sample), further 361 depressed inpatients (German replication sample), and 832 outpatients with major depression (STAR*D sample). Main Outcome Measures We generated a multi-locus genetic variable describing the individual number of alleles of the selected SNPs associated with beneficial treatment outcome in the MARS sample (“response” alleles) to evaluate additive genetic effects on antidepressant treatment outcome. Results Multi-locus analysis revealed a significant contribution of a binary variable categorizing patients as carriers of a high vs. low number of response alleles in predicting antidepressant treatment outcome in both samples, MARS and STAR*D. In addition, we observed that patients with a comorbid anxiety disorder in combination with a low number of response alleles showed the least favorable outcome. Conclusion Our results demonstrate the importance of multiple genetic factors in combination with clinical features to predict antidepressant treatment outcome underscoring the multifactorial nature of this trait. PMID

  13. Genome-wide association analyses identify SPOCK as a key novel gene underlying age at menarche.

    Directory of Open Access Journals (Sweden)

    Yao-Zhong Liu

    2009-03-01

    Full Text Available For females, menarche is a most significant physiological event. Age at menarche (AAM is a trait with high genetic determination and is associated with major complex diseases in women. However, specific genes for AAM variation are largely unknown. To identify genetic factors underlying AAM variation, a genome-wide association study (GWAS examining about 380,000 SNPs was conducted in 477 Caucasian women. A follow-up replication study was performed to validate our major GWAS findings using two independent Caucasian cohorts with 854 siblings and 762 unrelated subjects, respectively, and one Chinese cohort of 1,387 unrelated subjects--all females. Our GWAS identified a novel gene, SPOCK (Sparc/Osteonectin, CWCV, and Kazal-like domains proteoglycan, which had seven SNPs associated with AAM with genome-wide false discovery rate (FDR q<0.05. Six most significant SNPs of the gene were selected for validation in three independent replication cohorts. All of the six SNPs were replicated in at least one cohort. In particular, SNPs rs13357391 and rs1859345 were replicated both within and across different ethnic groups in all three cohorts, with p values of 5.09 x 10(-3 and 4.37 x 10(-3, respectively, in the Chinese cohort and combined p values (obtained by Fisher's method of 5.19 x 10(-5 and 1.02 x 10(-4, respectively, in all three replication cohorts. Interestingly, SPOCK can inhibit activation of MMP-2 (matrix metalloproteinase-2, a key factor promoting endometrial menstrual breakdown and onset of menstrual bleeding. Our findings, together with the functional relevance, strongly supported that the SPOCK gene underlies variation of AAM.

  14. Genome-Wide Detection of CNVs and Their Association with Meat Tenderness in Nelore Cattle

    Science.gov (United States)

    da Silva, Vinicius Henrique; Regitano, Luciana Correia de Almeida; Geistlinger, Ludwig; Pértille, Fábio; Morosini, Natália Silva; Zimmer, Ralf; Coutinho, Luiz Lehmann

    2016-01-01

    Brazil is one of the largest beef producers and exporters in the world with the Nelore breed representing the vast majority of Brazilian cattle (Bos taurus indicus). Despite the great adaptability of the Nelore breed to tropical climate, meat tenderness (MT) remains to be improved. Several factors including genetic composition can influence MT. In this article, we report a genome-wide analysis of copy number variation (CNV) inferred from Illumina® High Density SNP-chip data for a Nelore population of 723 males. We detected >2,600 CNV regions (CNVRs) representing ≈6.5% of the genome. Comparing our results with previous studies revealed an overlap in ≈1400 CNVRs (>50%). A total of 1,155 CNVRs (43.6%) overlapped 2,750 genes. They were enriched for processes involving guanosine triphosphate (GTP), previously reported to influence skeletal muscle physiology and morphology. Nelore CNVRs also overlapped QTLs for MT reported in other breeds (8.9%, 236 CNVRs) and from a previous study with this population (4.1%, 109 CNVRs). Two CNVRs were also proximal to glutathione metabolism genes that were previously associated with MT. Genome-wide association study of CN state with estimated breeding values derived from meat shear force identified 6 regions, including a region on BTA3 that contains genes of the cAMP and cGMP pathway. Ten CNVRs that overlapped regions associated with MT were successfully validated by qPCR. Our results represent the first comprehensive CNV study in Bos taurus indicus cattle and identify regions in which copy number changes are potentially of importance for the MT phenotype. PMID:27348523

  15. Genome-wide Association Study Identifies Loci for the Polled Phenotype in Yak

    Science.gov (United States)

    Wu, Xiaoyun; Wang, Kun; Ding, Xuezhi; Wang, Mingcheng; Chu, Min; Xie, Xiuyue; Qiu, Qiang; Yan, Ping

    2016-01-01

    The absence of horns, known as the polled phenotype, is an economically important trait in modern yak husbandry, but the genomic structure and genetic basis of this phenotype have yet to be discovered. Here, we conducted a genome-wide association study with a panel of 10 horned and 10 polled yaks using whole genome sequencing. We mapped the POLLED locus to a 200-kb interval, which comprises three protein-coding genes. Further characterization of the candidate region showed recent artificial selection signals resulting from the breeding process. We suggest that expressional variations rather than structural variations in protein probably contribute to the polled phenotype. Our results not only represent the first and important step in establishing the genomic structure of the polled region in yak, but also add to our understanding of the polled trait in bovid species. PMID:27389700

  16. Genome-wide association study identifies three novel loci for type 2 diabetes

    DEFF Research Database (Denmark)

    Hara, Kazuo; Fujita, Hayato; Johnson, Todd A;

    2014-01-01

    genotyped or imputed using East Asian references from the 1000 Genomes Project (June 2011 release) in 5976 Japanese patients with T2D and 20 829 nondiabetic individuals. Nineteen unreported loci were selected and taken forward to follow-up analyses. Combined discovery and follow-up analyses (30 392 cases...... (rs312457; risk allele = G; RAF = 0.078; P = 7.69 × 10(-13); OR = 1.20). This study demonstrates that GWASs based on the imputation of genotypes using modern reference haplotypes such as that from the 1000 Genomes Project data can assist in identification of new loci for common diseases.......Although over 60 loci for type 2 diabetes (T2D) have been identified, there still remains a large genetic component to be clarified. To explore unidentified loci for T2D, we performed a genome-wide association study (GWAS) of 6 209 637 single-nucleotide polymorphisms (SNPs), which were directly...

  17. Genome-Wide Association Study to Identify Genes Related to Renal Mercury Concentrations in Mice

    DEFF Research Database (Denmark)

    Alkaissi, Hammoudi; Ekstrand, Jimmy; Jawad, Aksa;

    2016-01-01

    BACKGROUND: Following human mercury (Hg) exposure, the metal accumulates with considerable concentrations in kidney, liver, and brain. Although the toxicokinetics of Hg has been studied extensively, factors responsible for inter-individual variation in humans are largely unknown. Differences in...... accumulation of renal Hg between inbred mouse strains suggest a genetic inter-strain variation regulating retention or/and excretion of Hg. A.SW, DBA/2 and BALB/C mouse strains accumulate higher amounts of Hg than B10.S. OBJECTIVES: To find candidate genes associated with regulation of renal Hg concentrations....... METHODS: A.SW, B10.S and their F1 and F2 offspring were exposed for 6 weeks to 2.0 mg Hg/L drinking water. Genotyping with Microsatellites were conducted on 84 F2 mice for Genome-Wide Scan by using Ion Pair Reverse Phase High Performance Liquid Chromatography (IP RP HPLC). Quantitative trait loci (QTL...

  18. Genome-wide association studies in systemic lupus erythematosus: a perspective

    Science.gov (United States)

    Cunninghame Graham, Deborah S

    2009-01-01

    Genome-wide association studies (GWAS) have been shown to be a powerful way of identifying novel susceptibility genes in systemic lupus erythematosus (SLE), as demonstrated by a series of publications in the past year. Lupus has been a late-comer to the GWAS community, being preceded by success stories for the GWAS approach in other autoimmune diseases, including type I diabetes, ankylosing spondylitis, rheumatoid arthritis, Crohn's disease and ulcerative colitis. The paper by Suarez-Gestal and colleagues seeks to exploit the wealth of data available from a total of four GWAS in SLE, three in European-American populations and one in a Swedish population. The authors describe replication of ten lupus susceptibility alleles in a Spanish SLE case-control study. PMID:19664177

  19. SNP-based pathway enrichment analysis for genome-wide association studies

    Directory of Open Access Journals (Sweden)

    Potkin Steven G

    2011-04-01

    Full Text Available Abstract Background Recently we have witnessed a surge of interest in using genome-wide association studies (GWAS to discover the genetic basis of complex diseases. Many genetic variations, mostly in the form of single nucleotide polymorphisms (SNPs, have been identified in a wide spectrum of diseases, including diabetes, cancer, and psychiatric diseases. A common theme arising from these studies is that the genetic variations discovered by GWAS can only explain a small fraction of the genetic risks associated with the complex diseases. New strategies and statistical approaches are needed to address this lack of explanation. One such approach is the pathway analysis, which considers the genetic variations underlying a biological pathway, rather than separately as in the traditional GWAS studies. A critical challenge in the pathway analysis is how to combine evidences of association over multiple SNPs within a gene and multiple genes within a pathway. Most current methods choose the most significant SNP from each gene as a representative, ignoring the joint action of multiple SNPs within a gene. This approach leads to preferential identification of genes with a greater number of SNPs. Results We describe a SNP-based pathway enrichment method for GWAS studies. The method consists of the following two main steps: 1 for a given pathway, using an adaptive truncated product statistic to identify all representative (potentially more than one SNPs of each gene, calculating the average number of representative SNPs for the genes, then re-selecting the representative SNPs of genes in the pathway based on this number; and 2 ranking all selected SNPs by the significance of their statistical association with a trait of interest, and testing if the set of SNPs from a particular pathway is significantly enriched with high ranks using a weighted Kolmogorov-Smirnov test. We applied our method to two large genetically distinct GWAS data sets of schizophrenia, one

  20. A genome-wide association study of pulmonary function measures in the Framingham Heart Study.

    Directory of Open Access Journals (Sweden)

    Jemma B Wilk

    2009-03-01

    Full Text Available The ratio of forced expiratory volume in one second to forced vital capacity (FEV(1/FVC is a measure used to diagnose airflow obstruction and is highly heritable. We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs associated with the FEV(1/FVC ratio, analyzed as a percent of the predicted value. Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction. Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV(1/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09. One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV(1/FVC (p-value = 2.0e-04. The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G associated with higher FEV(1/FVC ratio levels. Results from the Family Heart Study demonstrated that the association extended to FEV(1 and dichotomous airflow obstruction phenotypes, particularly among smokers. The SNP rs13147758 was associated with the percent predicted FEV(1/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript. The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP gene and several expressed sequence tags cloned from fetal lung. Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation.

  1. Genome-wide association study of insect bite hypersensitivity in two horse populations in the Netherlands

    Directory of Open Access Journals (Sweden)

    Schurink Anouk

    2012-10-01

    Full Text Available Abstract Background Insect bite hypersensitivity is a common allergic disease in horse populations worldwide. Insect bite hypersensitivity is affected by both environmental and genetic factors. However, little is known about genes contributing to the genetic variance associated with insect bite hypersensitivity. Therefore, the aim of our study was to identify and quantify genomic associations with insect bite hypersensitivity in Shetland pony mares and Icelandic horses in the Netherlands. Methods Data on 200 Shetland pony mares and 146 Icelandic horses were collected according to a matched case–control design. Cases and controls were matched on various factors (e.g. region, sire to minimize effects of population stratification. Breed-specific genome-wide association studies were performed using 70 k single nucleotide polymorphisms genotypes. Bayesian variable selection method Bayes-C with a threshold model implemented in GenSel software was applied. A 1 Mb non-overlapping window approach that accumulated contributions of adjacent single nucleotide polymorphisms was used to identify associated genomic regions. Results The percentage of variance explained by all single nucleotide polymorphisms was 13% in Shetland pony mares and 28% in Icelandic horses. The 20 non-overlapping windows explaining the largest percentages of genetic variance were found on nine chromosomes in Shetland pony mares and on 14 chromosomes in Icelandic horses. Overlap in identified associated genomic regions between breeds would suggest interesting candidate regions to follow-up on. Such regions common to both breeds (within 15 Mb were found on chromosomes 3, 7, 11, 20 and 23. Positional candidate genes within 2 Mb from the associated windows were identified on chromosome 20 in both breeds. Candidate genes are within the equine lymphocyte antigen class II region, which evokes an immune response by recognizing many foreign molecules. Conclusions The genome-wide association

  2. Agronomic and Seed Quality Traits Dissected by Genome-Wide Association Mapping in Brassica napus.

    Science.gov (United States)

    Körber, Niklas; Bus, Anja; Li, Jinquan; Parkin, Isobel A P; Wittkop, Benjamin; Snowdon, Rod J; Stich, Benjamin

    2016-01-01

    In Brassica napus breeding, traits related to commercial success are of highest importance for plant breeders. However, such traits can only be assessed in an advanced developmental stage. Molecular markers genetically linked to such traits have the potential to accelerate the breeding process of B. napus by marker-assisted selection. Therefore, the objectives of this study were to identify (i) genome regions associated with the examined agronomic and seed quality traits, (ii) the interrelationship of population structure and the detected associations, and (iii) candidate genes for the revealed associations. The diversity set used in this study consisted of 405 B. napus inbred lines which were genotyped using a 6K single nucleotide polymorphism (SNP) array and phenotyped for agronomic and seed quality traits in field trials. In a genome-wide association study, we detected a total of 112 associations between SNPs and the seed quality traits as well as 46 SNP-trait associations for the agronomic traits with a P rapa could be found for the agronomic SNP-trait associations and 187 hits of potential candidate genes for the seed quality SNP-trait associations. PMID:27066036

  3. Agronomic and seed quality traits dissected by genome-wide association mapping in Brassica napus

    Directory of Open Access Journals (Sweden)

    Niklas eKörber

    2016-03-01

    Full Text Available In Brassica napus breeding, traits related to commercial success are of highest importance for plant breeders. However, such traits can only be assessed in an advanced developmental stage. % as well as require high experimental effort due to their quantitative inheritance and the importance of genotype*environment interaction. Molecular markers genetically linked to such traits have the potential to accelerate the breeding process of B. napus by marker-assisted selection. Therefore, the objectives of this study were to identify (i genome regions associated with the examined agronomic and seed quality traits, (ii the interrelationship of population structure and the detected associations, and (iii candidate genes for the revealed associations. The diversity set used in this study consisted of 405 Brassica napus inbred lines which were genotyped using a 6K single nucleotide polymorphism (SNP array and phenotyped for agronomic and seed quality traits in field trials. In a genome-wide association study, we detected a total of 112 associations between SNPs and the seed quality traits as well as 46 SNP-trait associations for the agronomic traits with a P-value 100 and a sequence identity of > 70 % to A. thaliana or B. rapa could be found for the agronomic SNP-trait associations and 187 hits of potential candidate genes for the seed quality SNP-trait associations.

  4. Body mass index associated with genome-wide methylation in breast tissue.

    Science.gov (United States)

    Hair, Brionna Y; Xu, Zongli; Kirk, Erin L; Harlid, Sophia; Sandhu, Rupninder; Robinson, Whitney R; Wu, Michael C; Olshan, Andrew F; Conway, Kathleen; Taylor, Jack A; Troester, Melissa A

    2015-06-01

    Gene expression studies indicate that body mass index (BMI) is associated with molecular pathways involved in inflammation, insulin-like growth factor activation, and other carcinogenic processes in breast tissue. The goal of this study was to determine whether BMI is associated with gene methylation in breast tissue and to identify pathways that are commonly methylated in association with high BMI. Epigenome-wide methylation profiles were determined using the Illumina HumanMethylation450 BeadChip array in the non-diseased breast tissue of 81 women undergoing breast surgery between 2009 and 2013 at the University of North Carolina Hospitals. Multivariable, robust linear regression was performed to identify methylation sites associated with BMI at a false discovery rate q value analysis was conducted to assess which pathways were enriched among the BMI-associated methylation sites. Of the 431,568 methylation sites analyzed, 2573 were associated with BMI (q value <0.05), 57 % of which showed an inverse correlation with BMI. Pathways enriched among the 2573 probe sites included those involved in inflammation, insulin receptor signaling, and leptin signaling. We were able to map 1251 of the BMI-associated methylation sites to gene expression data, and, of these, 226 (18 %) showed substantial correlations with gene expression. Our results suggest that BMI is associated with genome-wide methylation in non-diseased breast tissue and may influence epigenetic pathways involved in inflammatory and other carcinogenic processes. PMID:25953686

  5. Accounting for multiple comparisons in a genome-wide association study (GWAS

    Directory of Open Access Journals (Sweden)

    Lautenberger James A

    2010-12-01

    Full Text Available Abstract Background As we enter an era when testing millions of SNPs in a single gene association study will become the standard, consideration of multiple comparisons is an essential part of determining statistical significance. Bonferroni adjustments can be made but are conservative due to the preponderance of linkage disequilibrium (LD between genetic markers, and permutation testing is not always a viable option. Three major classes of corrections have been proposed to correct the dependent nature of genetic data in Bonferroni adjustments: permutation testing and related alternatives, principal components analysis (PCA, and analysis of blocks of LD across the genome. We consider seven implementations of these commonly used methods using data from 1514 European American participants genotyped for 700,078 SNPs in a GWAS for AIDS. Results A Bonferroni correction using the number of LD blocks found by the three algorithms implemented by Haploview resulted in an insufficiently conservative threshold, corresponding to a genome-wide significance level of α = 0.15 - 0.20. We observed a moderate increase in power when using PRESTO, SLIDE, and simpleℳ when compared with traditional Bonferroni methods for population data genotyped on the Affymetrix 6.0 platform in European Americans (α = 0.05 thresholds between 1 × 10-7 and 7 × 10-8. Conclusions Correcting for the number of LD blocks resulted in an anti-conservative Bonferroni adjustment. SLIDE and simpleℳ are particularly useful when using a statistical test not handled in optimized permutation testing packages, and genome-wide corrected p-values using SLIDE, are much easier to interpret for consumers of GWAS studies.

  6. Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Gokhan Yildiz

    Full Text Available Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal" by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15

  7. Genome-wide transcriptional reorganization associated with senescence-to-immortality switch during human hepatocellular carcinogenesis.

    Science.gov (United States)

    Yildiz, Gokhan; Arslan-Ergul, Ayca; Bagislar, Sevgi; Konu, Ozlen; Yuzugullu, Haluk; Gursoy-Yuzugullu, Ozge; Ozturk, Nuri; Ozen, Cigdem; Ozdag, Hilal; Erdal, Esra; Karademir, Sedat; Sagol, Ozgul; Mizrak, Dilsa; Bozkaya, Hakan; Ilk, Hakki Gokhan; Ilk, Ozlem; Bilen, Biter; Cetin-Atalay, Rengul; Akar, Nejat; Ozturk, Mehmet

    2013-01-01

    Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene

  8. Genome wide association study of fetal hemoglobin in sickle cell anemia in Tanzania.

    Directory of Open Access Journals (Sweden)

    Siana Nkya Mtatiro

    Full Text Available BACKGROUND: Fetal hemoglobin (HbF is an important modulator of sickle cell disease (SCD. HbF has previously been shown to be affected by variants at three loci on chromosomes 2, 6 and 11, but it is likely that additional loci remain to be discovered. METHODS AND FINDINGS: We conducted a genome-wide association study (GWAS in 1,213 SCA (HbSS/HbSβ0 patients in Tanzania. Genotyping was done with Illumina Omni2.5 array and imputation using 1000 Genomes Phase I release data. Association with HbF was analysed using a linear mixed model to control for complex population structure within our study. We successfully replicated known associations for HbF near BCL11A and the HBS1L-MYB intergenic polymorphisms (HMIP, including multiple independent effects near BCL11A, consistent with previous reports. We observed eight additional associations with P<10(-6. These associations could not be replicated in a SCA population in the UK. CONCLUSIONS: This is the largest GWAS study in SCA in Africa. We have confirmed known associations and identified new genetic associations with HbF that require further replication in SCA populations in Africa.

  9. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy.

    Science.gov (United States)

    Kouri, Naomi; Ross, Owen A; Dombroski, Beth; Younkin, Curtis S; Serie, Daniel J; Soto-Ortolaza, Alexandra; Baker, Matthew; Finch, Ni Cole A; Yoon, Hyejin; Kim, Jungsu; Fujioka, Shinsuke; McLean, Catriona A; Ghetti, Bernardino; Spina, Salvatore; Cantwell, Laura B; Farlow, Martin R; Grafman, Jordan; Huey, Edward D; Ryung Han, Mi; Beecher, Sherry; Geller, Evan T; Kretzschmar, Hans A; Roeber, Sigrun; Gearing, Marla; Juncos, Jorge L; Vonsattel, Jean Paul G; Van Deerlin, Vivianna M; Grossman, Murray; Hurtig, Howard I; Gross, Rachel G; Arnold, Steven E; Trojanowski, John Q; Lee, Virginia M; Wenning, Gregor K; White, Charles L; Höglinger, Günter U; Müller, Ulrich; Devlin, Bernie; Golbe, Lawrence I; Crook, Julia; Parisi, Joseph E; Boeve, Bradley F; Josephs, Keith A; Wszolek, Zbigniew K; Uitti, Ryan J; Graff-Radford, Neill R; Litvan, Irene; Younkin, Steven G; Wang, Li-San; Ertekin-Taner, Nilüfer; Rademakers, Rosa; Hakonarsen, Hakon; Schellenberg, Gerard D; Dickson, Dennis W

    2015-01-01

    Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10(-12)), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10(-8)), and 2p22 at SOS1 (rs963731; P=1.76 × 10(-7)). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10(-7)) and MAPT H1c (17q21; rs242557; P=7.91 × 10(-6)). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein). PMID:26077951

  10. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy

    Science.gov (United States)

    Kouri, Naomi; Ross, Owen A.; Dombroski, Beth; Younkin, Curtis S.; Serie, Daniel J.; Soto-Ortolaza, Alexandra; Baker, Matthew; Finch, Ni Cole A.; Yoon, Hyejin; Kim, Jungsu; Fujioka, Shinsuke; McLean, Catriona A.; Ghetti, Bernardino; Spina, Salvatore; Cantwell, Laura B.; Farlow, Martin R.; Grafman, Jordan; Huey, Edward D.; Ryung Han, Mi; Beecher, Sherry; Geller, Evan T.; Kretzschmar, Hans A.; Roeber, Sigrun; Gearing, Marla; Juncos, Jorge L.; Vonsattel, Jean Paul G.; Van Deerlin, Vivianna M.; Grossman, Murray; Hurtig, Howard I.; Gross, Rachel G.; Arnold, Steven E.; Trojanowski, John Q.; Lee, Virginia M.; Wenning, Gregor K.; White, Charles L.; Höglinger, Günter U.; Müller, Ulrich; Devlin, Bernie; Golbe, Lawrence I.; Crook, Julia; Parisi, Joseph E.; Boeve, Bradley F.; Josephs, Keith A.; Wszolek, Zbigniew K.; Uitti, Ryan J.; Graff-Radford, Neill R.; Litvan, Irene; Younkin, Steven G.; Wang, Li-San; Ertekin-Taner, Nilüfer; Rademakers, Rosa; Hakonarsen, Hakon; Schellenberg, Gerard D.; Dickson, Dennis W.

    2015-01-01

    Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases (n=152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT (P=1.42 × 10−12), 8p12 at lnc-KIF13B-1, a long non-coding RNA (rs643472; P=3.41 × 10−8), and 2p22 at SOS1 (rs963731; P=1.76 × 10−7). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P=2.07 × 10−7) and MAPT H1c (17q21; rs242557; P=7.91 × 10−6). We previously reported SNP/transcript level associations with rs8070723/MAPT, rs242557/MAPT, and rs1768208/MOBP and herein identified association with rs963731/SOS1. We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein). PMID:26077951

  11. Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes.

    Directory of Open Access Journals (Sweden)

    Erin N Smith

    2011-06-01

    Full Text Available Although a highly heritable and disabling disease, bipolar disorder's (BD genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10(-7. To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.

  12. Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci.

    Science.gov (United States)

    Smith, D J; Escott-Price, V; Davies, G; Bailey, M E S; Colodro-Conde, L; Ward, J; Vedernikov, A; Marioni, R; Cullen, B; Lyall, D; Hagenaars, S P; Liewald, D C M; Luciano, M; Gale, C R; Ritchie, S J; Hayward, C; Nicholl, B; Bulik-Sullivan, B; Adams, M; Couvy-Duchesne, B; Graham, N; Mackay, D; Evans, J; Smith, B H; Porteous, D J; Medland, S E; Martin, N G; Holmans, P; McIntosh, A M; Pell, J P; Deary, I J; O'Donovan, M C

    2016-06-01

    Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured

  13. Genome-wide association of body fat distribution in African ancestry populations suggests new loci.

    Directory of Open Access Journals (Sweden)

    Ching-Ti Liu

    Full Text Available Central obesity, measured by waist circumference (WC or waist-hip ratio (WHR, is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS of fat distribution among those of predominantly African ancestry (AA. We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1. Overall, 25 SNPs with single genomic control (GC-corrected p-values<5.0 × 10(-6 were followed-up (stage 2 in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8 for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8 for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8; RREB1: p = 5.7 × 10(-8. Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN. Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02. In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept

  14. Searching joint association signals in CATIE schizophrenia genome-wide association studies through a refined integrative network approach

    OpenAIRE

    2012-01-01

    Background Genome-wide association studies (GWAS) have generated a wealth of valuable genotyping data for complex diseases/traits. A large proportion of these data are embedded with many weakly associated markers that have been missed in traditional single marker analyses, but they may provide valuable insights in dissecting the genetic components of diseases. Gene set analysis (GSA) augmented by protein-protein interaction network data provides a promising way to examine GWAS data by analyzi...

  15. Genome-wide association studies (GWAS) and their importance in asthma.

    Science.gov (United States)

    García-Sánchez, A; Isidoro-García, M; García-Solaesa, V; Sanz, C; Hernández-Hernández, L; Padrón-Morales, J; Lorente-Toledano, F; Dávila, I

    2015-01-01

    Asthma is a complex disease determined by the interaction of different genes and environmental factors. The first genetic investigations in asthma were candidate gene association studies and linkage studies. In recent years research has focused on association studies that scan the entire genome without any prior conditioning hypothesis: the so-called genome-wide association studies (GWAS). The first GWAS was published in 2007, and described a new locus associated to asthma in chromosome 17q12-q21, involving the ORMDL3, GSDMB and ZPBP2 genes (a description of the genes named in the manuscript are listed in Table 1). None of these genes would have been selected in a classical genetic association study since it was not known they could be implicated in asthma. To date, a number of GWAS studies in asthma have been made, with the identification of about 1000 candidate genes. Coordination of the different research groups in international consortiums and the application of new technologies such as new generation sequencing will help discover new implicated genes and improve our understanding of the molecular mechanisms underlying the disease. PMID:25433770

  16. A genome-wide association study of copy number variations with umbilical hernia in swine.

    Science.gov (United States)

    Long, Yi; Su, Ying; Ai, Huashui; Zhang, Zhiyan; Yang, Bin; Ruan, Guorong; Xiao, Shijun; Liao, Xinjun; Ren, Jun; Huang, Lusheng; Ding, Nengshui

    2016-06-01

    Umbilical hernia (UH) is one of the most common congenital defects in pigs, leading to considerable economic loss and serious animal welfare problems. To test whether copy number variations (CNVs) contribute to pig UH, we performed a case-control genome-wide CNV association study on 905 pigs from the Duroc, Landrace and Yorkshire breeds using the Porcine SNP60 BeadChip and penncnv algorithm. We first constructed a genomic map comprising 6193 CNVs that pertain to 737 CNV regions. Then, we identified eight CNVs significantly associated with the risk for UH in the three pig breeds. Six of seven significantly associated CNVs were validated using quantitative real-time PCR. Notably, a rare CNV (CNV14:13030843-13059455) encompassing the NUGGC gene was strongly associated with UH (permutation-corrected P = 0.0015) in Duroc pigs. This CNV occurred exclusively in seven Duroc UH-affected individuals. SNPs surrounding the CNV did not show association signals, indicating that rare CNVs may play an important role in complex pig diseases such as UH. The NUGGC gene has been implicated in human omphalocele and inguinal hernia. Our finding supports that CNVs, including the NUGGC CNV, contribute to the pathogenesis of pig UH. PMID:27028052

  17. Software engineering the mixed model for genome-wide association studies on large samples.

    Science.gov (United States)

    Zhang, Zhiwu; Buckler, Edward S; Casstevens, Terry M; Bradbury, Peter J

    2009-11-01

    Mixed models improve the ability to detect phenotype-genotype associations in the presence of population stratification and multiple levels of relatedness in genome-wide association studies (GWAS), but for large data sets the resource consumption becomes impractical. At the same time, the sample size and number of markers used for GWAS is increasing dramatically, resulting in greater statistical power to detect those associations. The use of mixed models with increasingly large data sets depends on the availability of software for analyzing those models. While multiple software packages implement the mixed model method, no single package provides the best combination of fast computation, ability to handle large samples, flexible modeling and ease of use. Key elements of association analysis with mixed models are reviewed, including modeling phenotype-genotype associations using mixed models, population stratification, kinship and its estimation, variance component estimation, use of best linear unbiased predictors or residuals in place of raw phenotype, improving efficiency and software-user interaction. The available software packages are evaluated, and suggestions made for future software development. PMID:19933212

  18. Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias.

    Directory of Open Access Journals (Sweden)

    Gary W Beecham

    2014-09-01

    Full Text Available Alzheimer's disease (AD and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs, and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA, Lewy body disease (LBD, hippocampal sclerosis of the elderly (HS, and vascular brain injury (VBI. Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE. GalNAc transferase 7 (GALNT7, ATP-Binding Cassette, Sub-Family G (WHITE, Member 1 (ABCG1, and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2 was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related

  19. Genome-wide association study for intramuscular fatty acid composition in an Iberian × Landrace cross.

    Science.gov (United States)

    Ramayo-Caldas, Y; Mercadé, A; Castelló, A; Yang, B; Rodríguez, C; Alves, E; Díaz, I; Ibáñez-Escriche, N; Noguera, J L; Pérez-Enciso, M; Fernández, A I; Folch, J M

    2012-09-01

    The lipid content and fatty acid (FA) profile have an important impact in human health as well as in the technological transformation and nutritional and organoleptic quality of meat. A genome-wide association study (GWAS) on 144 backcross pigs (25% Iberian × 75% Landrace) was performed for 32 traits associated with intramuscular FA composition and indices of FA metabolism. The GWAS was carried out using Qxpak 5.0 and the genotyping information obtained from the Porcine SNP60K BeadChip (Illumina Inc., San Diego, CA). Signals of significant association considering a false- discovery rate (q-value < 0.05) were observed in 15 of the 32 analyzed traits, and a total of 813 trait-associated SNP (TAS), distributed in 43 chromosomal intervals on almost all autosomes, were annotated. According to the clustering analysis based on functional classification, several of the annotated genes are related to FA composition and lipid metabolism. Some interesting positional concordances among TAS and previously reported QTL for FA compositions and/or other lipid traits were also found. These common genomic regions for different traits suggest pleiotropic effects for FA composition and were found primarily on SSC4, SSC8, and SSC16. These results contribute to our understanding of the complex genetic basis of FA composition and FA metabolism. PMID:22785162

  20. A genome-wide association study of the metabolic syndrome in Indian Asian men.

    Directory of Open Access Journals (Sweden)

    Delilah Zabaneh

    Full Text Available We conducted a two-stage genome-wide association study to identify common genetic variation altering risk of the metabolic syndrome and related phenotypes in Indian Asian men, who have a high prevalence of these conditions. In Stage 1, approximately 317,000 single nucleotide polymorphisms were genotyped in 2700 individuals, from which 1500 SNPs were selected to be genotyped in a further 2300 individuals. Selection for inclusion in Stage 1 was based on four metabolic syndrome component traits: HDL-cholesterol, plasma glucose and Type 2 diabetes, abdominal obesity measured by waist to hip ratio, and diastolic blood pressure. Association was tested with these four traits and a composite metabolic syndrome phenotype. Four SNPs reaching significance level p0.8 were found in genes CETP and LPL, associated with HDL-cholesterol. These associations have already been reported in Indian Asians and in Europeans. Five additional loci harboured SNPs significant at p0.5 for HDL-cholesterol, type 2 diabetes or diastolic blood pressure. Our results suggest that the primary genetic determinants of metabolic syndrome are the same in Indian Asians as in other populations, despite the higher prevalence. Further, we found little evidence of a common genetic basis for metabolic syndrome traits in our sample of Indian Asian men.

  1. A genome-wide association study of neuroticism in a population-based sample.

    Directory of Open Access Journals (Sweden)

    Federico C F Calboli

    Full Text Available Neuroticism is a moderately heritable personality trait considered to be a risk factor for developing major depression, anxiety disorders and dementia. We performed a genome-wide association study in 2,235 participants drawn from a population-based study of neuroticism, making this the largest association study for neuroticism to date. Neuroticism was measured by the Eysenck Personality Questionnaire. After Quality Control, we analysed 430,000 autosomal SNPs together with an additional 1.2 million SNPs imputed with high quality from the Hap Map CEU samples. We found a very small effect of population stratification, corrected using one principal component, and some cryptic kinship that required no correction. NKAIN2 showed suggestive evidence of association with neuroticism as a main effect (p < 10(-6 and GPC6 showed suggestive evidence for interaction with age (p approximately = 10(-7. We found support for one previously-reported association (PDE4D, but failed to replicate other recent reports. These results suggest common SNP variation does not strongly influence neuroticism. Our study was powered to detect almost all SNPs explaining at least 2% of heritability, and so our results effectively exclude the existence of loci having a major effect on neuroticism.

  2. Meta-analysis of genome-wide association from genomic prediction models.

    Science.gov (United States)

    Bernal Rubio, Y L; Gualdrón Duarte, J L; Bates, R O; Ernst, C W; Nonneman, D; Rohrer, G A; King, A; Shackelford, S D; Wheeler, T L; Cantet, R J C; Steibel, J P

    2016-02-01

    Genome-wide association (GWA) studies based on GBLUP models are a common practice in animal breeding. However, effect sizes of GWA tests are small, requiring larger sample sizes to enhance power of detection of rare variants. Because of difficulties in increasing sample size in animal populations, one alternative is to implement a meta-analysis (MA), combining information and results from independent GWA studies. Although this methodology has been used widely in human genetics, implementation in animal breeding has been limited. Thus, we present methods to implement a MA of GWA, describing the proper approach to compute weights derived from multiple genomic evaluations based on animal-centric GBLUP models. Application to real datasets shows that MA increases power of detection of associations in comparison with population-level GWA, allowing for population structure and heterogeneity of variance components across populations to be accounted for. Another advantage of MA is that it does not require access to genotype data that is required for a joint analysis. Scripts related to the implementation of this approach, which consider the strength of association as well as the sign, are distributed and thus account for heterogeneity in association phase between QTL and SNPs. Thus, MA of GWA is an attractive alternative to summarizing results from multiple genomic studies, avoiding restrictions with genotype data sharing, definition of fixed effects and different scales of measurement of evaluated traits. PMID:26607299

  3. Genome-wide association study for T lymphocyte subpopulations in swine

    Directory of Open Access Journals (Sweden)

    Lu Xin

    2012-09-01

    Full Text Available Abstract Background Lymphocytes act as a major component of the adaptive immune system, taking very crucial responsibility for immunity. Differences in proportions of T-cell subpopulations in peripheral blood among individuals under same conditions provide evidence of genetic control on these traits, but little is known about the genetic mechanism of them, especially in swine. Identification of the genetic control on these variants may help the genetic improvement of immune capacity through selection. Results To identify genomic regions responsible for these immune traits in swine, a genome-wide association study was conducted. A total of 675 pigs of three breeds were involved in the study. At 21 days of age, all individuals were vaccinated with modified live classical swine fever vaccine. Blood samples were collected when the piglets were 20 and 35 days of age, respectively. Seven traits, including the proportions of CD4+, CD8+, CD4+CD8+, CD4+CD8−, CD4−CD8+, CD4−CD8− and the ratio of CD4+ to CD8+ T cells were measured at the two ages. All the samples were genotyped for 62,163 single nucleotide polymorphisms (SNP using the Illumina porcineSNP60k BeadChip. 40833 SNPs were selected after quality control for association tests between SNPs and each immune trait considered based on a single-locus regression model. To tackle the issue of multiple testing in GWAS, 10,000 permutations were performed to determine the chromosome-wise and genome-wise significance levels of association tests. In total, 61 SNPs with chromosome-wise significance level and 3 SNPs with genome-wise significance level were identified. 27 significant SNPs were located within the immune-related QTL regions reported in previous studies. Furthermore, several significant SNPs fell into the regions harboring known immunity-related genes, 14 of them fell into the regions which harbor some known T cell-related genes. Conclusions Our study demonstrated that genome-wide association

  4. Genome Wide Association Studies (GWAS) and Common Forms of Human Epilepsy

    OpenAIRE

    Buono, Russell J.

    2013-01-01

    Several GWAS focused on common forms of epilepsy are underway. Currently, only one locus has been published that reached genome wide statistical significance. Two other loci that also reach genome wide statistical significance have been reported as preliminary data and are awaiting publication. Several additional loci identified in these studies fall just short of statistical significance and it is hoped that future large scale meta-analyses will confirm these early findings and identify new ...

  5. A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features

    OpenAIRE

    Adhikari, Kaustubh; Fontanil, Tania; Cal, Santiago; Mendoza-Revilla, Javier; Fuentes-Guajardo, Macarena; Chacón-Duque, Juan-Camilo; Al-Saadi, Farah; Johansson, Jeanette A.; Quinto-Sanchez, Mirsha; Acuña-Alonzo, Victor; Jaramillo, Claudia; Arias, William; Barquera Lozano, Rodrigo; Macín Pérez, Gastón; Gómez-Valdés, Jorge

    2016-01-01

    We report a genome-wide association scan in over 6,000 Latin Americans for features of scalp hair (shape, colour, greying, balding) and facial hair (beard thickness, monobrow, eyebrow thickness). We found 18 signals of association reaching genome-wide significance (P values 5 × 10(-8) to 3 × 10(-119)), including 10 novel associations. These include novel loci for scalp hair shape and balding, and the first reported loci for hair greying, monobrow, eyebrow and beard thickness. A newly identifi...

  6. A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features

    OpenAIRE

    Adhikari, Kaustubh; Fontanil, Tania; Cal, Santiago; Mendoza-Revilla, Javier; Fuentes-Guajardo, Macarena; Chacón-Duque, Juan-Camilo; Al-Saadi, Farah; Johansson, Jeanette A.; Quinto-Sanchez, Mirsha; Acuña-Alonzo, Victor; Jaramillo, Claudia; Arias, William; Barquera Lozano, Rodrigo; Macín Pérez, Gastón; Gómez-Valdés, Jorge

    2016-01-01

    We report a genome-wide association scan in over 6,000 Latin Americans for features of scalp hair (shape, colour, greying, balding) and facial hair (beard thickness, monobrow, eyebrow thickness). We found 18 signals of association reaching genome-wide significance (P values 5 × 10−8 to 3 × 10−119), including 10 novel associations. These include novel loci for scalp hair shape and balding, and the first reported loci for hair greying, monobrow, eyebrow and beard thickness. A newly identified l...

  7. Genome-wide association study identifies susceptibility loci for Dengue shock syndrome at MICB and PLCE1

    OpenAIRE

    Khor, Chiea Chuen; Bich, Chau Tran Nguyen; Pang, Junxiong; Davila, Sonia; Long, Hoang Truong; Ong, Rick T.H.; Dunstan, Sarah J; Wills, Bridget; Farrar, Jeremy; Tram, Ta Van; Gan, Tran Thi; Binh, Nguyen Thi Nguyet; Tri, Le Trung; Lien, Le Bich; Tuan, Nguyen Minh

    2011-01-01

    Hypovolemic shock (Dengue shock syndrome (DSS)), is the commonest life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and 2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese follow-up sample of 1,737 cases and 2,934 controls. Polymorphisms within two genes showed genome-wide significant association with DSS (P meta = 4.41 × 10−11, per-allele...

  8. An Empirical Bayes Mixture Model for Effect Size Distributions in Genome-Wide Association Studies.

    Science.gov (United States)

    Thompson, Wesley K; Wang, Yunpeng; Schork, Andrew J; Witoelar, Aree; Zuber, Verena; Xu, Shujing; Werge, Thomas; Holland, Dominic; Andreassen, Ole A; Dale, Anders M

    2015-12-01

    Characterizing the distribution of effects from genome-wide genotyping data is crucial for understanding important aspects of the genetic architecture of complex traits, such as number or proportion of non-null loci, average proportion of phenotypic variance explained per non-null effect, power for discovery, and polygenic risk prediction. To this end, previous work has used effect-size models based on various distributions, including the normal and normal mixture distributions, among others. In this paper we propose a scale mixture of two normals model for effect size distributions of genome-wide association study (GWAS) test statistics. Test statistics corresponding to null associations are modeled as random draws from a normal distribution with zero mean; test statistics corresponding to non-null associations are also modeled as normal with zero mean, but with larger variance. The model is fit via minimizing discrepancies between the parametric mixture model and resampling-based nonparametric estimates of replication effect sizes and variances. We describe in detail the implications of this model for estimation of the non-null proportion, the probability of replication in de novo samples, the local false discovery rate, and power for discovery of a specified proportion of phenotypic variance explained from additive effects of loci surpassing a given significance threshold. We also examine the crucial issue of the impact of linkage disequilibrium (LD) on effect sizes and parameter estimates, both analytically and in simulations. We apply this approach to meta-analysis test statistics from two large GWAS, one for Crohn's disease (CD) and the other for schizophrenia (SZ). A scale mixture of two normals distribution provides an excellent fit to the SZ nonparametric replication effect size estimates. While capturing the general behavior of the data, this mixture model underestimates the tails of the CD effect size distribution. We discuss the implications of

  9. Genome-wide association study for host response to bovine leukemia virus in Holstein cows.

    Science.gov (United States)

    Brym, P; Bojarojć-Nosowicz, B; Oleński, K; Hering, D M; Ruść, A; Kaczmarczyk, E; Kamiński, S

    2016-07-01

    The mechanisms of leukemogenesis induced by bovine leukemia virus (BLV) and the processes underlying the phenomenon of differential host response to BLV infection still remain poorly understood. The aim of the study was to screen the entire cattle genome to identify markers and candidate genes that might be involved in host response to bovine leukemia virus infection. A genome-wide association study was performed using Holstein cows naturally infected by BLV. A data set included 43 cows (BLV positive) and 30 cows (BLV negative) genotyped for 54,609 SNP markers (Illumina Bovine SNP50 BeadChip). The BLV status of cows was determined by serum ELISA, nested-PCR and hematological counts. Linear Regression Analysis with a False Discovery Rate and kinship matrix (computed on the autosomal SNPs) was calculated to find out which SNP markers significantly differentiate BLV-positive and BLV-negative cows. Nine markers reached genome-wide significance. The most significant SNPs were located on chromosomes 23 (rs41583098), 3 (rs109405425, rs110785500) and 8 (rs43564499) in close vicinity of a patatin-like phospholipase domain containing 1 (PNPLA1); adaptor-related protein complex 4, beta 1 subunit (AP4B1); tripartite motif-containing 45 (TRIM45) and cell division cycle associated 2 (CDCA2) genes, respectively. Furthermore, a list of 41 candidate genes was composed based on their proximity to significant markers (within a distance of ca. 1 Mb) and functional involvement in processes potentially underlying BLV-induced pathogenesis. In conclusion, it was demonstrated that host response to BLV infection involves nine sub-regions of the cattle genome (represented by 9 SNP markers), containing many genes which, based on the literature, could be involved to enzootic bovine leukemia progression. New group of promising candidate genes associated with the host response to BLV infection were identified and could therefore be a target for future studies. The functions of candidate genes

  10. Neuropsychological effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253.

    Science.gov (United States)

    Donohoe, G; Walters, J; Hargreaves, A; Rose, E J; Morris, D W; Fahey, C; Bellini, S; Cummins, E; Giegling, I; Hartmann, A M; Möller, H-J; Muglia, P; Owen, M J; Gill, M; O'Donovan, M C; Tropea, D; Rujescu, D; Corvin, A

    2013-03-01

    The single-nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, was recently identified as genome-wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk 'A' allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk 'A' allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified 'A' risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk. PMID:23320435

  11. Confluence of genes, environment, development, and behavior in a post Genome-Wide Association Study world.

    Science.gov (United States)

    Vrieze, Scott I; Iacono, William G; McGue, Matt

    2012-11-01

    This article serves to outline a research paradigm to investigate main effects and interactions of genes, environment, and development on behavior and psychiatric illness. We provide a historical context for candidate gene studies and genome-wide association studies, including benefits, limitations, and expected payoffs. Using substance use and abuse as our driving example, we then turn to the importance of etiological psychological theory in guiding genetic, environmental, and developmental research, as well as the utility of refined phenotypic measures, such as endophenotypes, in the pursuit of etiological understanding and focused tests of genetic and environmental associations. Phenotypic measurement has received considerable attention in the history of psychology and is informed by psychometrics, whereas the environment remains relatively poorly measured and is often confounded with genetic effects (i.e., gene-environment correlation). Genetically informed designs, which are no longer limited to twin and adoption studies thanks to ever-cheaper genotyping, are required to understand environmental influences. Finally, we outline the vast amount of individual difference in structural genomic variation, most of which remains to be leveraged in genetic association tests. Although the genetic data can be massive and burdensome (tens of millions of variants per person), we argue that improved understanding of genomic structure and function will provide investigators with new tools to test specific a priori hypotheses derived from etiological psychological theory, much like current candidate gene research but with less confusion and more payoff than candidate gene research has to date. PMID:23062291

  12. Beyond Endometriosis Genome-Wide Association Study: From Genomics to Phenomics to the Patient.

    Science.gov (United States)

    Zondervan, Krina T; Rahmioglu, Nilufer; Morris, Andrew P; Nyholt, Dale R; Montgomery, Grant W; Becker, Christian M; Missmer, Stacey A

    2016-07-01

    Endometriosis is a heritable, complex chronic inflammatory disease, for which much of the causal pathogenic mechanism remains unknown. Genome-wide association studies (GWAS) to date have identified 12 single nucleotide polymorphisms at 10 independent genetic loci associated with endometriosis. Most of these were more strongly associated with revised American Fertility Society stage III/IV, rather than stage I/II. The loci are almost all located in intergenic regions that are known to play a role in the regulation of expression of target genes yet to be identified. To identify the target genes and pathways perturbed by the implicated variants, studies are required involving functional genomic annotation of the surrounding chromosomal regions, in terms of transcription factor binding, epigenetic modification (e.g., DNA methylation and histone modification) sites, as well as their correlation with RNA transcription. These studies need to be conducted in tissue types relevant to endometriosis-in particular, endometrium. In addition, to allow biologically and clinically relevant interpretation of molecular profiling data, they need to be combined and correlated with detailed, systematically collected phenotypic information (surgical and clinical). The WERF Endometriosis Phenome and Biobanking Harmonisation Project is a global standardization initiative that has produced consensus data and sample collection protocols for endometriosis research. These now pave the way for collaborative studies integrating phenomic with genomic data, to identify informative subtypes of endometriosis that will enhance understanding of the pathogenic mechanisms of the disease and discovery of novel, targeted treatments. PMID:27513026

  13. Genome-wide association with residual body weight gain in Bos indicus cattle.

    Science.gov (United States)

    Santana, M H A; Gomes, R C; Utsunomiya, Y T; Neves, H H R; Novais, F J; Bonin, M N; Fukumasu, H; Garcia, J F; Alexandre, P A; Oliveira Junior, G A; Coutinho, L L; Ferraz, J B S

    2015-01-01

    Weight gain is a key performance trait for beef cat-tle; however, attention should be given to the production costs for better profitability. Therefore, a feed efficiency trait based on per-formance can be an interesting approach to improve performance without increasing food costs. To identify candidate genes and ge-nomic regions associated with residual body weight gain (RWG), we conducted a genome-wide association study (GWAS) with 720 Nellore cattle using the GRAMMAR-Gamma association test. We identified 30 significant single nucleotide polymorphisms (SNPs), especially on chromosomes 2, 8, 12, and 17. Several genes and quantitative train loci (QTLs) present in the regions identified were appointed; we highlight DMRT2 (doublesex and mab-3 related tran-scription factor 2), IFFO2 (intermediate filament family orphan 2), LNX2 (ligand of numb-protein X 2), MTIF3 (mitochondrial transla-tional initiation factor 3), and TRNAG-CCC (transfer RNA glycine anticodon CCC). The metabolic pathways that can explain part of the phenotypic variation in RWG are related to oxidative stress and muscle control. PMID:26125717

  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. PMID:27064256

  15. Neuropsychological effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253.

    LENUS (Irish Health Repository)

    Donohoe, G

    2013-03-01

    The single-nucleotide polymorphism (SNP) rs10503253, located within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2, was recently identified as genome-wide significant for schizophrenia (SZ), but is of unknown function. We investigated the neurocognitive effects of this CSMD1 variant in vivo in patients and healthy participants using behavioral and imaging measures of brain structure and function. We compared carriers and non-carriers of the risk \\'A\\' allele on measures of neuropsychological performance typically impaired in SZ (general cognitive ability, episodic and working memory and attentional control) in independent samples of Irish patients (n = 387) and controls (n = 171) and German patients (205) and controls (n = 533). Across these groups, the risk \\'A\\' allele at CSMD1 was associated with deleterious effects across a number of neurocognitive phenotypes. Specifically, the risk allele was associated with poorer performance on neuropsychological measures of general cognitive ability and memory function but not attentional control. These effects, while significant, were subtle, and varied between samples. Consistent with previous evidence suggesting that CSMD1 may be involved in brain mechanisms related to memory and learning, these data appear to reflect the deleterious effects of the identified \\'A\\' risk allele on neurocognitive function, possibly as part of the mechanism by which CSMD1 is associated with SZ risk.

  16. Pathway-Based Genome-wide Association Studies Reveal That the Rac1 Pathway Is Associated with Plasma Adiponectin Levels

    OpenAIRE

    Wei-Dong Li; Hongxiao Jiao; Kai Wang; Fuhua Yang; Grant, Struan F.A.; Hakon Hakonarson; Rexford Ahima; R. Arlen Price

    2015-01-01

    Pathway-based analysis as an alternative and effective approach to identify disease-related genes or loci has been verified. To decipher the genetic background of plasma adiponectin levels, we performed genome wide pathway-based association studies in extremely obese individuals and normal-weight controls. The modified Gene Set Enrichment Algorithm (GSEA) was used to perform the pathway-based analyses (the GenGen Program) in 746 European American females, which were collected from our previou...

  17. Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study.

    Directory of Open Access Journals (Sweden)

    Toshiko Tanaka

    2009-01-01

    Full Text Available Polyunsaturated fatty acids (PUFA have a role in many physiological processes, including energy production, modulation of inflammation, and maintenance of cell membrane integrity. High plasma PUFA concentrations have been shown to have beneficial effects on cardiovascular disease and mortality. To identify genetic contributors of plasma PUFA concentrations, we conducted a genome-wide association study of plasma levels of six omega-3 and omega-6 fatty acids in 1,075 participants in the InCHIANTI study on aging. The strongest evidence for association was observed in a region of chromosome 11 that encodes three fatty acid desaturases (FADS1, FADS2, FADS3. The SNP with the most significant association was rs174537 near FADS1 in the analysis of arachidonic acid (AA; p = 5.95 x 10(-46. Minor allele homozygotes had lower AA compared to the major allele homozygotes and rs174537 accounted for 18.6% of the additive variance in AA concentrations. This SNP was also associated with levels of eicosadienoic acid (EDA; p = 6.78 x 10(-9 and eicosapentanoic acid (EPA; p = 1.07 x 10(-14. Participants carrying the allele associated with higher AA, EDA, and EPA also had higher low-density lipoprotein (LDL-C and total cholesterol levels. Outside the FADS gene cluster, the strongest region of association mapped to chromosome 6 in the region encoding an elongase of very long fatty acids 2 (ELOVL2. In this region, association was observed with EPA (rs953413; p = 1.1 x 10(-6. The effects of rs174537 were confirmed in an independent sample of 1,076 subjects participating in the GOLDN study. The ELOVL2 SNP was associated with docosapentanoic and DHA but not with EPA in GOLDN. These findings show that polymorphisms of genes encoding enzymes in the metabolism of PUFA contribute to plasma concentrations of fatty acids.

  18. Univariate/multivariate genome-wide association scans using data from families and unrelated samples.

    Directory of Open Access Journals (Sweden)

    Lei Zhang

    Full Text Available As genome-wide association studies (GWAS are becoming more popular, two approaches, among others, could be considered in order to improve statistical power for identifying genes contributing subtle to moderate effects to human diseases. The first approach is to increase sample size, which could be achieved by combining both unrelated and familial subjects together. The second approach is to jointly analyze multiple correlated traits. In this study, by extending generalized estimating equations (GEEs, we propose a simple approach for performing univariate or multivariate association tests for the combined data of unrelated subjects and nuclear families. In particular, we correct for population stratification by integrating principal component analysis and transmission disequilibrium test strategies. The proposed method allows for multiple siblings as well as missing parental information. Simulation studies show that the proposed test has improved power compared to two popular methods, EIGENSTRAT and FBAT, by analyzing the combined data, while correcting for population stratification. In addition, joint analysis of bivariate traits has improved power over univariate analysis when pleiotropic effects are present. Application to the Genetic Analysis Workshop 16 (GAW16 data sets attests to the feasibility and applicability of the proposed method.

  19. [Genome-Wide Association Studies for life-style related diseases].

    Science.gov (United States)

    Maeda, Shiro

    2016-03-01

    After the completion of human genome project, development of single nucleotide polymorphism (SNP) typing technology and collation of information regarding linkage disequilibrium in the human genome have facilitated genome-wide association studies (GWAS) for investigating genes associated with disease susceptibility across the entire human genome. In case of type 2 diabetes, approximately 100 genetic loci have been identified and confirmed as susceptibility to the disease through GWAS in different ethnic groups, including Japanese, European, East Asian and South Asian populations. However, integration of these information accounts for less than 20% of the disease heritability, and thus most of the heritability of type 2 diabetes remain to be identified. Since the rationale of GWAS is based on the hypothesis that common variants contribute to the susceptibility to common diseases, common disease-common variant hypothesis, GWAS have selectively identified common susceptibility variants (allele frequency>=0.05) with lower effect size (odds ratiogenome sequencing to identify rare variants with greater effect size or integration of genetic and environmental information, will be required to elucidate a heritability of life-style related diseases completely. PMID:26923980

  20. Genome-Wide Association Study of a Varroa-Specific Defense Behavior in Honeybees (Apis mellifera).

    Science.gov (United States)

    Spötter, Andreas; Gupta, Pooja; Mayer, Manfred; Reinsch, Norbert; Bienefeld, Kaspar

    2016-05-01

    Honey bees are exposed to many damaging pathogens and parasites. The most devastating is Varroa destructor, which mainly affects the brood. A promising approach for preventing its spread is to breed Varroa-resistant honey bees. One trait that has been shown to provide significant resistance against the Varroa mite is hygienic behavior, which is a behavioral response of honeybee workers to brood diseases in general. Here, we report the use of an Affymetrix 44K SNP array to analyze SNPs associated with detection and uncapping of Varroa-parasitized brood by individual worker bees (Apis mellifera). For this study, 22 000 individually labeled bees were video-monitored and a sample of 122 cases and 122 controls was collected and analyzed to determine the dependence/independence of SNP genotypes from hygienic and nonhygienic behavior on a genome-wide scale. After false-discovery rate correction of the P values, 6 SNP markers had highly significant associations with the trait investigated (α < 0.01). Inspection of the genomic regions around these SNPs led to the discovery of putative candidate genes. PMID:26774061

  1. Genome-wide association mapping of heritable temperament variation in the Tennessee Walking Horse.

    Science.gov (United States)

    Staiger, E A; Albright, J D; Brooks, S A

    2016-06-01

    Temperament is a key criterion in the selection of horses for both leisure and competitive riding to ensure optimal performance and safety. The Tennessee Walking Horse (TWH) is described as a calm, docile breed and is often used as a trail, show and pleasure horse. However, among horse owners and caretakers, there are anecdotes supporting familial and disciplinal typical behaviors and personalities. To investigate the contribution of genetics to temperament, we collected a behavior questionnaire, brief training history and identifying information for 276 TWH, as well as blood or hair samples for DNA. Factor analysis was conducted on the 20-item questionnaire for the set of 216 horses that met inclusion thresholds. Factor analysis identified four temperament factors in TWH: 'anxious', 'tractable', 'agonistic' and 'gregarious'. These four factors account for 64% of the total trait variance. DNA from 113 TWHs were selected and genotyped using the Equine SNP70 bead chip for three separate genome-wide association studies (GWAs) using the factor 1-anxious, factor 2-tractable and factor 3-agonistic scores as the phenotype. Quantitative association analysis identified significant candidate loci for each factor that warrant further investigation. PMID:26991152

  2. Genome wide association mapping for the tolerance to the polyamine oxidase inhibitor guazatine in Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Kostadin Evgeniev eAtanasov

    2016-04-01

    Full Text Available Guazatine is a potent inhibitor of polyamine oxidase (PAO activity. In agriculture, guazatine is used as non-systemic contact fungicide efficient in the protection of cereals and citrus fruits against disease. The composition of guazatine is complex, mainly constituted by a mixture of synthetic guanidated polyamines (polyaminoguanidines. Here we have studied the effects from exposure to guazatine in the weed Arabidopsis thaliana. We report that micromolar concentrations of guazatine are sufficient to inhibit growth of Arabidopsis seedlings and induce chlorosis, whereas germination is barely affected. We observed the occurrence of quantitative variation in the response to guazatine between 107 randomly chosen Arabidopsis accessions. This enabled us to undertake genome-wide association (GWA mapping that identified a locus on chromosome one associated with guazatine tolerance. CHLOROPHYLLASE 1 (CLH1 within this locus was studied as candidate gene, together with its paralog (CLH2. The analysis of independent clh1-2, clh1-3, clh2-3, clh2-2 and double clh1-2 clh2-3 mutant alleles indicated that CLH1 and/or CLH2 loss-of-function or expression down-regulation promote guazatine tolerance in Arabidopsis. We report a natural mechanism by which Arabidopsis populations can overcome toxicity by the fungicide guazatine.

  3. Genome Wide Association Mapping for the Tolerance to the Polyamine Oxidase Inhibitor Guazatine in Arabidopsis thaliana.

    Science.gov (United States)

    Atanasov, Kostadin E; Barboza-Barquero, Luis; Tiburcio, Antonio F; Alcázar, Rubén

    2016-01-01

    Guazatine is a potent inhibitor of polyamine oxidase (PAO) activity. In agriculture, guazatine is used as non-systemic contact fungicide efficient in the protection of cereals and citrus fruits against disease. The composition of guazatine is complex, mainly constituted by a mixture of synthetic guanidated polyamines (polyaminoguanidines). Here, we have studied the effects from exposure to guazatine in the weed Arabidopsis thaliana. We report that micromolar concentrations of guazatine are sufficient to inhibit growth of Arabidopsis seedlings and induce chlorosis, whereas germination is barely affected. We observed the occurrence of quantitative variation in the response to guazatine between 107 randomly chosen Arabidopsis accessions. This enabled us to undertake genome-wide association (GWA) mapping that identified a locus on chromosome one associated with guazatine tolerance. CHLOROPHYLLASE 1 (CLH1) within this locus was studied as candidate gene, together with its paralog (CLH2). The analysis of independent clh1-2, clh1-3, clh2-3, clh2-2, and double clh1-2 clh2-3 mutant alleles indicated that CLH1 and/or CLH2 loss-of-function or expression down-regulation promote guazatine tolerance in Arabidopsis. We report a natural mechanism by which Arabidopsis populations can overcome toxicity by the fungicide guazatine. PMID:27092150

  4. Genome-wide association study of metabolic traits reveals novel gene-metabolite-disease links.

    Directory of Open Access Journals (Sweden)

    Rico Rueedi

    2014-02-01

    Full Text Available Metabolic traits are molecular phenotypes that can drive clinical phenotypes and may predict disease progression. Here, we report results from a metabolome- and genome-wide association study on (1H-NMR urine metabolic profiles. The study was conducted within an untargeted approach, employing a novel method for compound identification. From our discovery cohort of 835 Caucasian individuals who participated in the CoLaus study, we identified 139 suggestively significant (P<5×10(-8 and independent associations between single nucleotide polymorphisms (SNP and metabolome features. Fifty-six of these associations replicated in the TasteSensomics cohort, comprising 601 individuals from São Paulo of vastly diverse ethnic background. They correspond to eleven gene-metabolite associations, six of which had been previously identified in the urine metabolome and three in the serum metabolome. Our key novel findings are the associations of two SNPs with NMR spectral signatures pointing to fucose (rs492602, P = 6.9×10(-44 and lysine (rs8101881, P = 1.2×10(-33, respectively. Fine-mapping of the first locus pinpointed the FUT2 gene, which encodes a fucosyltransferase enzyme and has previously been associated with Crohn's disease. This implicates fucose as a potential prognostic disease marker, for which there is already published evidence from a mouse model. The second SNP lies within the SLC7A9 gene, rare mutations of which have been linked to severe kidney damage. The replication of previous associations and our new discoveries demonstrate the potential of untargeted metabolomics GWAS to robustly identify molecular disease markers.

  5. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution.

    Science.gov (United States)

    Ramagopalan, Sreeram V; Heger, Andreas; Berlanga, Antonio J; Maugeri, Narelle J; Lincoln, Matthew R; Burrell, Amy; Handunnetthi, Lahiru; Handel, Adam E; Disanto, Giulio; Orton, Sarah-Michelle; Watson, Corey T; Morahan, Julia M; Giovannoni, Gavin; Ponting, Chris P; Ebers, George C; Knight, Julian C

    2010-10-01

    Initially thought to play a restricted role in calcium homeostasis, the pleiotropic actions of vitamin D in biology and their clinical significance are only now becoming apparent. However, the mode of action of vitamin D, through its cognate nuclear vitamin D receptor (VDR), and its contribution to diverse disorders, remain poorly understood. We determined VDR binding throughout the human genome using chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq). After calcitriol stimulation, we identified 2776 genomic positions occupied by the VDR and 229 genes with significant changes in expression in response to vitamin D. VDR binding sites were significantly enriched near autoimmune and cancer associated genes identified from genome-wide association (GWA) studies. Notable genes with VDR binding included IRF8, associated with MS, and PTPN2 associated with Crohn's disease and T1D. Furthermore, a number of single nucleotide polymorphism associations from GWA were located directly within VDR binding intervals, for example, rs13385731 associated with SLE and rs947474 associated with T1D. We also observed significant enrichment of VDR intervals within regions of positive selection among individuals of Asian and European descent. ChIP-seq determination of transcription factor binding, in combination with GWA data, provides a powerful approach to further understanding the molecular bases of complex diseases. PMID:20736230

  6. Genome-wide association analysis of oxidative stress resistance in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Allison L Weber

    Full Text Available BACKGROUND: Aerobic organisms are susceptible to damage by reactive oxygen species. Oxidative stress resistance is a quantitative trait with population variation attributable to the interplay between genetic and environmental factors. Drosophila melanogaster provides an ideal system to study the genetics of variation for resistance to oxidative stress. METHODS AND FINDINGS: We used 167 wild-derived inbred lines of the Drosophila Genetic Reference Panel for a genome-wide association study of acute oxidative stress resistance to two oxidizing agents, paraquat and menadione sodium bisulfite. We found significant genetic variation for both stressors. Single nucleotide polymorphisms (SNPs associated with variation in oxidative stress resistance were often sex-specific and agent-dependent, with a small subset common for both sexes or treatments. Associated SNPs had moderately large effects, with an inverse relationship between effect size and allele frequency. Linear models with up to 12 SNPs explained 67-79% and 56-66% of the phenotypic variance for resistance to paraquat and menadione sodium bisulfite, respectively. Many genes implicated were novel with no known role in oxidative stress resistance. Bioinformatics analyses revealed a cellular network comprising DNA metabolism and neuronal development, consistent with targets of oxidative stress-inducing agents. We confirmed associations of seven candidate genes associated with natural variation in oxidative stress resistance through mutational analysis. CONCLUSIONS: We identified novel candidate genes associated with variation in resistance to oxidative stress that have context-dependent effects. These results form the basis for future translational studies to identify oxidative stress susceptibility/resistance genes that are evolutionary conserved and might play a role in human disease.

  7. Genome-wide association mapping of root traits in a japonica rice panel.

    Directory of Open Access Journals (Sweden)

    Brigitte Courtois

    Full Text Available Rice is a crop prone to drought stress in upland and rainfed lowland ecosystems. A deep root system is recognized as the best drought avoidance mechanism. Genome-wide association mapping offers higher resolution for locating quantitative trait loci (QTLs than QTL mapping in biparental populations. We performed an association mapping study for root traits using a panel of 167 japonica accessions, mostly of tropical origin. The panel was genotyped at an average density of one marker per 22.5 kb using genotyping by sequencing technology. The linkage disequilibrium in the panel was high (r(2>0.6, on average, for 20 kb mean distances between markers. The plants were grown in transparent 50 cm × 20 cm × 2 cm Plexiglas nailboard sandwiches filled with 1.5 mm glass beads through which a nutrient solution was circulated. Root system architecture and biomass traits were measured in 30-day-old plants. The panel showed a moderate to high diversity in the various traits, particularly for deep (below 30 cm depth root mass and the number of deep roots. Association analyses were conducted using a mixed model involving both population structure and kinship to control for false positives. Nineteen associations were significant at P<1e-05, and 78 were significant at P<1e-04. The greatest numbers of significant associations were detected for deep root mass and the number of deep roots, whereas no significant associations were found for total root biomass or deep root proportion. Because several QTLs for different traits were co-localized, 51 unique loci were detected; several co-localized with meta-QTLs for root traits, but none co-localized with rice genes known to be involved in root growth. Several likely candidate genes were found in close proximity to these loci. Additional work is necessary to assess whether these markers are relevant in other backgrounds and whether the genes identified are robust candidates.

  8. A genome wide association study of Plasmodium falciparum susceptibility to 22 antimalarial drugs in Kenya.

    Directory of Open Access Journals (Sweden)

    Jason P Wendler

    Full Text Available BACKGROUND: Drug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs. METHODS AND PRINCIPAL FINDINGS: Parasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set. CONCLUSIONS/SIGNIFICANCE: Sequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.

  9. Genome-wide association study dissects the genetic architecture of oil biosynthesis and accumulation in maize kernel

    Science.gov (United States)

    A Genome Wide Association Study (GWAS) on a population of 368 maize inbreds with 1.06 million SNPs was performed and identified 74 highly significantly associated genes influencing maize kernel oil content and fatty acid composition. To validate these findings, three biparental linkage mapping popul...

  10. GRASP: analysis of genotype–phenotype results from 1390 genome-wide association studies and corresponding open access database

    OpenAIRE

    Leslie, Richard; O’Donnell, Christopher J.; Johnson, Andrew D.

    2014-01-01

    Summary: We created a deeply extracted and annotated database of genome-wide association studies (GWAS) results. GRASP v1.0 contains >6.2 million SNP-phenotype association from among 1390 GWAS studies. We re-annotated GWAS results with 16 annotation sources including some rarely compared to GWAS results (e.g. RNAediting sites, lincRNAs, PTMs).

  11. Meta-Analysis of Genome-Wide Association Studies Identifies Six New Loci for Serum Calcium Concentrations

    NARCIS (Netherlands)

    C.M. O'Seaghdha (Conall); H. Wu (Hongsheng); Q. Yang (Qiong); K. Kapur (Karen); I. Guessous (Idris); P. Zuber (Patrick); A. Köttgen (Anna); C. Stoudmann (Candice); A. Teumer (Alexander); Z. Kutalik (Zoltán); M. Mangino (Massimo); A. Dehghan (Abbas); W. Zhang (Weihua); G. Eiriksdottir (Gudny); G. Li (Guo); T. Tanaka (Toshiko); L. Portas (Laura); L.M. Lopez (Lorna); C. Hayward (Caroline); K. Lohman (Kurt); K. Matsuda (Koichi); S. Padmanabhan (Sandosh); D. Firsov (Dmitri); R. Sorice; S. Ulivi (Shelia); A.C. Brockhaus (A. Catharina); M.E. Kleber (Marcus); A. Mahajan (Anubha); F.D.J. Ernst (Florian); V. Gudnason (Vilmundur); L.J. Launer (Lenore); A. Mace (Aurelien); E. Boerwinckle (Eric); D.E. Arking (Dan); C. Tanikawa (Chizu); Y. Nakamura (Yusuke); M.J. Brown (Morris); J.-M. Gaspoz (Jean-Michel); J.-M. Theler (Jean-Marc); D.S. Siscovick (David); B.M. Psaty (Bruce); S.M. Bergmann (Sven); P. Vollenweider (Peter); V. Vitart (Veronique); A.F. Wright (Alan); T. Zemunik (Tatijana); M. Boban (Mladen); I. Kolcic (Ivana); P. Navarro (Pau); E.M. Brown (Edward); K. Estrada Gil (Karol); J. Ding (Jinhui); T.B. Harris (Tamara); S. Bandinelli (Stefania); D.G. Hernandez (Dena); A. Singleton (Andrew); S. Girotto; D. Ruggiero; A.P. d' Adamo (Adamo Pio); A. Robino (Antonietta); T. Meitinger (Thomas); C. Meisinger (Christa); G. Davies (Gail); J.M. Starr (John); J.C. Chambers (John); B.O. Boehm (Bernhard); B. Winkelmann; J. Huang (Jian); D. Murgia (Daniela); S.H. Wild (Sarah); H. Campbell (Harry); A.D. Morris (Andrew); O.H. Franco (Oscar); A. Hofman (Albert); A.G. Uitterlinden (André); F. Rivadeneira Ramirez (Fernando); U. Vol̈ker (Uwe); M. Hannemann (Mario); R. Biffar (Reiner); W. Hoffmann (Wolfgang); S.-Y. Shin; P. Lescuyer (Pierre); H. Henry (Hughes); C. Schurmann (Claudia); P. Munroe (Patricia); P. Gasparini (Paolo); N. Pirastu (Nicola); M. Ciullo; C. Gieger (Christian); W. März (Winfried); L. Lind (Lars); T.D. Spector (Timothy); G.D. Smith; I. Rudan (Igor); J.F. Wilson (James); O. Polasek (Ozren); I.J. Deary (Ian); M. Pirastu (Mario); L. Ferrucci (Luigi); Y. Liu (Yongmei); B. Kestenbaum (Bryan); J.S. Kooner (Jaspal); J.C.M. Witteman (Jacqueline); M. Nauck (Matthias); W.H.L. Kao (Wen); H. Wallaschofski (Henri); O. Bonny (Olivier); C. Fox (Craig); M. Bochud (Murielle)

    2013-01-01

    textabstractCalcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 populati

  12. Exploiting SNP correlations within random forest for genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Vincent Botta

    Full Text Available The primary goal of genome-wide association studies (GWAS is to discover variants that could lead, in isolation or in combination, to a particular trait or disease. Standard approaches to GWAS, however, are usually based on univariate hypothesis tests and therefore can account neither for correlations due to linkage disequilibrium nor for combinations of several markers. To discover and leverage such potential multivariate interactions, we propose in this work an extension of the Random Forest algorithm tailored for structured GWAS data. In terms of risk prediction, we show empirically on several GWAS datasets that the proposed T-Trees method significantly outperforms both the original Random Forest algorithm and standard linear models, thereby suggesting the actual existence of multivariate non-linear effects due to the combinations of several SNPs. We also demonstrate that variable importances as derived from our method can help identify relevant loci. Finally, we highlight the strong impact that quality control procedures may have, both in terms of predictive power and loci identification. Variable importance results and T-Trees source code are all available at www.montefiore.ulg.ac.be/~botta/ttrees/ and github.com/0asa/TTree-source respectively.

  13. Genetic variations underlying Alzheimer's disease: evidence from genome-wide association studies and beyond.

    Science.gov (United States)

    Cuyvers, Elise; Sleegers, Kristel

    2016-07-01

    With the advent of genome-wide association studies (GWAS) and next-generation sequencing, more than 20 risk loci that affect Alzheimer's disease have been identified. These loci are estimated to explain about 28% of the heritability of liability, 30% of familial risk, and over 50% of sibling recurrence risk of developing Alzheimer's disease. These estimates are high in comparison with those for other complex diseases for which more risk loci have been discovered, such as type 2 diabetes, which is mostly a result of the strong effect of APOE ɛ4 and to a lesser extent the rare variant TREM2 p.Arg47His. The search for functionally relevant genetic variants in risk loci detected in GWAS has revealed that the genetic variations underlying Alzheimer's disease include common variants affecting expression and splicing, a functional intragenic copy number variation, and rare pathogenic variants in risk loci, some of which might lead to familial Alzheimer's disease. An understanding of the contribution of these variants to the development of Alzheimer's disease has several clinical implications, including enhancing diagnostic accuracy and providing targets for the development of novel treatments. PMID:27302364

  14. Genome Wide Association Analysis Reveals New Production Trait Genes in a Male Duroc Population.

    Directory of Open Access Journals (Sweden)

    Kejun Wang

    Full Text Available In this study, 796 male Duroc pigs were used to identify genomic regions controlling growth traits. Three production traits were studied: food conversion ratio, days to 100 KG, and average daily gain, using a panel of 39,436 single nucleotide polymorphisms. In total, we detected 11 genome-wide and 162 chromosome-wide single nucleotide polymorphism trait associations. The Gene ontology analysis identified 14 candidate genes close to significant single nucleotide polymorphisms, with growth-related functions: six for days to 100 KG (WT1, FBXO3, DOCK7, PPP3CA, AGPAT9, and NKX6-1, seven for food conversion ratio (MAP2, TBX15, IVL, ARL15, CPS1, VWC2L, and VAV3, and one for average daily gain (COL27A1. Gene ontology analysis indicated that most of the candidate genes are involved in muscle, fat, bone or nervous system development, nutrient absorption, and metabolism, which are all either directly or indirectly related to growth traits in pigs. Additionally, we found four haplotype blocks composed of suggestive single nucleotide polymorphisms located in the growth trait-related quantitative trait loci and further narrowed down the ranges, the largest of which decreased by ~60 Mb. Hence, our results could be used to improve pig production traits by increasing the frequency of favorable alleles via artificial selection.

  15. SNPpy--database management for SNP data from genome wide association studies.

    Directory of Open Access Journals (Sweden)

    Faheem Mitha

    Full Text Available BACKGROUND: We describe SNPpy, a hybrid script database system using the Python SQLAlchemy library coupled with the PostgreSQL database to manage genotype data from Genome-Wide Association Studies (GWAS. This system makes it possible to merge study data with HapMap data and merge across studies for meta-analyses, including data filtering based on the values of phenotype and Single-Nucleotide Polymorphism (SNP data. SNPpy and its dependencies are open source software. RESULTS: The current version of SNPpy offers utility functions to import genotype and annotation data from two commercial platforms. We use these to import data from two GWAS studies and the HapMap Project. We then export these individual datasets to standard data format files that can be imported into statistical software for downstream analyses. CONCLUSIONS: By leveraging the power of relational databases, SNPpy offers integrated management and manipulation of genotype and phenotype data from GWAS studies. The analysis of these studies requires merging across GWAS datasets as well as patient and marker selection. To this end, SNPpy enables the user to filter the data and output the results as standardized GWAS file formats. It does low level and flexible data validation, including validation of patient data. SNPpy is a practical and extensible solution for investigators who seek to deploy central management of their GWAS data.

  16. Neural effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253.

    Science.gov (United States)

    Rose, Emma J; Morris, Derek W; Hargreaves, April; Fahey, Ciara; Greene, Ciara; Garavan, Hugh; Gill, Michael; Corvin, Aiden; Donohoe, Gary

    2013-09-01

    The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2 has been identified as genome-wide significant for schizophrenia (SZ). This gene is of unknown function but has been implicated in multiple neurodevelopmental disorders that impact upon cognition, leading us to hypothesize that an effect on brain structure and function underlying cognitive processes may be part of the mechanism by which CMSD1 increases illness risk. To test this hypothesis, we investigated this CSMD1 variant in vivo in healthy participants in a magnetic resonance imaging (MRI) study comprised of both fMRI of spatial working memory (N = 50) and a voxel-based morphometry investigation of grey and white matter (WM) volume (N = 150). Analyses of these data indicated that the risk "A" allele was associated with comparatively reduced cortical activations in BA18, that is, middle occipital gyrus and cuneus; posterior brain regions that support maintenance processes during performance of a spatial working memory task. Conversely, there was an absence of significant structural differences in brain volume (i.e., grey or WM). In accordance with previous evidence, these data suggest that CSMD1 may mediate brain function related to cognitive processes (i.e., executive function); with the relatively deleterious effects of the identified "A" risk allele on brain activity possibly constituting part of the mechanism by which CSMD1 increases schizophrenia risk. PMID:23839771

  17. A mega-analysis of genome-wide association studies for major depressive disorder.

    Science.gov (United States)

    Ripke, Stephan; Wray, Naomi R; Lewis, Cathryn M; Hamilton, Steven P; Weissman, Myrna M; Breen, Gerome; Byrne, Enda M; Blackwood, Douglas H R; Boomsma, Dorret I; Cichon, Sven; Heath, Andrew C; Holsboer, Florian; Lucae, Susanne; Madden, Pamela A F; Martin, Nicholas G; McGuffin, Peter; Muglia, Pierandrea; Noethen, Markus M; Penninx, Brenda P; Pergadia, Michele L; Potash, James B; Rietschel, Marcella; Lin, Danyu; Müller-Myhsok, Bertram; Shi, Jianxin; Steinberg, Stacy; Grabe, Hans J; Lichtenstein, Paul; Magnusson, Patrik; Perlis, Roy H; Preisig, Martin; Smoller, Jordan W; Stefansson, Kari; Uher, Rudolf; Kutalik, Zoltan; Tansey, Katherine E; Teumer, Alexander; Viktorin, Alexander; Barnes, Michael R; Bettecken, Thomas; Binder, Elisabeth B; Breuer, René; Castro, Victor M; Churchill, Susanne E; Coryell, William H; Craddock, Nick; Craig, Ian W; Czamara, Darina; De Geus, Eco J; Degenhardt, Franziska; Farmer, Anne E; Fava, Maurizio; Frank, Josef; Gainer, Vivian S; Gallagher, Patience J; Gordon, Scott D; Goryachev, Sergey; Gross, Magdalena; Guipponi, Michel; Henders, Anjali K; Herms, Stefan; Hickie, Ian B; Hoefels, Susanne; Hoogendijk, Witte; Hottenga, Jouke Jan; Iosifescu, Dan V; Ising, Marcus; Jones, Ian; Jones, Lisa; Jung-Ying, Tzeng; Knowles, James A; Kohane, Isaac S; Kohli, Martin A; Korszun, Ania; Landen, Mikael; Lawson, William B; Lewis, Glyn; Macintyre, Donald; Maier, Wolfgang; Mattheisen, Manuel; McGrath, Patrick J; McIntosh, Andrew; McLean, Alan; Middeldorp, Christel M; Middleton, Lefkos; Montgomery, Grant M; Murphy, Shawn N; Nauck, Matthias; Nolen, Willem A; Nyholt, Dale R; O'Donovan, Michael; Oskarsson, Högni; Pedersen, Nancy; Scheftner, William A; Schulz, Andrea; Schulze, Thomas G; Shyn, Stanley I; Sigurdsson, Engilbert; Slager, Susan L; Smit, Johannes H; Stefansson, Hreinn; Steffens, Michael; Thorgeirsson, Thorgeir; Tozzi, Federica; Treutlein, Jens; Uhr, Manfred; van den Oord, Edwin J C G; Van Grootheest, Gerard; Völzke, Henry; Weilburg, Jeffrey B; Willemsen, Gonneke; Zitman, Frans G; Neale, Benjamin; Daly, Mark; Levinson, Douglas F; Sullivan, Patrick F

    2013-04-01

    Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with Pgenetic effects typical for complex traits. Therefore, we were unable to identify robust and replicable findings. We discuss what this means for genetic research for MDD. The 3p21.1 MDD-BIP finding should be interpreted with caution as the most significant SNP did not replicate in MDD samples, and genotyping in independent samples will be needed to resolve its status. PMID:22472876

  18. A novel algorithm for simultaneous SNP selection in high-dimensional genome-wide association studies

    Directory of Open Access Journals (Sweden)

    Zuber Verena

    2012-10-01

    Full Text Available Abstract Background Identification of causal SNPs in most genome wide association studies relies on approaches that consider each SNP individually. However, there is a strong correlation structure among SNPs that needs to be taken into account. Hence, increasingly modern computationally expensive regression methods are employed for SNP selection that consider all markers simultaneously and thus incorporate dependencies among SNPs. Results We develop a novel multivariate algorithm for large scale SNP selection using CAR score regression, a promising new approach for prioritizing biomarkers. Specifically, we propose a computationally efficient procedure for shrinkage estimation of CAR scores from high-dimensional data. Subsequently, we conduct a comprehensive comparison study including five advanced regression approaches (boosting, lasso, NEG, MCP, and CAR score and a univariate approach (marginal correlation to determine the effectiveness in finding true causal SNPs. Conclusions Simultaneous SNP selection is a challenging task. We demonstrate that our CAR score-based algorithm consistently outperforms all competing approaches, both uni- and multivariate, in terms of correctly recovered causal SNPs and SNP ranking. An R package implementing the approach as well as R code to reproduce the complete study presented here is available from http://strimmerlab.org/software/care/.

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

    Science.gov (United States)

    Mitchell, Jonathan S.; Li, Ni; Weinhold, Niels; Försti, Asta; Ali, Mina; van Duin, Mark; Thorleifsson, Gudmar; Johnson, David C.; Chen, Bowang; Halvarsson, Britt-Marie; Gudbjartsson, Daniel F.; Kuiper, Rowan; Stephens, Owen W.; Bertsch, Uta; Broderick, Peter; Campo, Chiara; Einsele, Hermann; Gregory, Walter A.; Gullberg, Urban; Henrion, Marc; Hillengass, Jens; Hoffmann, Per; Jackson, Graham H.; Johnsson, Ellinor; Jöud, Magnus; Kristinsson, Sigurður Y.; Lenhoff, Stig; Lenive, Oleg; Mellqvist, Ulf-Henrik; Migliorini, Gabriele; Nahi, Hareth; Nelander, Sven; Nickel, Jolanta; Nöthen, Markus M.; Rafnar, Thorunn; Ross, Fiona M.; da Silva Filho, Miguel Inacio; Swaminathan, Bhairavi; Thomsen, Hauke; Turesson, Ingemar; Vangsted, Annette; Vogel, Ulla; Waage, Anders; Walker, Brian A.; Wihlborg, Anna-Karin; Broyl, Annemiek; Davies, Faith E.; Thorsteinsdottir, Unnur; Langer, Christian; Hansson, Markus; Kaiser, Martin; Sonneveld, Pieter; Stefansson, Kari; Morgan, Gareth J.; Goldschmidt, Hartmut; Hemminki, Kari; Nilsson, Björn; Houlston, Richard S.

    2016-01-01

    Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add 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 × 10−11), 9p21.3 (rs2811710, P=1.72 × 10−13), 10p12.1 (rs2790457, P=1.77 × 10−8), 16q23.1 (rs7193541, P=5.00 × 10−12) and 20q13.13 (rs6066835, P=1.36 × 10−13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development. PMID:27363682

  20. Neural effects of the CSMD1 genome-wide associated schizophrenia risk variant rs10503253.

    LENUS (Irish Health Repository)

    Rose, Emma J

    2013-09-01

    The single nucleotide polymorphism rs10503253 within the CUB and Sushi multiple domains-1 (CSMD1) gene on 8p23.2 has been identified as genome-wide significant for schizophrenia (SZ). This gene is of unknown function but has been implicated in multiple neurodevelopmental disorders that impact upon cognition, leading us to hypothesize that an effect on brain structure and function underlying cognitive processes may be part of the mechanism by which CMSD1 increases illness risk. To test this hypothesis, we investigated this CSMD1 variant in vivo in healthy participants in a magnetic resonance imaging (MRI) study comprised of both fMRI of spatial working memory (N = 50) and a voxel-based morphometry investigation of grey and white matter (WM) volume (N = 150). Analyses of these data indicated that the risk "A" allele was associated with comparatively reduced cortical activations in BA18, that is, middle occipital gyrus and cuneus; posterior brain regions that support maintenance processes during performance of a spatial working memory task. Conversely, there was an absence of significant structural differences in brain volume (i.e., grey or WM). In accordance with previous evidence, these data suggest that CSMD1 may mediate brain function related to cognitive processes (i.e., executive function); with the relatively deleterious effects of the identified "A" risk allele on brain activity possibly constituting part of the mechanism by which CSMD1 increases schizophrenia risk.

  1. Genome-wide association studies using haplotypes and individual SNPs in Simmental cattle.

    Directory of Open Access Journals (Sweden)

    Yang Wu

    Full Text Available Recent advances in high-throughput genotyping technologies have provided the opportunity to map genes using associations between complex traits and markers. Genome-wide association studies (GWAS based on either a single marker or haplotype have identified genetic variants and underlying genetic mechanisms of quantitative traits. Prompted by the achievements of studies examining economic traits in cattle and to verify the consistency of these two methods using real data, the current study was conducted to construct the haplotype structure in the bovine genome and to detect relevant genes genuinely affecting a carcass trait and a meat quality trait. Using the Illumina BovineHD BeadChip, 942 young bulls with genotyping data were introduced as a reference population to identify the genes in the beef cattle genome significantly associated with foreshank weight and triglyceride levels. In total, 92,553 haplotype blocks were detected in the genome. The regions of high linkage disequilibrium extended up to approximately 200 kb, and the size of haplotype blocks ranged from 22 bp to 199,266 bp. Additionally, the individual SNP analysis and the haplotype-based analysis detected similar regions and common SNPs for these two representative traits. A total of 12 and 7 SNPs in the bovine genome were significantly associated with foreshank weight and triglyceride levels, respectively. By comparison, 4 and 5 haplotype blocks containing the majority of significant SNPs were strongly associated with foreshank weight and triglyceride levels, respectively. In addition, 36 SNPs with high linkage disequilibrium were detected in the GNAQ gene, a potential hotspot that may play a crucial role for regulating carcass trait components.

  2. Genome-wide association studies using haplotypes and individual SNPs in Simmental cattle.

    Science.gov (United States)

    Wu, Yang; Fan, Huizhong; Wang, Yanhui; Zhang, Lupei; Gao, Xue; Chen, Yan; Li, Junya; Ren, HongYan; Gao, Huijiang

    2014-01-01

    Recent advances in high-throughput genotyping technologies have provided the opportunity to map genes using associations between complex traits and markers. Genome-wide association studies (GWAS) based on either a single marker or haplotype have identified genetic variants and underlying genetic mechanisms of quantitative traits. Prompted by the achievements of studies examining economic traits in cattle and to verify the consistency of these two methods using real data, the current study was conducted to construct the haplotype structure in the bovine genome and to detect relevant genes genuinely affecting a carcass trait and a meat quality trait. Using the Illumina BovineHD BeadChip, 942 young bulls with genotyping data were introduced as a reference population to identify the genes in the beef cattle genome significantly associated with foreshank weight and triglyceride levels. In total, 92,553 haplotype blocks were detected in the genome. The regions of high linkage disequilibrium extended up to approximately 200 kb, and the size of haplotype blocks ranged from 22 bp to 199,266 bp. Additionally, the individual SNP analysis and the haplotype-based analysis detected similar regions and common SNPs for these two representative traits. A total of 12 and 7 SNPs in the bovine genome were significantly associated with foreshank weight and triglyceride levels, respectively. By comparison, 4 and 5 haplotype blocks containing the majority of significant SNPs were strongly associated with foreshank weight and triglyceride levels, respectively. In addition, 36 SNPs with high linkage disequilibrium were detected in the GNAQ gene, a potential hotspot that may play a crucial role for regulating carcass trait components. PMID:25330174

  3. Genome-Wide Association Study Identifies Candidate Genes for Starch Content Regulation in Maize Kernels

    Science.gov (United States)

    Liu, Na; Xue, Yadong; Guo, Zhanyong; Li, Weihua; Tang, Jihua

    2016-01-01

    Kernel starch content is an important trait in maize (Zea mays L.) as it accounts for 65–75% of the dry kernel weight and positively correlates with seed yield. A number of starch synthesis-related genes have been identified in maize in recent years. However, many loci underlying variation in starch content among maize inbred lines still remain to be identified. The current study is a genome-wide association study that used a set of 263 maize inbred lines. In this panel, the average kernel starch content was 66.99%, ranging from 60.60 to 71.58% over the three study years. These inbred lines were genotyped with the SNP50 BeadChip maize array, which is comprised of 56,110 evenly spaced, random SNPs. Population structure was controlled by a mixed linear model (MLM) as implemented in the software package TASSEL. After the statistical analyses, four SNPs were identified as significantly associated with starch content (P ≤ 0.0001), among which one each are located on chromosomes 1 and 5 and two are on chromosome 2. Furthermore, 77 candidate genes associated with starch synthesis were found within the 100-kb intervals containing these four QTLs, and four highly associated genes were within 20-kb intervals of the associated SNPs. Among the four genes, Glucose-1-phosphate adenylyltransferase (APS1; Gene ID GRMZM2G163437) is known as an important regulator of kernel starch content. The identified SNPs, QTLs, and candidate genes may not only be readily used for germplasm improvement by marker-assisted selection in breeding, but can also elucidate the genetic basis of starch content. Further studies on these identified candidate genes may help determine the molecular mechanisms regulating kernel starch content in maize and other important cereal crops.

  4. Two-stage two-locus models in genome-wide association.

    Directory of Open Access Journals (Sweden)

    David M Evans

    2006-09-01

    Full Text Available Studies in model organisms suggest that epistasis may play an important role in the etiology of complex diseases and traits in humans. With the era of large-scale genome-wide association studies fast approaching, it is important to quantify whether it will be possible to detect interacting loci using realistic sample sizes in humans and to what extent undetected epistasis will adversely affect power to detect association when single-locus approaches are employed. We therefore investigated the power to detect association for an extensive range of two-locus quantitative trait models that incorporated varying degrees of epistasis. We compared the power to detect association using a single-locus model that ignored interaction effects, a full two-locus model that allowed for interactions, and, most important, two two-stage strategies whereby a subset of loci initially identified using single-locus tests were analyzed using the full two-locus model. Despite the penalty introduced by multiple testing, fitting the full two-locus model performed better than single-locus tests for many of the situations considered, particularly when compared with attempts to detect both individual loci. Using a two-stage strategy reduced the computational burden associated with performing an exhaustive two-locus search across the genome but was not as powerful as the exhaustive search when loci interacted. Two-stage approaches also increased the risk of missing interacting loci that contributed little effect at the margins. Based on our extensive simulations, our results suggest that an exhaustive search involving all pairwise combinations of markers across the genome might provide a useful complement to single-locus scans in identifying interacting loci that contribute to moderate proportions of the phenotypic variance.

  5. A network-based approach to prioritize results from genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Nirmala Akula

    Full Text Available Genome-wide association studies (GWAS are a valuable approach to understanding the genetic basis of complex traits. One of the challenges of GWAS is the translation of genetic association results into biological hypotheses suitable for further investigation in the laboratory. To address this challenge, we introduce Network Interface Miner for Multigenic Interactions (NIMMI, a network-based method that combines GWAS data with human protein-protein interaction data (PPI. NIMMI builds biological networks weighted by connectivity, which is estimated by use of a modification of the Google PageRank algorithm. These weights are then combined with genetic association p-values derived from GWAS, producing what we call 'trait prioritized sub-networks.' As a proof of principle, NIMMI was tested on three GWAS datasets previously analyzed for height, a classical polygenic trait. Despite differences in sample size and ancestry, NIMMI captured 95% of the known height associated genes within the top 20% of ranked sub-networks, far better than what could be achieved by a single-locus approach. The top 2% of NIMMI height-prioritized sub-networks were significantly enriched for genes involved in transcription, signal transduction, transport, and gene expression, as well as nucleic acid, phosphate, protein, and zinc metabolism. All of these sub-networks were ranked near the top across all three height GWAS datasets we tested. We also tested NIMMI on a categorical phenotype, Crohn's disease. NIMMI prioritized sub-networks involved in B- and T-cell receptor, chemokine, interleukin, and other pathways consistent with the known autoimmune nature of Crohn's disease. NIMMI is a simple, user-friendly, open-source software tool that efficiently combines genetic association data with biological networks, translating GWAS findings into biological hypotheses.

  6. Genome-Wide Pathway Analysis Identifies Genetic Pathways Associated with Psoriasis.

    Science.gov (United States)

    Aterido, Adrià; Julià, Antonio; Ferrándiz, Carlos; Puig, Lluís; Fonseca, Eduardo; Fernández-López, Emilia; Dauden, Esteban; Sánchez-Carazo, José Luís; López-Estebaranz, José Luís; Moreno-Ramírez, David; Vanaclocha, Francisco; Herrera, Enrique; de la Cueva, Pablo; Dand, Nick; Palau, Núria; Alonso, Arnald; López-Lasanta, María; Tortosa, Raül; García-Montero, Andrés; Codó, Laia; Gelpí, Josep Lluís; Bertranpetit, Jaume; Absher, Devin; Capon, Francesca; Myers, Richard M; Barker, Jonathan N; Marsal, Sara

    2016-03-01

    Psoriasis is a chronic inflammatory disease with a complex genetic architecture. To date, the psoriasis heritability is only partially explained. However, there is increasing evidence that the missing heritability in psoriasis could be explained by multiple genetic variants of low effect size from common genetic pathways. The objective of this study was to identify new genetic variation associated with psoriasis risk at the pathway level. We genotyped 598,258 single nucleotide polymorphisms in a discovery cohort of 2,281 case-control individuals from Spain. We performed a genome-wide pathway analysis using 1,053 reference biological pathways. A total of 14 genetic pathways (PFDR ≤ 2.55 × 10(-2)) were found to be significantly associated with psoriasis risk. Using an independent validation cohort of 7,353 individuals from the UK, a total of 6 genetic pathways were significantly replicated (PFDR ≤ 3.46 × 10(-2)). We found genetic pathways that had not been previously associated with psoriasis risk such as retinol metabolism (Pcombined = 1.84 × 10(-4)), the transport of inorganic ions and amino acids (Pcombined = 1.57 × 10(-7)), and post-translational protein modification (Pcombined = 1.57 × 10(-7)). In the latter pathway, MGAT5 showed a strong network centrality, and its association with psoriasis risk was further validated in an additional case-control cohort of 3,429 individuals (P < 0.05). These findings provide insights into the biological mechanisms associated with psoriasis susceptibility. PMID:26743605

  7. Genome-wide association study of HLA-DQB1*06:02 negative essential hypersomnia

    Directory of Open Access Journals (Sweden)

    Seik-Soon Khor

    2013-04-01

    Full Text Available Essential hypersomnia (EHS, a sleep disorder characterized by excessive daytime sleepiness, can be divided into two broad classes based on the presence or absence of the HLA-DQB1*06:02 allele. HLA-DQB1*06:02-positive EHS and narcolepsy with cataplexy are associated with the same susceptibility genes. In contrast, there are fewer studies of HLA-DQB1*06:02 negative EHS which, we hypothesized, involves a different pathophysiological pathway than does narcolepsy with cataplexy. In order to identify susceptibility genes associated with HLA-DQB1*06:02 negative EHS, we conducted a genome-wide association study (GWAS of 125 unrelated Japanese EHS patients lacking the HLA-DQB1*06:02 allele and 562 Japanese healthy controls. A comparative study was also performed on 268 HLA-DQB1*06:02 negative Caucasian hypersomnia patients and 1761 HLA-DQB1*06:02 negative Caucasian healthy controls. We identified three SNPs that each represented a unique locus— rs16826005 (P = 1.02E-07; NCKAP5, rs11854769 (P = 6.69E-07; SPRED1, and rs10988217 (P = 3.43E-06; CRAT that were associated with an increased risk of EHS in this Japanese population. Interestingly, rs10988217 showed a similar tendency in its association with both HLA-DQB1*06:02 negative EHS and narcolepsy with cataplexy in both Japanese and Caucasian populations. This is the first GWAS of HLA-DQB1*06:02 negative EHS, and the identification of these three new susceptibility loci should provide additional insights to the pathophysiological pathway of this condition.

  8. Genome-Wide Association Study Identifies Candidate Genes for Starch Content Regulation in Maize Kernels.

    Science.gov (United States)

    Liu, Na; Xue, Yadong; Guo, Zhanyong; Li, Weihua; Tang, Jihua

    2016-01-01

    Kernel starch content is an important trait in maize (Zea mays L.) as it accounts for 65-75% of the dry kernel weight and positively correlates with seed yield. A number of starch synthesis-related genes have been identified in maize in recent years. However, many loci underlying variation in starch content among maize inbred lines still remain to be identified. The current study is a genome-wide association study that used a set of 263 maize inbred lines. In this panel, the average kernel starch content was 66.99%, ranging from 60.60 to 71.58% over the three study years. These inbred lines were genotyped with the SNP50 BeadChip maize array, which is comprised of 56,110 evenly spaced, random SNPs. Population structure was controlled by a mixed linear model (MLM) as implemented in the software package TASSEL. After the statistical analyses, four SNPs were identified as significantly associated with starch content (P ≤ 0.0001), among which one each are located on chromosomes 1 and 5 and two are on chromosome 2. Furthermore, 77 candidate genes associated with starch synthesis were found within the 100-kb intervals containing these four QTLs, and four highly associated genes were within 20-kb intervals of the associated SNPs. Among the four genes, Glucose-1-phosphate adenylyltransferase (APS1; Gene ID GRMZM2G163437) is known as an important regulator of kernel starch content. The identified SNPs, QTLs, and candidate genes may not only be readily used for germplasm improvement by marker-assisted selection in breeding, but can also elucidate the genetic basis of starch content. Further studies on these identified candidate genes may help determine the molecular mechanisms regulating kernel starch content in maize and other important cereal crops. PMID:27512395

  9. A Two-Stage Penalized Logistic Regression Approach to Case-Control Genome-Wide Association Studies

    Directory of Open Access Journals (Sweden)

    Jingyuan Zhao

    2012-01-01

    Full Text Available We propose a two-stage penalized logistic regression approach to case-control genome-wide association studies. This approach consists of a screening stage and a selection stage. In the screening stage, main-effect and interaction-effect features are screened by using L1-penalized logistic like-lihoods. In the selection stage, the retained features are ranked by the logistic likelihood with the smoothly clipped absolute deviation (SCAD penalty (Fan and Li, 2001 and Jeffrey’s Prior penalty (Firth, 1993, a sequence of nested candidate models are formed, and the models are assessed by a family of extended Bayesian information criteria (J. Chen and Z. Chen, 2008. The proposed approach is applied to the analysis of the prostate cancer data of the Cancer Genetic Markers of Susceptibility (CGEMS project in the National Cancer Institute, USA. Simulation studies are carried out to compare the approach with the pair-wise multiple testing approach (Marchini et al. 2005 and the LASSO-patternsearch algorithm (Shi et al. 2007.

  10. Genome-wide association study of shared components of reading disability and language impairment.

    Science.gov (United States)

    Eicher, J D; Powers, N R; Miller, L L; Akshoomoff, N; Amaral, D G; Bloss, C S; Libiger, O; Schork, N J; Darst, B F; Casey, B J; Chang, L; Ernst, T; Frazier, J; Kaufmann, W E; Keating, B; Kenet, T; Kennedy, D; Mostofsky, S; Murray, S S; Sowell, E R; Bartsch, H; Kuperman, J M; Brown, T T; Hagler, D J; Dale, A M; Jernigan, T L; St Pourcain, B; Davey Smith, G; Ring, S M; Gruen, J R

    2013-11-01

    Written and verbal languages are neurobehavioral traits vital to the development of communication skills. Unfortunately, disorders involving these traits-specifically reading disability (RD) and language impairment (LI)-are common and prevent affected individuals from developing adequate communication skills, leaving them at risk for adverse academic, socioeconomic and psychiatric outcomes. Both RD and LI are complex traits that frequently co-occur, leading us to hypothesize that these disorders share genetic etiologies. To test this, we performed a genome-wide association study on individuals affected with both RD and LI in the Avon Longitudinal Study of Parents and Children. The strongest associations were seen with markers in ZNF385D (OR = 1.81, P = 5.45 × 10(-7) ) and COL4A2 (OR = 1.71, P = 7.59 × 10(-7) ). Markers within NDST4 showed the strongest associations with LI individually (OR = 1.827, P = 1.40 × 10(-7) ). We replicated association of ZNF385D using receptive vocabulary measures in the Pediatric Imaging Neurocognitive Genetics study (P = 0.00245). We then used diffusion tensor imaging fiber tract volume data on 16 fiber tracts to examine the implications of replicated markers. ZNF385D was a predictor of overall fiber tract volumes in both hemispheres, as well as global brain volume. Here, we present evidence for ZNF385D as a candidate gene for RD and LI. The implication of transcription factor ZNF385D in RD and LI underscores the importance of transcriptional regulation in the development of higher order neurocognitive traits. Further study is necessary to discern target genes of ZNF385D and how it functions within neural development of fluent language. PMID:24024963

  11. Translating Lung Function Genome-Wide Association Study (GWAS) Findings: New Insights for Lung Biology.

    Science.gov (United States)

    Kheirallah, A K; Miller, S; Hall, I P; Sayers, I

    2016-01-01

    Chronic respiratory diseases are a major cause of worldwide mortality and morbidity. Although hereditary severe deficiency of α1 antitrypsin (A1AD) has been established to cause emphysema, A1AD accounts for only ∼1% of Chronic Obstructive Pulmonary Disease (COPD) cases. Genome-wide association studies (GWAS) have been successful at detecting multiple loci harboring variants predicting the variation in lung function measures and risk of COPD. However, GWAS are incapable of distinguishing causal from noncausal variants. Several approaches can be used for functional translation of genetic findings. These approaches have the scope to identify underlying alleles and pathways that are important in lung function and COPD. Computational methods aim at effective functional variant prediction by combining experimentally generated regulatory information with associated region of the human genome. Classically, GWAS association follow-up concentrated on manipulation of a single gene. However association data has identified genetic variants in >50 loci predicting disease risk or lung function. Therefore there is a clear precedent for experiments that interrogate multiple candidate genes in parallel, which is now possible with genome editing technology. Gene expression profiling can be used for effective discovery of biological pathways underpinning gene function. This information may be used for informed decisions about cellular assays post genetic manipulation. Investigating respiratory phenotypes in human lung tissue and specific gene knockout mice is a valuable in vivo approach that can complement in vitro work. Herein, we review state-of-the-art in silico, in vivo, and in vitro approaches that may be used to accelerate functional translation of genetic findings. PMID:26915270

  12. Marker-trait associations in Virginia Tech winter barley identified using genome-wide mapping.

    Science.gov (United States)

    Berger, Gregory L; Liu, Shuyu; Hall, Marla D; Brooks, Wynse S; Chao, Shiaoman; Muehlbauer, Gary J; Baik, B-K; Steffenson, Brian; Griffey, Carl A

    2013-03-01

    Genome-wide association studies (GWAS) provide an opportunity to examine the genetic architecture of quantitatively inherited traits in breeding populations. The objectives of this study were to use GWAS to identify chromosome regions governing traits of importance in six-rowed winter barley (Hordeum vulgare L.) germplasm and to identify single-nucleotide polymorphisms (SNPs) markers that can be implemented in a marker-assisted breeding program. Advanced hulled and hulless lines (329 total) were screened using 3,072 SNPs as a part of the US. Barley Coordinated Agricultural Project (CAP). Phenotypic data collected over 4 years for agronomic and food quality traits and resistance to leaf rust (caused by Puccinia hordei G. Otth), powdery mildew [caused by Blumeria graminis (DC.) E.O. Speer f. sp. hordei Em. Marchal], net blotch (caused by Pyrenophora teres), and spot blotch [caused by Cochliobolus sativus (Ito and Kuribayashi) Drechsler ex Dastur] were analyzed with SNP genotypic data in a GWAS to determine marker-trait associations. Significant SNPs associated with previously described quantitative trait loci (QTL) or genes were identified for heading date on chromosome 3H, test weight on 2H, yield on 7H, grain protein on 5H, polyphenol oxidase activity on 2H and resistance to leaf rust on 2H and 3H, powdery mildew on 1H, 2H and 4H, net blotch on 5H, and spot blotch on 7H. Novel QTL also were identified for agronomic, quality, and disease resistance traits. These SNP-trait associations provide the opportunity to directly select for QTL contributing to multiple traits in breeding programs. PMID:23139143

  13. Explorations in genome-wide association studies and network analyses with dairy cattle fertility traits.

    Science.gov (United States)

    Parker Gaddis, K L; Null, D J; Cole, J B

    2016-08-01

    The objective of this study was to identify single nucleotide polymorphisms and gene networks associated with 3 fertility traits in dairy cattle-daughter pregnancy rate, heifer conception rate, and cow conception rate-using different approaches. Deregressed predicted transmitting abilities were available for approximately 24,000 Holstein bulls and 36,000 Holstein cows sampled from the National Dairy Database with high-density genotypes. Of those, 1,732 bulls and 375 cows had been genotyped with the Illumina BovineHD Genotyping BeadChip (Illumina Inc., San Diego, CA). The remaining animals were genotyped with various chips of lower density that were imputed to high density. Univariate and trivariate genome-wide association studies (GWAS) with both medium- (60,671 markers) and high-density (312,614 markers) panels were performed for daughter pregnancy rate, heifer conception rate, and cow conception rate using GEMMA (version 0.94; http://www.xzlab.org/software.html). Analyses were conducted using bulls only, cows only, and a sample of both bulls and cows. The partial correlation and information theory algorithm was used to develop gene interaction networks. The most significant markers were further investigated to identify putatively associated genes. Little overlap in associated genes could be found between GWAS using different reference populations of bulls only, cows only, and combined bulls and cows. The partial correlation and information theory algorithm was able to identify several genes that were not identified by ordinary GWAS. The results obtained herein will aid in further dissecting the complex biology underlying fertility traits in dairy cattle, while also providing insight into the nuances of GWAS. PMID:27209127

  14. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.

    Directory of Open Access Journals (Sweden)

    Elizabeth K Speliotes

    2011-03-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA analysis of computed tomography (CT measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27% in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070. By carrying out a fixed-effects meta-analysis of genome-wide association (GWA results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES, Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8 in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN. In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen, we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

  15. Genome-Wide Scan for Adaptive Divergence and Association with Population-Specific Covariates.

    Science.gov (United States)

    Gautier, Mathieu

    2015-12-01

    In population genomics studies, accounting for the neutral covariance structure across population allele frequencies is critical to improve the robustness of genome-wide scan approaches. Elaborating on the BayEnv model, this study investigates several modeling extensions (i) to improve the estimation accuracy of the population covariance matrix and all the related measures, (ii) to identify significantly overly differentiated SNPs based on a calibration procedure of the XtX statistics, and (iii) to consider alternative covariate models for analyses of association with population-specific covariables. In particular, the auxiliary variable model allows one to deal with multiple testing issues and, providing the relative marker positions are available, to capture some linkage disequilibrium information. A comprehensive simulation study was carried out to evaluate the performances of these different models. Also, when compared in terms of power, robustness, and computational efficiency to five other state-of-the-art genome-scan methods (BayEnv2, BayScEnv, BayScan, flk, and lfmm), the proposed approaches proved highly effective. For illustration purposes, genotyping data on 18 French cattle breeds were analyzed, leading to the identification of 13 strong signatures of selection. Among these, four (surrounding the KITLG, KIT, EDN3, and ALB genes) contained SNPs strongly associated with the piebald coloration pattern while a fifth (surrounding PLAG1) could be associated to morphological differences across the populations. Finally, analysis of Pool-Seq data from 12 populations of Littorina saxatilis living in two different ecotypes illustrates how the proposed framework might help in addressing relevant ecological issues in nonmodel species. Overall, the proposed methods define a robust Bayesian framework to characterize adaptive genetic differentiation across populations. The BayPass program implementing the different models is available at http://www1.montpellier

  16. Genome-wide association for heifer reproduction and calf performance traits in beef cattle.

    Science.gov (United States)

    Akanno, Everestus C; Plastow, Graham; Fitzsimmons, Carolyn; Miller, Stephen P; Baron, Vern; Ominski, Kimberly; Basarab, John A

    2015-12-01

    The aim of this study was to identify SNP markers that associate with variation in beef heifer reproduction and performance of their calves. A genome-wide association study was performed by means of the generalized quasi-likelihood score (GQLS) method using heifer genotypes from the BovineSNP50 BeadChip and estimated breeding values for pre-breeding body weight (PBW), pregnancy rate (PR), calving difficulty (CD), age at first calving (AFC), calf birth weight (BWT), calf weaning weight (WWT), and calf pre-weaning average daily gain (ADG). Data consisted of 785 replacement heifers from three Canadian research herds, namely Brandon Research Centre, Brandon, Manitoba, University of Alberta Roy Berg Kinsella Ranch, Kinsella, Alberta, and Lacombe Research Centre, Lacombe, Alberta. After applying a false discovery rate correction at a 5% significance level, a total of 4, 3, 3, 9, 6, 2, and 1 SNPs were significantly associated with PBW, PR, CD, AFC, BWT, WWT, and ADG, respectively. These SNPs were located on chromosomes 1, 5-7, 9, 13-16, 19-21, 24, 25, and 27-29. Chromosomes 1, 5, and 24 had SNPs with pleiotropic effects. New significant SNPs that impact functional traits were detected, many of which have not been previously reported. The results of this study support quantitative genetic studies related to the inheritance of these traits, and provides new knowledge regarding beef cattle quantitative trait loci effects. The identification of these SNPs provides a starting point to identify genes affecting heifer reproduction traits and performance of their calves (BWT, WWT, and ADG). They also contribute to a better understanding of the biology underlying these traits and will be potentially useful in marker- and genome-assisted selection and management. PMID:26484575

  17. Statistical power of model selection strategies for genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Zheyang Wu

    2009-07-01

    Full Text Available Genome-wide association studies (GWAS aim to identify genetic variants related to diseases by examining the associations between phenotypes and hundreds of thousands of genotyped markers. Because many genes are potentially involved in common diseases and a large number of markers are analyzed, it is crucial to devise an effective strategy to identify truly associated variants that have individual and/or interactive effects, while controlling false positives at the desired level. Although a number of model selection methods have been proposed in the literature, including marginal search, exhaustive search, and forward search, their relative performance has only been evaluated through limited simulations due to the lack of an analytical approach to calculating the power of these methods. This article develops a novel statistical approach for power calculation, derives accurate formulas for the power of different model selection strategies, and then uses the formulas to evaluate and compare these strategies in genetic model spaces. In contrast to previous studies, our theoretical framework allows for random genotypes, correlations among test statistics, and a false-positive control based on GWAS practice. After the accuracy of our analytical results is validated through simulations, they are utilized to systematically evaluate and compare the performance of these strategies in a wide class of genetic models. For a specific genetic model, our results clearly reveal how different factors, such as effect size, allele frequency, and interaction, jointly affect the statistical power of each strategy. An example is provided for the application of our approach to empirical research. The statistical approach used in our derivations is general and can be employed to address the model selection problems in other random predictor settings. We have developed an R package markerSearchPower to implement our formulas, which can be downloaded from the

  18. A genome-wide association study identifies five loci influencing facial morphology in Europeans.

    Directory of Open Access Journals (Sweden)

    Fan Liu

    2012-09-01

    Full Text Available Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes--PRDM16, PAX3, TP63, C5orf50, and COL17A1--in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications.

  19. Population structure and linkage disequilibrium in oat (Avena sativa L.): implications for genome-wide association studies

    Science.gov (United States)

    The level of population structure and the extent of linkage disequilibrium (LD) can have large impacts on the power, resolution, and design of genome-wide association studies (GWAS) in plants. Until recently, the topics of LD and population structure have not been explored in oat due to the lack of...

  20. A genome wide association study for milk production traits in Danish Jersey cattle using a 50K SNP chip

    DEFF Research Database (Denmark)

    Mai, M D; Sahana, G; Christiansen, F B;

    2010-01-01

    QTL for milk production traits in Danish Jersey cattle were mapped by a genome-wide association analysis using a mixed model. The analysis incorporated 1,039 bulls and 33,090 SNP, and resulted in 98 detected combinations of QTL and traits on 27 BTA. These QTL comprised 30 for milk index, 50 for fat...

  1. 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 of...

  2. Genome-wide association study of production and stability traits in barley cultivated under future climate scenarios

    DEFF Research Database (Denmark)

    Ingvordsen, Cathrine Heinz; Backes, Gunter; Lyngkjær, Michael Foged;

    2015-01-01

    temperature (+5 °C) and [CO2] (700 ppm) as single factors and in combination as well as under elevated [O3] (100–150 ppb) as single factor. The setting in general resembled changes projected by IPCC (AR5) to take place at the end of this century. A genome-wide association study (GWAS) was performed to...

  3. Using the Coriell Personalized Medicine Collaborative Data to conduct a genome-wide association study of sleep duration.

    Science.gov (United States)

    Scheinfeldt, Laura B; Gharani, Neda; Kasper, Rachel S; Schmidlen, Tara J; Gordon, Erynn S; Jarvis, Joseph P; Delaney, Susan; Kronenthal, Courtney J; Gerry, Norman P; Christman, Michael F

    2015-12-01

    Sleep is critical to health and functionality, and several studies have investigated the inherited component of insomnia and other sleep disorders using genome-wide association studies (GWAS). However, genome-wide studies focused on sleep duration are less common. Here, we used data from participants in the Coriell Personalized Medicine Collaborative (CPMC) (n = 4,401) to examine putative associations between self-reported sleep duration, demographic and lifestyle variables, and genome-wide single nucleotide polymorphism (SNP) data to better understand genetic contributions to variation in sleep duration. We employed stepwise ordered logistic regression to select our model and retained the following predictive variables: age, gender, weight, physical activity, physical activity at work, smoking status, alcohol consumption, ethnicity, and ancestry (as measured by principal components analysis) in our association testing. Several of our strongest candidate genes were previously identified in GWAS related to sleep duration (TSHZ2, ABCC9, FBXO15) and narcolepsy (NFATC2, SALL4). In addition, we have identified novel candidate genes for involvement in sleep duration including SORCS1 and ELOVL2. Our results demonstrate that the self-reported data collected through the CPMC are robust, and our genome-wide association analysis has identified novel candidate genes involved in sleep duration. More generally, this study contributes to a better understanding of the complexity of human sleep. PMID:26333835

  4. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

    DEFF Research Database (Denmark)

    Bønnelykke, Klaus; Sleiman, Patrick; Nielsen, Kasper;

    2014-01-01

    years of age in a total of 1,173 cases and 2,522 controls. Cases were identified from national health registries of hospitalization, and DNA was obtained from the Danish Neonatal Screening Biobank. We identified five loci with genome-wide significant association. Four of these, GSDMB, IL33, RAD50 and IL...

  5. Use of Longitudinal Data in Genetic Studies in the Genome-wide Association Studies Era: Summary of Group 14

    OpenAIRE

    Kerner, Berit; North, Kari E; Fallin, M. Daniele

    2009-01-01

    Participants analyzed actual and simulated longitudinal data from the Framingham Heart Study for various metabolic and cardiovascular traits. The genetic information incorporated into these investigations ranged from selected single-nucleotide polymorphisms to genome-wide association arrays. Genotypes were incorporated using a broad range of methodological approaches including conditional logistic regression, linear mixed models, generalized estimating equations, linear growth curve estimatio...

  6. A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations

    NARCIS (Netherlands)

    Bonnelykke, Klaus; Sleiman, Patrick; Nielsen, Kasper; Kreiner-Moller, Eskil; Mercader, Josep M.; Belgrave, Danielle; den Dekker, Herman T.; Husby, Anders; Sevelsted, Astrid; Faura Tellez, Grissel; Mortensen, Li Juel; Paternoster, Lavinia; Flaaten, Richard; Molgaard, Anne; Smart, David E.; Thomsen, Philip F.; Rasmussen, Morten A.; Bonas-Guarch, Silvia; Holst, Claus; Nohr, Ellen A.; Yadav, Rachita; March, Michael E.; Blicher, Thomas; Lackie, Peter M.; Jaddoe, Vincent W. V.; Simpson, Angela; Holloway, John W.; Duijts, Liesbeth; Custovic, Adnan; Davies, Donna E.; Torrents, David; Gupta, Ramneek; Hollegaard, Mads V.; Hougaard, David M.; Hakonarson, Hakon; Bisgaard, Hans

    2014-01-01

    Asthma exacerbations are among the most frequent causes of hospitalization during childhood, but the underlying mechanisms are poorly understood. We performed a genome-wide association study of a specific asthma phenotype characterized by recurrent, severe exacerbations occurring between 2 and 6 yea

  7. Genome-wide association studies identified novel loci for non-high-density lipoprotein cholesterol and its postprandial lipemic response

    Science.gov (United States)

    Non-high-density lipoprotein cholesterol (NHDL) is an independent and superior predictor of CVD risk as compared to low-density lipoprotein alone. It represents a spectrum of atherogenic lipid fractions with possibly a distinct genomic signature. We performed genome-wide association studies (GWAS) t...

  8. Genome-wide association study of motor coordination problems in ADHD identifies genes for brain and muscle function.

    NARCIS (Netherlands)

    Fliers, E.A.; Arias Vasquez, A.; Poelmans, G.J.V.; Rommelse, N.N.; Altink, M.E.; Buschgens, C.J.M.; Asherson, P.; Banaschewski, T.; Ebstein, R.; Gill, M.; Miranda, A.; Mulas, F.; Oades, R.D.; Roeyers, H.; Rothenberger, A.; Sergeant, J.A.; Sonuga-Barke, E.S.J.; Steinhausen, H.C.; Faraone, S.V.; Buitelaar, J.K.; Franke, B.

    2012-01-01

    OBJECTIVES: Motor coordination problems are frequent in children with attention deficit/hyperactivity disorder (ADHD). We performed a genome-wide association study to identify genes contributing to motor coordination problems, hypothesizing that the presence of such problems in children with ADHD ma

  9. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

    NARCIS (Netherlands)

    Springelkamp, Henriet; Hoehn, Rene; Mishra, Aniket; Hysi, Pirro G.; Khor, Chiea-Chuen; Loomis, Stephanie J.; Bailey, Jessica N. Cooke; Gibson, Jane; Thorleifsson, Gudmar; Janssen, Sarah F.; Luo, Xiaoyan; Ramdas, Wishal D.; Vithana, Eranga; Nongpiur, Monisha E.; Montgomery, GrantW.; Xu, Liang; Mountain, Jenny E.; Gharahkhani, Puya; Lu, Yi; Amin, Najaf; Karssen, Lennart C.; Sim, Kar-Seng; van Leeuwen, Elisabeth M.; Iglesias, Adriana I.; Verhoeven, Virginie J. M.; Hauser, Michael A.; Loon, Seng-Chee; Despriet, Dominiek D. G.; Nag, Abhishek; Venturini, Cristina; Sanfilippo, Paul G.; Schillert, Arne; Kang, Jae H.; Landers, John; Jonasson, Fridbert; Cree, Angela J.; van Koolwijk, Leonieke M. E.; Rivadeneira, Fernando; Souzeau, Emmanuelle; Jonsson, Vesteinn; Menon, Geeta; Weinreb, Robert N.; de Jong, Paulus T. V. M.; Oostra, Ben A.; Uitterlinden, Andre G.; Hofman, Albert; Ennis, Sarah; Thorsteinsdottir, Unnur; Burdon, Kathryn P.; Spector, Timothy D.; Mirshahi, Alireza; Saw, Seang-Mei; Vingerling, Johannes R.; Teo, Yik-Ying; Haines, Jonathan L.; Wolfs, Roger C. W.; Lemij, Hans G.; Tai, E-Shyong; Jansonius, Nomdo M.; Jonas, Jost B.; Cheng, Ching-Yu; Aung, Tin; Viswanathan, Ananth C.; Klaver, Caroline C. W.; Craig, Jamie E.; Macgregor, Stuart; Mackey, David A.; Lotery, Andrew J.; Stefansson, Kari; Bergen, Arthur A. B.; Young, Terri L.; Wiggs, Janey L.; Pfeiffer, Norbert; Wong, Tien-Yin; Pasquale, Louis R.; Hewitt, Alex W.; van Duijn, Cornelia M.; Hammond, Christopher J.

    2014-01-01

    Glaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an important dise

  10. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

    NARCIS (Netherlands)

    H. Springelkamp (Henriët); R. Höhn (René); A. Mishra (Aniket); P.G. Hysi (Pirro); C.C. Khor; S.J. Loomis (Stephanie J.); J.N.C. Bailey (Jessica N. Cooke); J. Gibson (Jane); G. Thorleifsson (Gudmar); X. Luo (Xiaoyan); W.D. Ramdas (Wishal); E.N. Vithana (Eranga); M.E. Nongpiur (Monisha E.); G.W. Montgomery (Grant); L. Xu (Liang); J.E. Mountain (Jenny E.); P. Gharahkhani (Puya); Y. Lu (Yi); N. Amin (Najaf); L.C. Karssen (Lennart); K.S. Sim; E.M. van Leeuwen (Elisa); O. Iglesias (Oriol); V.J.M. Verhoeven (Virginie); M.A. Hauser (Michael); S.-C. Loon (Seng-Chee); D.D.G. Despriet (Dominique); A. Nag (Abhishek); C. Venturini (Cristina); P.G. Sanfilippo (Paul G.); A. Schillert (Arne); J.H. Kang (Jae H.); J. Landers (John); F. Jonasson (Fridbert); A.J. Cree (Angela); L.M.E. van Koolwijk (Leonieke); F. Rivadeneira Ramirez (Fernando); E. Souzeau (Emmanuelle); V. Jonsson (Vesteinn); G. Menon (Geeta); P. Mitchell (Paul); J.J. Wang (Jie Jin); E. Rochtchina (Elena); J. Attia (John); R. Scott (Rodney); E.G. Holliday (Elizabeth); P.N. Baird (Paul); J. Xie (Jing); M. Inouye (Michael); A.C. Viswanathan (Ananth); X. Sim (Xueling); R.N. Weinreb (Robert N.); P.T.V.M. de Jong (Paulus); B.A. Oostra (Ben); A.G. Uitterlinden (André); A. Hofman (Albert); S. Ennis (Sarah); U. Thorsteinsdottir (Unnur); K.P. Burdon (Kathryn); R.R. Allingham (R Rand); M.H. Brilliant (Murray H.); D.L. Budenz (Donald L.); W.G. Christen (William G.); J. Fingert (John); D.S. Friedman (David); D. Gaasterland (Douglas); T. Gaasterland (Terry); J.L. Haines (Jonathan); J.H. Kang; P. Kraft (Peter); R.K. Lee (Richard K.); P.A. Lichter (Paul A.); Y. Liu (Yutao); S.E. Moroi (Sayoko); M.A. Pericak-Vance (Margaret); A. Realini (Anthony); J.E. Richards (Julia); J.S. Schuman (Joel S.); W.K. Scott (William); K. Singh (Kuldev); A.J. Sit (Arthur J.); D. Vollrath (Douglas); G. Wollstein (Gadi); D.J. Zack (Donald); K. Zhang (Kang); I. Barroso (Inês); K.L. Blackwell (Kimberly); E. Bramon (Elvira); M.A. Brown (Matthew); J.P. Casas (Juan); A. Corvin (Aiden); P. Deloukas (Panagiotis); A. Duncanson (Audrey); J.A. Jankowski (Janusz Antoni); H.S. Markus (Hugh); J. Mathew (Joseph); C.N.A. Palmer (Colin); R. Plomin (Robert); A. Rautanen (Anna); S.J. Sawcer (Stephen); R.C. Trembath (Richard); A.C. Viswanathan (Ananth C.); N.W. Wood (Nicholas); C.C.A. Spencer (Chris C.); G. Band (Gavin); C. Bellenguez (Céline); C. Freeman (Colin); F.A. Hellenthal; E. Giannoulatou (Eleni); M. Pirinen (Matti); R. Pearson (Richard); A. Strange (Amy); Z. Su (Zhan); D. Vukcevic (Damjan); P. Donnelly (Peter); C. Langford (Cordelia); S.E. Hunt (Sarah); T. Edkins (Ted); R. Gwilliam (Rhian); H. Blackburn (Hannah); S. Bumpstead (Suzannah); S. Dronov (Serge); M. Gillman (Matthew); E. Gray (Emma); N. Hammond (Naomi); A. Jayakumar (Alagurevathi); O.T. McCann (Owen); J. Liddle (Jennifer); S.C. Potter (Simon); R. Ravindrarajah (Radhi); M. Ricketts (Michelle); P. Waller (Patrick); P. Weston (Paul); S. Widaa (Sara); P. Whittaker (Pamela); T.D. Spector (Timothy); A. Mirshahi (Alireza); S-M. Saw (Seang-Mei); J.R. Vingerling (Hans); Y.Y. Teo (Yik Ying); R.C.W. Wolfs (Roger); H.G. Lemij (Hans); E.S. Tai (Shyong); N.M. Jansonius (Nomdo); J.B. Jonas (Jost B.); C-Y. Cheng (Ching-Yu); T. Aung (Tin); C.C.W. Klaver (Caroline); J.E. Craig (Jamie); S. MacGregor (Stuart); D.A. Mackey (David); A.J. Lotery (Andrew); J-A. Zwart (John-Anker); A.A.B. Bergen (Arthur); T.L. Young (Terri); J.L. Wiggs (Janey); A.F.H. Pfeiffer (Andreas); T.Y. Wong (Tien); L.R. Pasquale (Louis); A.W. Hewit (Alex); C.M. van Duijn (Cock); C.J. Hammond (Christopher); S.F. Janssen (Sarah)

    2014-01-01

    textabstractGlaucoma is characterized by irreversible optic nerve degeneration and is the most frequent cause of irreversible blindness worldwide. Here, the International Glaucoma Genetics Consortium conducts a meta-analysis of genome-wide association studies of vertical cup-disc ratio (VCDR), an im

  11. Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

    DEFF Research Database (Denmark)

    Okbay, Aysu; Baselmans, Bart M L; De Neve, Jan-Emmanuel;

    2016-01-01

    Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conduct...

  12. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function

    NARCIS (Netherlands)

    Soler Artigas, María; Loth, Daan W; Wain, Louise V; Gharib, Sina A; Obeidat, Ma'en; Tang, Wenbo; Zhai, Guangju; Zhao, Jing Hua; Smith, Albert Vernon; Huffman, Jennifer E; Albrecht, Eva; Jackson, Catherine M; Evans, David M; Cadby, Gemma; Fornage, Myriam; Manichaikul, Ani; Lopez, Lorna M; Johnson, Toby; Aldrich, Melinda C; Aspelund, Thor; Barroso, Inês; Campbell, Harry; Cassano, Patricia A; Couper, David J; Eiriksdottir, Gudny; Franceschini, Nora; Garcia, Melissa; Gieger, Christian; Gislason, Gauti Kjartan; Grkovic, Ivica; Hammond, Christopher J; Hancock, Dana B; Harris, Tamara B; Ramasamy, Adaikalavan; Heckbert, Susan R; Heliövaara, Markku; Homuth, Georg; Hysi, Pirro G; James, Alan L; Jankovic, Stipan; Joubert, Bonnie R; Karrasch, Stefan; Klopp, Norman; Koch, Beate; Kritchevsky, Stephen B; Launer, Lenore J; Liu, Yongmei; Loehr, Laura R; Lohman, Kurt; Loos, Ruth J F; Lumley, Thomas; Al Balushi, Khalid A; Ang, Wei Q; Barr, R Graham; Beilby, John; Blakey, John D; Boban, Mladen; Boraska, Vesna; Brisman, Jonas; Britton, John R; Brusselle, Guy G; Cooper, Cyrus; Curjuric, Ivan; Dahgam, Santosh; Deary, Ian J; Ebrahim, Shah; Eijgelsheim, Mark; Francks, Clyde; Gaysina, Darya; Granell, Raquel; Gu, Xiangjun; Hankinson, John L; Hardy, Rebecca; Harris, Sarah E; Henderson, John; Henry, Amanda; Hingorani, Aroon D; Hofman, Albert; Holt, Patrick G; Hui, Jennie; Hunter, Michael L; Imboden, Medea; Jameson, Karen A; Kerr, Shona M; Kolcic, Ivana; Kronenberg, Florian; Liu, Jason Z; Marchini, Jonathan; McKeever, Tricia; Morris, Andrew D; Olin, Anna-Carin; Porteous, David J; Postma, Dirkje S; Rich, Stephen S; Ring, Susan M; Rivadeneira, Fernando; Rochat, Thierry; Sayer, Avan Aihie; Sayers, Ian; Sly, Peter D; Smith, George Davey; Sood, Akshay; Starr, John M; Uitterlinden, André G; Vonk, Judith M; Wannamethee, S Goya; Whincup, Peter H; Wijmenga, Cisca; Williams, O Dale; Wong, Andrew; Mangino, Massimo; Marciante, Kristin D; McArdle, Wendy L; Meibohm, Bernd; Morrison, Alanna C; North, Kari E; Omenaas, Ernst; Palmer, Lyle J; Pietiläinen, Kirsi H; Pin, Isabelle; Pola Sbreve Ek, Ozren; Pouta, Anneli; Psaty, Bruce M; Hartikainen, Anna-Liisa; Rantanen, Taina; Ripatti, Samuli; Rotter, Jerome I; Rudan, Igor; Rudnicka, Alicja R; Schulz, Holger; Shin, So-Youn; Spector, Tim D; Surakka, Ida; Vitart, Veronique; Völzke, Henry; Wareham, Nicholas J; Warrington, Nicole M; Wichmann, H-Erich; Wild, Sarah H; Wilk, Jemma B; Wjst, Matthias; Wright, Alan F; Zgaga, Lina; Zemunik, Tatijana; Pennell, Craig E; Nyberg, Fredrik; Kuh, Diana; Holloway, John W; Boezen, Hendrika; Lawlor, Debbie A; Morris, Richard W; Probst-Hensch, Nicole; Kaprio, Jaakko; Wilson, James F; Hayward, Caroline; Kähönen, Mika; Heinrich, Joachim; Musk, Arthur W; Jarvis, Deborah L; Gläser, Sven; Järvelin, Marjo-Riitta; Ch Stricker, Bruno H; Elliott, Paul; O'Connor, George T; Strachan, David P; London, Stephanie J; Hall, Ian P; Gudnason, Vilmundur; Tobin, Martin D

    2011-01-01

    Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individu

  13. Genome-wide linkage disequilibruim revealed by microsatellite markers and association study of fiber quality traits in cotton

    Science.gov (United States)

    The application of association mapping based on existing genome-wide linkage disequilibrium (LD) between DNA polymorphisms and genes underlying traits is becoming powerful tool that overcome many limitations (high cost, poor resolution, requirement for bi-parentally crossed lines assessing only two ...

  14. A genome-wide association study of malting quality across eight U.S. barley breeding programs

    Science.gov (United States)

    This study leverages the breeding data of 1,862 breeding lines evaluated in 97 field trials for genome-wide association study of malting quality traits in barley. The breeding lines were six-row and two-row barley advanced breeding lines from eight barley breeding populations established at six pub...

  15. Genome wide association study of seedling and adult plant leaf rust resistance in elite spring wheat breeding lines

    Science.gov (United States)

    Leaf rust is an important disease, threatening wheat production annually. Identification of resistance genes or QTLs for effective field resistance could greatly enhance our ability to breed durably resistant varieties. We applied a genome wide association study (GWAS) approach to identify resista...

  16. Genome-wide association mapping of fusarium head blight resistance in wheat (Triticum aestivum L.) using genotyping by sequencing

    Science.gov (United States)

    Fusarium head blight (FHB) is one of the most important wheat diseases worldwide and host resistance displays complex genetic control. A genome-wide association study (GWAS) was performed on 273 winter wheat breeding lines from the mid-western and eastern regions of the US to identify chromosomal re...

  17. A multi-marker test based on family data in genome-wide association study

    Directory of Open Access Journals (Sweden)

    Zhang Shuanglin

    2007-09-01

    Full Text Available Abstract Background Complex diseases are believed to be the results of many genes and environmental factors. Hence, multi-marker methods that can use the information of markers from different genes are appropriate for mapping complex disease genes. There already have been several multi-marker methods proposed for case-control studies. In this article, we propose a multi-marker test called a Multi-marker Pedigree Disequilibrium Test (MPDT to analyze family data from genome-wide association studies. If the parental phenotypes are available, we also propose a two-stage test in which a genomic screening test is used to select SNPs, and then the MPDT is used to test the association of the selected SNPs. Results We use simulation studies to evaluate the performance of the MPDT and the two-stage approach. The results show that the MPDT constantly outperforms the single marker transmission/disequilibrium test (TDT 1. Comparing the power of the two-stage approach with that of the one-stage approach, which approach is more powerful depends on the value of the prevalence; when the prevalence is no less than 10%, the two-stage approach may be more powerful than the one-stage approach. Otherwise, the one-stage approach is more powerful. Conclusion The proposed MPDT, is more powerful than the single marker TDT. When the parental phenotypes are available and the prevalence is no less than 10%, the proposed two-stage approach is more powerful than the one-stage approach.

  18. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption.

    Science.gov (United States)

    Cornelis, M C; Byrne, E M; Esko, T; Nalls, M A; Ganna, A; Paynter, N; Monda, K L; Amin, N; Fischer, K; Renstrom, F; Ngwa, J S; Huikari, V; Cavadino, A; Nolte, I M; Teumer, A; Yu, K; Marques-Vidal, P; Rawal, R; Manichaikul, A; Wojczynski, M K; Vink, J M; Zhao, J H; Burlutsky, G; Lahti, J; Mikkilä, V; Lemaitre, R N; Eriksson, J; Musani, S K; Tanaka, T; Geller, F; Luan, J; Hui, J; Mägi, R; Dimitriou, M; Garcia, M E; Ho, W-K; Wright, M J; Rose, L M; Magnusson, P K E; Pedersen, N L; Couper, D; Oostra, B A; Hofman, A; Ikram, M A; Tiemeier, H W; Uitterlinden, A G; van Rooij, F J A; Barroso, I; Johansson, I; Xue, L; Kaakinen, M; Milani, L; Power, C; Snieder, H; Stolk, R P; Baumeister, S E; Biffar, R; Gu, F; Bastardot, F; Kutalik, Z; Jacobs, D R; Forouhi, N G; Mihailov, E; Lind, L; Lindgren, C; Michaëlsson, K; Morris, A; Jensen, M; Khaw, K-T; Luben, R N; Wang, J J; Männistö, S; Perälä, M-M; Kähönen, M; Lehtimäki, T; Viikari, J; Mozaffarian, D; Mukamal, K; Psaty, B M; Döring, A; Heath, A C; Montgomery, G W; Dahmen, N; Carithers, T; Tucker, K L; Ferrucci, L; Boyd, H A; Melbye, M; Treur, J L; Mellström, D; Hottenga, J J; Prokopenko, I; Tönjes, A; Deloukas, P; Kanoni, S; Lorentzon, M; Houston, D K; Liu, Y; Danesh, J; Rasheed, A; Mason, M A; Zonderman, A B; Franke, L; Kristal, B S; Karjalainen, J; Reed, D R; Westra, H-J; Evans, M K; Saleheen, D; Harris, T B; Dedoussis, G; Curhan, G; Stumvoll, M; Beilby, J; Pasquale, L R; Feenstra, B; Bandinelli, S; Ordovas, J M; Chan, A T; Peters, U; Ohlsson, C; Gieger, C; Martin, N G; Waldenberger, M; Siscovick, D S; Raitakari, O; Eriksson, J G; Mitchell, P; Hunter, D J; Kraft, P; Rimm, E B; Boomsma, D I; Borecki, I B; Loos, R J F; Wareham, N J; Vollenweider, P; Caporaso, N; Grabe, H J; Neuhouser, M L; Wolffenbuttel, B H R; Hu, F B; Hyppönen, E; Järvelin, M-R; Cupples, L A; Franks, P W; Ridker, P M; van Duijn, C M; Heiss, G; Metspalu, A; North, K E; Ingelsson, E; Nettleton, J A; van Dam, R M; Chasman, D I

    2015-05-01

    Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91,462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee. PMID:25288136

  19. Genome-wide transcriptional analysis of genes associated with acute desiccation stress in Anopheles gambiae.

    Directory of Open Access Journals (Sweden)

    Mei-Hui Wang

    Full Text Available Malaria transmission in sub-Saharan Africa varies seasonally in intensity. Outbreaks of malaria occur after the beginning of the rainy season, whereas, during the dry season, reports of the disease are less frequent. Anopheles gambiae mosquitoes, the main malaria vector, are observed all year long but their densities are low during the dry season that generally lasts several months. Aestivation, seasonal migration, and local adaptation have been suggested as mechanisms that enable mosquito populations to persist through the dry season. Studies of chromosomal inversions have shown that inversions 2La, 2Rb, 2Rc, 2Rd, and 2Ru are associated with various physiological changes that confer aridity resistance. However, little is known about how phenotypic plasticity responds to seasonally dry conditions. This study examined the effects of desiccation stress on transcriptional regulation in An. gambiae. We exposed female An. gambiae G3 mosquitoes to acute desiccation and conducted a genome-wide analysis of their transcriptomes using the Affymetrix Plasmodium/Anopheles Genome Array. The transcription of 248 genes (1.7% of all transcripts was significantly affected in all experimental conditions, including 96 with increased expression and 152 with decreased expression. In general, the data indicate a reduction in the metabolic rate of mosquitoes exposed to desiccation. Transcripts accumulated at higher levels during desiccation are associated with oxygen radical detoxification, DNA repair and stress responses. The proportion of transcripts within 2La and 2Rs (2Rb, 2Rc, 2Rd, and 2Ru (67/248, or 27% is similar to the percentage of transcripts located within these inversions (31%. These data may be useful in efforts to elucidate the role of chromosomal inversions in aridity tolerance. The scope of application of the anopheline genome demonstrates that examining transcriptional activity in relation to genotypic adaptations greatly expands the number of

  20. Genome-Wide Association Mapping of Anther Extrusion in Hexaploid Spring Wheat

    Science.gov (United States)

    Muqaddasi, Quddoos H.; Lohwasser, Ulrike; Nagel, Manuela; Börner, Andreas; Pillen, Klaus; Röder, Marion S.

    2016-01-01

    In a number of crop species hybrids are able to outperform line varieties. The anthers of the autogamous bread wheat plant are normally extruded post anthesis, a trait which is unfavourable for the production of F1 hybrid grain. Higher anther extrusion (AE) promotes cross fertilization for more efficient hybrid seed production. Therefore, this study aimed at the genetic dissection of AE by genome wide association studies (GWAS) and determination of the main effect QTL. We applied GWAS approach to identify DArT markers potentially linked to AE to unfold its genetic basis in a panel of spring wheat accessions. Phenotypic data were collected for three years and best linear unbiased estimate (BLUE) values were calculated across all years. The extent of the AE correlation between growing years and BLUE values ranged from r = +0.56 (2013 vs 2015) to 0.91 (2014 vs BLUE values). The broad sense heritability was 0.84 across all years. Six accessions displayed stable AE >80% across all the years. Genotyping data included 2,575 DArT markers (with minimum of 0.05 minor allele frequency applied). AE was influenced both by genotype and by the growing environment. In all, 131 significant marker trait associations (MTAs) (|log10 (P)| >FDR) were established for AE. AE behaved as a quantitative trait, with five consistently significant markers (significant across at least two years with a significant BLUE value) contributing a minor to modest proportion (4.29% to 8.61%) of the phenotypic variance and affecting the trait either positively or negatively. For this reason, there is potential for breeding for improved AE by gene pyramiding. The consistently significant markers linked to AE could be helpful for marker assisted selection to transfer AE to high yielding varieties allowing to promote the exploitation of hybrid-heterosis in the key crop wheat. PMID:27191600

  1. Genome-Wide Association Study on Male Genital Shape and Size in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Baku Takahara

    Full Text Available Male genital morphology of animals with internal fertilization and promiscuous mating systems have been one of the most diverse and rapidly evolving morphological traits. The male genital morphology in general is known to have low phenotypic and genetic variations, but the genetic basis of the male genital variation remains unclear. Drosophila melanogaster and its closely related species are morphologically very similar, but the shapes of the posterior lobe, a cuticular projection on the male genital arch are distinct from each other, representing a model system for studying the genetic basis of male genital morphology. In this study, we used highly inbred whole genome sequenced strains of D. melanogaster to perform genome wide association analysis on posterior lobe morphology. We quantified the outline shape of posterior lobes with Fourier coefficients obtained from elliptic Fourier analysis and performed principal component analysis, and posterior lobe size. The first and second principal components (PC1 and PC2 explained approximately 88% of the total variation of the posterior lobe shape. We then examined the association between the principal component scores and posterior lobe size and 1902142 single nucleotide polymorphisms (SNPs. As a result, we obtained 15, 14 and 15 SNPs for PC1, PC2 and posterior lobe size with P-values smaller than 10(-5. Based on the location of the SNPs, 13, 13 and six protein coding genes were identified as potential candidates for PC1, PC2 and posterior lobe size, respectively. In addition to the previous findings showing that the intraspecific posterior shape variation are regulated by multiple QTL with strong effects, the present study suggests that the intraspecific variation may be under polygenic regulation with a number of loci with small effects. Further studies are required for investigating whether these candidate genes are responsible for the intraspecific posterior lobe shape variation.

  2. Genome-wide association study for cytokines and immunoglobulin G in swine.

    Directory of Open Access Journals (Sweden)

    Xin Lu

    Full Text Available Increased disease resistance through improved immune capacity would be beneficial for the welfare and productivity of farm animals. To identify genomic regions responsible for immune capacity traits in swine, a genome-wide association study was conducted. In total, 675 pigs were included. At 21 days of age, all piglets were vaccinated with modified live classical swine fever vaccine. Blood samples were sampled when the piglets were 20 and 35 days of age, respectively. Four traits, including Interferon-gamma (IFN-γ and Interleukin 10 (IL-10 levels, the ratio of IFN-γ to IL-10 and Immunoglobulin G (IgG blocking percentage to CSFV in serum were measured. All the samples were genotyped for 62,163 single nucleotide polymorphisms (SNP using the Illumina porcineSNP60k BeadChip. After quality control, 46,079 SNPs were selected for association tests based on a single-locus regression model. To tackle the issue of multiple testing, 10,000 permutations were performed to determine the chromosome-wise and genome-wise significance level. In total, 32 SNPs with chromosome-wise significance level (including 4 SNPs with genome-wise significance level were identified. These SNPs account for 3.23% to 13.81% of the total phenotypic variance individually. For the four traits, the numbers of significant SNPs range from 5 to 15, which jointly account for 37.52%, 82.94%, 26.74% and 24.16% of the total phenotypic variance of IFN-γ, IL-10, IFN-γ/IL-10, and IgG, respectively. Several significant SNPs are located within the QTL regions reported in previous studies. Furthermore, several significant SNPs fall into the regions which harbour a number of known immunity-related genes. Results herein lay a preliminary foundation for further identifying the causal mutations affecting swine immune capacity in follow-up studies.

  3. Genome-Wide Association Study of Anthracnose Resistance in Andean Beans (Phaseolus vulgaris.

    Directory of Open Access Journals (Sweden)

    Grady H Zuiderveen

    Full Text Available Anthracnose is a seed-borne disease of common bean (Phaseolus vulgaris L. caused by the fungus Colletotrichum lindemuthianum, and the pathogen is cosmopolitan in distribution. The objectives of this study were to identify new sources of anthracnose resistance in a diverse panel of 230 Andean beans comprised of multiple seed types and market classes from the Americas, Africa, and Europe, and explore the genetic basis of this resistance using genome-wide association mapping analysis (GWAS. Twenty-eight of the 230 lines tested were resistant to six out of the eight races screened, but only one cultivar Uyole98 was resistant to all eight races (7, 39, 55, 65, 73, 109, 2047, and 3481 included in the study. Outputs from the GWAS indicated major quantitative trait loci (QTL for resistance on chromosomes, Pv01, Pv02, and Pv04 and two minor QTL on Pv10 and Pv11. Candidate genes associated with the significant SNPs were detected on all five chromosomes. An independent QTL study was conducted to confirm the physical location of the Co-1 locus identified on Pv01 in an F4:6 recombinant inbred line (RIL population. Resistance was determined to be conditioned by the single dominant gene Co-1 that mapped between 50.16 and 50.30 Mb on Pv01, and an InDel marker (NDSU_IND_1_50.2219 tightly linked to the gene was developed. The information reported will provide breeders with new and diverse sources of resistance and genomic regions to target in the development of anthracnose resistance in Andean beans.

  4. Genome-Wide Association Study of Anthracnose Resistance in Andean Beans (Phaseolus vulgaris).

    Science.gov (United States)

    Zuiderveen, Grady H; Padder, Bilal A; Kamfwa, Kelvin; Song, Qijian; Kelly, James D

    2016-01-01

    Anthracnose is a seed-borne disease of common bean (Phaseolus vulgaris L.) caused by the fungus Colletotrichum lindemuthianum, and the pathogen is cosmopolitan in distribution. The objectives of this study were to identify new sources of anthracnose resistance in a diverse panel of 230 Andean beans comprised of multiple seed types and market classes from the Americas, Africa, and Europe, and explore the genetic basis of this resistance using genome-wide association mapping analysis (GWAS). Twenty-eight of the 230 lines tested were resistant to six out of the eight races screened, but only one cultivar Uyole98 was resistant to all eight races (7, 39, 55, 65, 73, 109, 2047, and 3481) included in the study. Outputs from the GWAS indicated major quantitative trait loci (QTL) for resistance on chromosomes, Pv01, Pv02, and Pv04 and two minor QTL on Pv10 and Pv11. Candidate genes associated with the significant SNPs were detected on all five chromosomes. An independent QTL study was conducted to confirm the physical location of the Co-1 locus identified on Pv01 in an F4:6 recombinant inbred line (RIL) population. Resistance was determined to be conditioned by the single dominant gene Co-1 that mapped between 50.16 and 50.30 Mb on Pv01, and an InDel marker (NDSU_IND_1_50.2219) tightly linked to the gene was developed. The information reported will provide breeders with new and diverse sources of resistance and genomic regions to target in the development of anthracnose resistance in Andean beans. PMID:27270627

  5. Genome-Wide Association Mapping of Anther Extrusion in Hexaploid Spring Wheat.

    Science.gov (United States)

    Muqaddasi, Quddoos H; Lohwasser, Ulrike; Nagel, Manuela; Börner, Andreas; Pillen, Klaus; Röder, Marion S

    2016-01-01

    In a number of crop species hybrids are able to outperform line varieties. The anthers of the autogamous bread wheat plant are normally extruded post anthesis, a trait which is unfavourable for the production of F1 hybrid grain. Higher anther extrusion (AE) promotes cross fertilization for more efficient hybrid seed production. Therefore, this study aimed at the genetic dissection of AE by genome wide association studies (GWAS) and determination of the main effect QTL. We applied GWAS approach to identify DArT markers potentially linked to AE to unfold its genetic basis in a panel of spring wheat accessions. Phenotypic data were collected for three years and best linear unbiased estimate (BLUE) values were calculated across all years. The extent of the AE correlation between growing years and BLUE values ranged from r = +0.56 (2013 vs 2015) to 0.91 (2014 vs BLUE values). The broad sense heritability was 0.84 across all years. Six accessions displayed stable AE >80% across all the years. Genotyping data included 2,575 DArT markers (with minimum of 0.05 minor allele frequency applied). AE was influenced both by genotype and by the growing environment. In all, 131 significant marker trait associations (MTAs) (|log10 (P)| >FDR) were established for AE. AE behaved as a quantitative trait, with five consistently significant markers (significant across at least two years with a significant BLUE value) contributing a minor to modest proportion (4.29% to 8.61%) of the phenotypic variance and affecting the trait either positively or negatively. For this reason, there is potential for breeding for improved AE by gene pyramiding. The consistently significant markers linked to AE could be helpful for marker assisted selection to transfer AE to high yielding varieties allowing to promote the exploitation of hybrid-heterosis in the key crop wheat. PMID:27191600

  6. Genome-Wide Association Study of Anthracnose Resistance in Andean Beans (Phaseolus vulgaris)

    Science.gov (United States)

    Zuiderveen, Grady H.; Padder, Bilal A.; Kamfwa, Kelvin; Song, Qijian; Kelly, James D.

    2016-01-01

    Anthracnose is a seed-borne disease of common bean (Phaseolus vulgaris L.) caused by the fungus Colletotrichum lindemuthianum, and the pathogen is cosmopolitan in distribution. The objectives of this study were to identify new sources of anthracnose resistance in a diverse panel of 230 Andean beans comprised of multiple seed types and market classes from the Americas, Africa, and Europe, and explore the genetic basis of this resistance using genome-wide association mapping analysis (GWAS). Twenty-eight of the 230 lines tested were resistant to six out of the eight races screened, but only one cultivar Uyole98 was resistant to all eight races (7, 39, 55, 65, 73, 109, 2047, and 3481) included in the study. Outputs from the GWAS indicated major quantitative trait loci (QTL) for resistance on chromosomes, Pv01, Pv02, and Pv04 and two minor QTL on Pv10 and Pv11. Candidate genes associated with the significant SNPs were detected on all five chromosomes. An independent QTL study was conducted to confirm the physical location of the Co-1 locus identified on Pv01 in an F4:6 recombinant inbred line (RIL) population. Resistance was determined to be conditioned by the single dominant gene Co-1 that mapped between 50.16 and 50.30 Mb on Pv01, and an InDel marker (NDSU_IND_1_50.2219) tightly linked to the gene was developed. The information reported will provide breeders with new and diverse sources of resistance and genomic regions to target in the development of anthracnose resistance in Andean beans. PMID:27270627

  7. A Bayesian Method for Detecting and Characterizing Allelic Heterogeneity and Boosting Signals in Genome-Wide Association Studies

    OpenAIRE

    Su, Zhan; Cardin, Niall; Consortium, the Wellcome Trust Case Control; Donnelly, Peter; Marchini, Jonathan

    2009-01-01

    The standard paradigm for the analysis of genome-wide association studies involves carrying out association tests at both typed and imputed SNPs. These methods will not be optimal for detecting the signal of association at SNPs that are not currently known or in regions where allelic heterogeneity occurs. We propose a novel association test, complementary to the SNP-based approaches, that attempts to extract further signals of association by explicitly modeling and estimating both unknown SNP...

  8. A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip

    OpenAIRE

    Evangelou, Evangelos; Kerkhof, Hanneke J.; Styrkarsdottir, Unnur; Ntzani, Evangelia E; Bos, Steffan D.; Esko, Tonu; Evans, Daniel S.; Metrustry, Sarah; Panoutsopoulou, Kalliope; Ramos, Yolande F M; Thorleifsson, Gudmar; Tsilidis, Konstantinos K.; ,; Arden, Nigel; Aslam, Nadim

    2013-01-01

    Objectives Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for ‘in silico’ or ‘de novo’ replication. Besides the main analysis, a stratified by sex a...

  9. A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip.

    OpenAIRE

    Evangelou, Evangelos; Kerkhof, Hanneke; Styrkarsdottir, Unnur; Ntzani, Evangelia; Bos, Steffan; Esko, Tõnu; Evans, Daniel; Metrustry, Sarah; Panoutsopoulou, Kalliope; Ramos, Yolande; Thorleifsson, Gudmar; Tsilidis, Konstantinos; Arden, Nigel; Aslam, Nadim; Bellamy, Nicholas

    2014-01-01

    Objectives Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a str...

  10. Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility

    NARCIS (Netherlands)

    Yin, Xianyong; Low, Hui Qi; Wang, Ling; Li, Yonghong; Ellinghaus, Eva; Han, Jiali; Estivill, Xavier; Sun, Liangdan; Zuo, Xianbo; Shen, Changbing; Zhu, Caihong; Zhang, Anping; Sanchez, Fabio; Padyukov, Leonid; Catanese, Joseph J; Krueger, Gerald G; Duffin, Kristina Callis; Mucha, Sören; Weichenthal, Michael; Weidinger, Stephan; Lieb, Wolfgang; Foo, Jia Nee; Li, Yi; Sim, Karseng; Liany, Herty; Irwan, Ishak; Teo, Yikying; Theng, Colin T S; Gupta, Rashmi; Bowcock, Anne; De Jager, Philip L; Qureshi, Abrar A; de Bakker, Paul I W; Seielstad, Mark; Liao, Wilson; Ståhle, Mona; Franke, Andre; Zhang, Xuejun; Liu, Jianjun

    2015-01-01

    Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We iden

  11. Genome-Wide Association Mapping for Cell Wall Composition and Properties in Temperate Grasses

    DEFF Research Database (Denmark)

    Bellucci, Andrea

    -glucans. Plant cell wall biosynthesis is regulated by a large number of genes and regulatory factors but very few of these are known and characterized. This PhD project aimed to the identification of putative candidate genes involved in plant cell wall composition and properties using a genome wide (GWAS...

  12. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

    NARCIS (Netherlands)

    Cornelis, M. C.; Byrne, E. M.; Esko, T.; Nalls, M. A.; Ganna, A.; Paynter, N.; Monda, K. L.; Amin, N.; Fischer, K.; Renstrom, F.; Ngwa, J. S.; Huikari, V.; Cavadino, A.; Nolte, I. M.; Teumer, A.; Yu, K.; Marques-Vidal, P.; Rawal, R.; Manichaikul, A.; Wojczynski, M. K.; Vink, J. M.; Zhao, J. H.; Burlutsky, G.; Lahti, J.; Mikkila, V.; Lemaitre, R. N.; Eriksson, J.; Musani, S. K.; Tanaka, T.; Geller, F.; Luan, J.; Hui, J.; Maegi, R.; Dimitriou, M.; Garcia, M. E.; Ho, W-K; Wright, M. J.; Rose, L. M.; Magnusson, P. K. E.; Pedersen, N. L.; Couper, D.; Oostra, B. A.; Hofman, A.; Ikram, M. A.; Tiemeier, H. W.; Uitterlinden, A. G.; van Rooij, F. J. A.; Barroso, I.; Johansson, I.; Xue, L.; Kaakinen, M.; Milani, L.; Power, C.; Snieder, H.; Stolk, R. P.; Baumeister, S. E.; Biffar, R.; Gu, F.; Bastardot, F.; Kutalik, Z.; Jacobs, D. R.; Forouhi, N. G.; Mihailov, E.; Lind, L.; Lindgren, C.; Michaelsson, K.; Morris, A.; Jensen, M.; Khaw, K-T; Luben, R. N.; Wang, J. J.; Mannisto, S.; Perala, M-M; Kahonen, M.; Lehtimaki, T.; Viikari, J.; Mozaffarian, D.; Mukamal, K.; Psaty, B. M.; Doering, A.; Heath, A. C.; Montgomery, G. W.; Dahmen, N.; Carithers, T.; Tucker, K. L.; Ferrucci, L.; Boyd, H. A.; Melbye, M.; Treur, J. L.; Mellstrom, D.; Hottenga, J. J.; Prokopenko, I.; Toenjes, A.; Deloukas, P.; Kanoni, S.; Lorentzon, M.; Houston, D. K.; Liu, Y.; Danesh, J.; Rasheed, A.; Mason, M. A.; Zonderman, A. B.; Franke, L.; Kristal, B. S.; Karjalainen, J.; Reed, D. R.; Westra, H-J; Evans, M. K.; Saleheen, D.; Harris, T. B.; Dedoussis, G.; Curhan, G.; Stumvoll, M.; Beilby, J.; Pasquale, L. R.; Feenstra, B.; Bandinelli, S.; Ordovas, J. M.; Chan, A. T.; Peters, U.; Ohlsson, C.; Gieger, C.; Martin, N. G.; Waldenberger, M.; Siscovick, D. S.; Raitakari, O.; Eriksson, J. G.; Mitchell, P.; Hunter, D. J.; Kraft, P.; Rimm, E. B.; Boomsma, D. I.; Borecki, I. B.; Loos, R. J. F.; Wareham, N. J.; Vollenweider, P.; Caporaso, N.; Grabe, H. J.; Neuhouser, M. L.; Wolffenbuttel, B. H. R.; Hu, F. B.; Hyppoenen, E.; Jarvelin, M-R; Cupples, L. A.; Franks, P. W.; Ridker, P. M.; van Duijn, C. M.; Heiss, G.; Metspalu, A.; North, K. E.; Ingelsson, E.; Nettleton, J. A.; van Dam, R. M.; Chasman, D. I.

    2015-01-01

    Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to

  13. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption

    NARCIS (Netherlands)

    M. Cornelis (Marilyn); E.M. Byrne; T. Esko (Tõnu); M.A. Nalls (Michael); A. Ganna (Andrea); N.P. Paynter (Nina); K.L. Monda (Keri); N. Amin; K. Fischer (Krista); F. Renström (Frida); J.S. Ngwa; V. Huikari (Ville); A. Cavadino (Alana); I.M. Nolte (Ilja M.); A. Teumer (Alexander); K. Yu; P. Marques-Vidal; R. Rawal; A. Manichaikul (Ani); M.K. Wojczynski (Mary ); J.M. Vink; J.H. Zhao; G. Burlutsky (George); J. Lahti (Jari); V. Mikkilä (Vera); R.N. Lemaitre (Rozenn ); J. Eriksson; S. Musani (Solomon); T. Tanaka; F. Geller (Frank); J. Luan; J. Hui; R. Mägi (Reedik); M. Dimitriou (Maria); M. Garcia (Melissa); W.-K. Ho; M.J. Wright (Margaret); L.M. Rose (Lynda M.); P.K.E. Magnusson (Patrik K. E.); N.L. Pedersen (Nancy L.); D.J. Couper (David); B.A. Oostra (Ben); A. Hofman (Albert); M.A. Ikram (Arfan); H.W. Tiemeier (Henning); A.G. Uitterlinden (André); F.J.A. van Rooij (Frank); I. Barroso; I. Johansson (Ingegerd); L. Xue (Luting); M. Kaakinen (Marika); L. Milani (Lili); C. Power (Christine); H. Snieder (Harold); R.P. Stolk; S.E. Baumeister (Sebastian); R. Biffar; F. Gu; F. Bastardot (Francois); Z. Kutalik; D.R. Jacobs (David); N.G. Forouhi (Nita G.); E. Mihailov (Evelin); L. Lind (Lars); C. Lindgren; K. Michaëlsson; A.P. Morris (Andrew); M.K. Jensen (Majken K.); K.T. Khaw; R.N. Luben (Robert); J.J. Wang; S. Männistö (Satu); M.-M. Perälä; M. Kähönen (Mika); T. Lehtimäki (Terho); J. Viikari (Jorma); D. Mozaffarian; K. Mukamal (Kenneth); B.M. Psaty (Bruce); A. Döring; A.C. Heath (Andrew C.); G.W. Montgomery (Grant W.); N. Dahmen (N.); T. Carithers; K.L. Tucker; L. Ferrucci (Luigi); H.A. Boyd; M. Melbye (Mads); J.L. Treur; D. Mellström (Dan); J.J. Hottenga (Jouke Jan); I. Prokopenko (Inga); A. Tönjes (Anke); P. Deloukas (Panagiotis); S. Kanoni (Stavroula); M. Lorentzon (Mattias); D.K. Houston; Y. Liu; J. Danesh (John); A. Rasheed; M.A. Mason; A.B. Zonderman; L. Franke (Lude); B.S. Kristal; J. Karjalainen (Juha); D.R. Reed; H.-J. Westra; M.K. Evans; D. Saleheen; T.B. Harris (Tamara B.); G.V. Dedoussis (George V.); G.C. Curhan (Gary); M. Stumvoll (Michael); J. Beilby (John); L.R. Pasquale; B. Feenstra; S. Bandinelli; J.M. Ordovas; A.T. Chan; U. Peters (Ulrike); C. Ohlsson (Claes); C. Gieger (Christian); N.G. Martin (Nicholas); M. Waldenberger (Melanie); D.S. Siscovick (David); O. Raitakari (Olli); J.G. Eriksson (Johan G.); P. Mitchell (Paul); D. Hunter (David); P. Kraft (Peter); E.B. Rimm (Eric B.); D.I. Boomsma (Dorret); I.B. Borecki (Ingrid); R.J.F. Loos (Ruth J.F.); N.J. Wareham (Nick); P.K. Vollenweider (Peter K.); N. Caporaso; H.J. Grabe (Hans Jörgen); M.L. Neuhouser (Marian L.); B.H.R. Wolffenbuttel (Bruce H. R.); F.B. Hu (Frank); E. Hypponen (Elina); M.-R. Jarvelin (Marjo-Riitta); L.A. Cupples (Adrienne); P.W. Franks; P.M. Ridker (Paul); C.M. Van Duijn (Cornelia M.); G. Heiss (Gerardo); A. Metspalu (Andres); K.E. North (Kari); E. Ingelsson (Erik); J.A. Nettleton; R.M. van Dam (Rob); D.I. Chasman (Daniel)

    2015-01-01

    textabstractCoffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day)

  14. Genome-wide association studies of human adiposity: Zooming in on synapses

    DEFF Research Database (Denmark)

    Sandholt, Camilla H.; Grarup, Niels; Pedersen, Oluf;

    2015-01-01

    The decade anniversary for genome-wide assocn. studies (GWAS) is approaching, and this exptl. approach has commenced a deeper understanding of the genetics underlying complex diseases. In obesity genetics the GIANT (Genetic Investigation of ANthropometric Traits) consortium has played a crucial r...

  15. Genome Wide Association Study to predict severe asthma exacerbations in children using random forests classifiers

    Directory of Open Access Journals (Sweden)

    Litonjua Augusto A

    2011-06-01

    Full Text Available Abstract Background Personalized health-care promises tailored health-care solutions to individual patients based on their genetic background and/or environmental exposure history. To date, disease prediction has been based on a few environmental factors and/or single nucleotide polymorphisms (SNPs, while complex diseases are usually affected by many genetic and environmental factors with each factor contributing a small portion to the outcome. We hypothesized that the use of random forests classifiers to select SNPs would result in an improved predictive model of asthma exacerbations. We tested this hypothesis in a population of childhood asthmatics. Methods In this study, using emergency room visits or hospitalizations as the definition of a severe asthma exacerbation, we first identified a list of top Genome Wide Association Study (GWAS SNPs ranked by Random Forests (RF importance score for the CAMP (Childhood Asthma Management Program population of 127 exacerbation cases and 290 non-exacerbation controls. We predict severe asthma exacerbations using the top 10 to 320 SNPs together with age, sex, pre-bronchodilator FEV1 percentage predicted, and treatment group. Results Testing in an independent set of the CAMP population shows that severe asthma exacerbations can be predicted with an Area Under the Curve (AUC = 0.66 with 160-320 SNPs in comparison to an AUC score of 0.57 with 10 SNPs. Using the clinical traits alone yielded AUC score of 0.54, suggesting the phenotype is affected by genetic as well as environmental factors. Conclusions Our study shows that a random forests algorithm can effectively extract and use the information contained in a small number of samples. Random forests, and other machine learning tools, can be used with GWAS studies to integrate large numbers of predictors simultaneously.

  16. Genome-wide association study identifies novel locus for neuroticism and shows polygenic association with Major Depressive Disorder

    Science.gov (United States)

    de Moor, Marleen H.M.; van den Berg, Stéphanie M.; Verweij, Karin J.H.; Krueger, Robert F.; Luciano, Michelle; Vasquez, Alejandro Arias; Matteson, Lindsay K.; Derringer, Jaime; Esko, Tõnu; Amin, Najaf; Gordon, Scott D.; Hansell, Narelle K.; Hart, Amy B.; Seppälä, Ilkka; Huffman, Jennifer E.; Konte, Bettina; Lahti, Jari; Lee, Minyoung; Miller, Mike; Nutile, Teresa; Tanaka, Toshiko; Teumer, Alexander; Viktorin, Alexander; Wedenoja, Juho; Abecasis, Goncalo R.; Adkins, Daniel E.; Agrawal, Arpana; Allik, Jüri; Appel, Katja; Bigdeli, Timothy B.; Busonero, Fabio; Campbell, Harry; Costa, Paul T.; Smith, George Davey; Davies, Gail; de Wit, Harriet; Ding, Jun; Engelhardt, Barbara E.; Eriksson, Johan G.; Fedko, Iryna O.; Ferrucci, Luigi; Franke, Barbara; Giegling, Ina; Grucza, Richard; Hartmann, Annette M.; Heath, Andrew C.; Heinonen, Kati; Henders, Anjali K.; Homuth, Georg; Hottenga, Jouke-Jan; Janzing, Joost; Jokela, Markus; Karlsson, Robert; Kemp, John P.; Kirkpatrick, Matthew G.; Latvala, Antti; Lehtimäki, Terho; Liewald, David C.; Madden, Pamela A.F.; Magri, Chiara; Magnusson, Patrik K.E.; Marten, Jonathan; Maschio, Andrea; Medland, Sarah E.; Mihailov, Evelin; Milaneschi, Yuri; Montgomery, Grant W.; Nauck, Matthias; Ouwens, Klaasjan G.; Palotie, Aarno; Pettersson, Erik; Polasek, Ozren; Qian, Yong; Pulkki-Råback, Laura; Raitakari, Olli T.; Realo, Anu; Rose, Richard J.; Ruggiero, Daniela; Schmidt, Carsten O.; Slutske, Wendy S.; Sorice, Rossella; Starr, John M.; Pourcain, Beate St; Sutin, Angelina R.; Timpson, Nicholas J.; Trochet, Holly; Vermeulen, Sita; Vuoksimaa, Eero; Widen, Elisabeth; Wouda, Jasper; Wright, Margaret J.; Zgaga, Lina; Scotland, Generation; Porteous, David; Minelli, Alessandra; Palmer, Abraham A.; Rujescu, Dan; Ciullo, Marina; Hayward, Caroline; Rudan, Igor; Metspalu, Andres; Kaprio, Jaakko; Deary, Ian J.; Räikkönen, Katri; Wilson, James F.; Keltikangas-Järvinen, Liisa; Bierut, Laura J.; Hettema, John M.; Grabe, Hans J.; van Duijn, Cornelia M.; Evans, David M.; Schlessinger, David; Pedersen, Nancy L.; Terracciano, Antonio; McGue, Matt; Penninx, Brenda W.J.H.; Martin, Nicholas G.; Boomsma, Dorret I.

    2015-01-01

    Importance Neuroticism is a personality trait that is briefly defined by emotional instability. It is a robust genetic risk factor for Major Depressive Disorder (MDD) and other psychiatric disorders. Hence, neuroticism is an important phenotype for psychiatric genetics. The Genetics of Personality Consortium (GPC) has created a resource for genome-wide association analyses of personality traits in over 63,000 participants (including MDD cases). Objective To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association (GWA) results based on 1000Genomes imputation, to evaluate if common genetic variants as assessed by Single Nucleotide Polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability, and to examine whether SNPs that predict neuroticism also predict MDD. Setting 30 cohorts with genome-wide genotype, personality and MDD data from the GPC. Participants The study included 63,661 participants from 29 discovery cohorts and 9,786 participants from a replication cohort. Participants came from Europe, the United States or Australia. Main outcome measure(s) Neuroticism scores harmonized across all cohorts by Item Response Theory (IRT) analysis, and clinically assessed MDD case-control status. Results A genome-wide significant SNP was found in the MAGI1 gene (rs35855737; P=9.26 × 10−9 in the discovery meta-analysis, and P=2.38 × 10−8 in the meta-analysis of all 30 cohorts). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 of the discovery cohorts significantly predicted neuroticism in 2 independent cohorts. Importantly, polygenic scores also predicted MDD in these cohorts. Conclusions and relevance This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study

  17. Genome-wide association study of neocortical Lewy-related pathology

    Science.gov (United States)

    Peuralinna, Terhi; Myllykangas, Liisa; Oinas, Minna; Nalls, Mike A; Keage, Hannah A D; Isoviita, Veli-Matti; Valori, Miko; Polvikoski, Tuomo; Paetau, Anders; Sulkava, Raimo; Ince, Paul G; Zaccai, Julia; Brayne, Carol; Traynor, Bryan J; Hardy, John; Singleton, Andrew B; Tienari, Pentti J

    2015-01-01

    Objective Dementia with Lewy bodies is an α-synucleinopathy characterized by neocortical Lewy-related pathology (LRP). We carried out a genome-wide association study (GWAS) on neocortical LRP in a population-based sample of subjects aged 85 or over. Methods LRP was analyzed in 304 subjects in the Vantaa 85+ sample from Southern Finland. The GWAS included 41 cases with midbrain, hippocampal, and neocortical LRP and 177 controls without midbrain and hippocampal LRP. The Medical Research Council Cognitive Function and Ageing Study (CFAS) material was used for replication (51 cases and 131 controls). Results By analyzing 327,010 markers the top signal was obtained at the HLA-DPA1/DPB1 locus (P = 1.29 × 10−7); five other loci on chromosomes 15q14, 2p21, 2q31, 18p11, and 5q23 were associated with neocortical LRP at P < 10−5. Two loci were marked by multiple markers, 2p21 (P = 3.9 × 10−6, upstream of the SPTBN1 gene), and HLA-DPA1/DPB1; these were tested in the CFAS material. Single marker (P = 0.0035) and haplotype (P = 0.04) associations on 2p21 were replicated in CFAS, whereas HLA-DPA1/DPB1 association was not. Bioinformatic analyses suggest functional effects for the HLA-DPA1/DPB1 markers as well as the 15q14 marker rs8037309. Interpretation We identified suggestive novel risk factors for neocortical LRP. SPTBN1 is the candidate on 2p21, it encodes beta-spectrin, an α-synuclein binding protein and a component of Lewy bodies. The HLA-DPA1/DPB1 association suggests a role for antigen presentation or alternatively, cis-regulatory effects, one of the regulated neighboring genes identified here (vacuolar protein sorting 52) plays a role in vesicular trafficking and has been shown to interact with α-synuclein in a yeast model. PMID:26401513

  18. Gene ontology analysis of pairwise genetic associations in two genome-wide studies of sporadic ALS

    Directory of Open Access Journals (Sweden)

    Kim Nora

    2012-07-01

    Full Text Available Abstract Background It is increasingly clear that common human diseases have a complex genetic architecture characterized by both additive and nonadditive genetic effects. The goal of the present study was to determine whether patterns of both additive and nonadditive genetic associations aggregate in specific functional groups as defined by the Gene Ontology (GO. Results We first estimated all pairwise additive and nonadditive genetic effects using the multifactor dimensionality reduction (MDR method that makes few assumptions about the underlying genetic model. Statistical significance was evaluated using permutation testing in two genome-wide association studies of ALS. The detection data consisted of 276 subjects with ALS and 271 healthy controls while the replication data consisted of 221 subjects with ALS and 211 healthy controls. Both studies included genotypes from approximately 550,000 single-nucleotide polymorphisms (SNPs. Each SNP was mapped to a gene if it was within 500 kb of the start or end. Each SNP was assigned a p-value based on its strongest joint effect with the other SNPs. We then used the Exploratory Visual Analysis (EVA method and software to assign a p-value to each gene based on the overabundance of significant SNPs at the α = 0.05 level in the gene. We also used EVA to assign p-values to each GO group based on the overabundance of significant genes at the α = 0.05 level. A GO category was determined to replicate if that category was significant at the α = 0.05 level in both studies. We found two GO categories that replicated in both studies. The first, ‘Regulation of Cellular Component Organization and Biogenesis’, a GO Biological Process, had p-values of 0.010 and 0.014 in the detection and replication studies, respectively. The second, ‘Actin Cytoskeleton’, a GO Cellular Component, had p-values of 0.040 and 0.046 in the detection and replication studies, respectively. Conclusions Pathway

  19. RS-SNP: a random-set method for genome-wide association studies

    Directory of Open Access Journals (Sweden)

    Mukherjee Sayan

    2011-03-01

    Full Text Available Abstract Background The typical objective of Genome-wide association (GWA studies is to identify single-nucleotide polymorphisms (SNPs and corresponding genes with the strongest evidence of association (the 'most-significant SNPs/genes' approach. Borrowing ideas from micro-array data analysis, we propose a new method, named RS-SNP, for detecting sets of genes enriched in SNPs moderately associated to the phenotype. RS-SNP assesses whether the number of significant SNPs, with p-value P ≤ α, belonging to a given SNP set is statistically significant. The rationale of proposed method is that two kinds of null hypotheses are taken into account simultaneously. In the first null model the genotype and the phenotype are assumed to be independent random variables and the null distribution is the probability of the number of significant SNPs in greater than observed by chance. The second null model assumes the number of significant SNPs in depends on the size of and not on the identity of the SNPs in . Statistical significance is assessed using non-parametric permutation tests. Results We applied RS-SNP to the Crohn's disease (CD data set collected by the Wellcome Trust Case Control Consortium (WTCCC and compared the results with GENGEN, an approach recently proposed in literature. The enrichment analysis using RS-SNP and the set of pathways contained in the MSigDB C2 CP pathway collection highlighted 86 pathways rich in SNPs weakly associated to CD. Of these, 47 were also indicated to be significant by GENGEN. Similar results were obtained using the MSigDB C5 pathway collection. Many of the pathways found to be enriched by RS-SNP have a well-known connection to CD and often with inflammatory diseases. Conclusions The proposed method is a valuable alternative to other techniques for enrichment analysis of SNP sets. It is well founded from a theoretical and statistical perspective. Moreover, the experimental comparison with GENGEN highlights that it is

  20. Genome-wide population-based association study of extremely overweight young adults--the GOYA study

    DEFF Research Database (Denmark)

    Paternoster, Lavinia; Evans, David M; Nøhr, Ellen Aagaard; Holst, Claus; Gaborieau, Valerie; Brennan, Paul; Gjesing, Anette Prior; Grarup, Niels; Witte, Daniel Rinse; Jørgensen, Torben; Linneberg, Allan René; Hansen, Torben; Lauritzen, Torsten; Sandbæk, Annelli; Pedersen, Oluf; Elliott, Katherine S; Kemp, John P; St Pourcain, Beate; McMahon, George; Zelenika, Diana; Hager, Jörg; Lathrop, Mark; Timpson, Nicholas J; Smith, George Davey; Sørensen, Thorkild I.A.

    2011-01-01

    Background: Thirty-two common variants associated with body mass index (BMI) have been identified in genome-wide association studies, explaining,similar to 1.45% of BMI variation in general population cohorts. We performed a genome-wide association study in a sample of young adults enriched for...... extremely overweight individuals. We aimed to identify new loci associated with BMI and to ascertain whether using an extreme sampling design would identify the variants known to be associated with BMI in general populations. Methodology/Principal Findings: From two large Danish cohorts we selected all...... extremely overweight young men and women (n = 2,633), and equal numbers of population-based controls (n = 2,740, drawn randomly from the same populations as the extremes, representing similar to 212,000 individuals). We followed up novel (at the time of the study) association signals (p...

  1. Genome-wide association study to identify the genetic determinants of otitis media susceptibility in childhood.

    Directory of Open Access Journals (Sweden)

    Marie S Rye

    Full Text Available BACKGROUND: Otitis media (OM is a common childhood disease characterised by middle ear inflammation and effusion. Susceptibility to recurrent acute OM (rAOM; ≥ 3 episodes of AOM in 6 months and chronic OM with effusion (COME; MEE ≥ 3 months is 40-70% heritable. Few underlying genes have been identified to date, and no genome-wide association study (GWAS of OM has been reported. METHODS AND FINDINGS: Data for 2,524,817 single nucleotide polymorphisms (SNPs; 535,544 quality-controlled SNPs genotyped by Illumina 660W-Quad; 1,989,273 by imputation were analysed for association with OM in 416 cases and 1,075 controls from the Western Australian Pregnancy Cohort (Raine Study. Logistic regression analyses under an additive model undertaken in GenABEL/ProbABEL adjusting for population substructure using principal components identified SNPs at CAPN14 (rs6755194: OR = 1.90; 95%CI 1.47-2.45; P(adj-PCA = 8.3 × 10(-7 on chromosome 2p23.1 as the top hit, with independent effects (rs1862981: OR = 1.60; 95%CI 1.29-1.99; P(adj-PCA = 2.2 × 10(-5 observed at the adjacent GALNT14 gene. In a gene-based analysis in VEGAS, BPIFA3 (P(Gene = 2 × 10(-5 and BPIFA1 (P(Gene = 1.07 × 10(-4 in the BPIFA gene cluster on chromosome 20q11.21 were the top hits. In all, 32 genomic regions show evidence of association (P(adj-PCA<10(-5 in this GWAS, with pathway analysis showing a connection between top candidates and the TGFβ pathway. However, top and tag-SNP analysis for seven selected candidate genes in this pathway did not replicate in 645 families (793 affected individuals from the Western Australian Family Study of Otitis Media (WAFSOM. Lack of replication may be explained by sample size, difference in OM disease severity between primary and replication cohorts or due to type I error in the primary GWAS. CONCLUSIONS: This first discovery GWAS for an OM phenotype has identified CAPN14 and GALNT14 on chromosome 2p23.1 and the BPIFA gene cluster on chromosome 20q11.21 as

  2. Genome-wide association study identifies polymorphisms in LEPR as determinants of plasma soluble leptin receptor levels

    OpenAIRE

    Sun, Qi; Cornelis, Marilyn C; Kraft, Peter; Qi, Lu; van Dam, Rob M.; Girman, Cynthia J.; Cathy C Laurie; Mirel, Daniel B.; Gong, Huizi; Sheu, Chau-Chyun; Christiani, David C.; Hunter, David J.; Mantzoros, Christos S.; Hu, Frank B.

    2010-01-01

    Plasma soluble leptin receptor (sOB-R) levels were inversely associated with diabetes risk factors, including adiposity and insulin resistance, and highly correlated with the expression levels of leptin receptor, which is ubiquitously expressed in most tissues. We conducted a genome-wide association study of sOB-R in 1504 women of European ancestry from the Nurses' Health Study. The initial scan yielded 26 single nucleotide polymorphisms (SNPs) significantly associated with sOB-R levels (P < ...

  3. On the analysis of genome-wide association studies in family-based designs: a universal, robust analysis approach and an application to four genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Sungho Won

    2009-11-01

    Full Text Available For genome-wide association studies in family-based designs, we propose a new, universally applicable approach. The new test statistic exploits all available information about the association, while, by virtue of its design, it maintains the same robustness against population admixture as traditional family-based approaches that are based exclusively on the within-family information. The approach is suitable for the analysis of almost any trait type, e.g. binary, continuous, time-to-onset, multivariate, etc., and combinations of those. We use simulation studies to verify all theoretically derived properties of the approach, estimate its power, and compare it with other standard approaches. We illustrate the practical implications of the new analysis method by an application to a lung-function phenotype, forced expiratory volume in one second (FEV1 in 4 genome-wide association studies.

  4. Meta-analysis of genome-wide expression patterns associated with behavioral maturation in honey bees

    Directory of Open Access Journals (Sweden)

    Southey Bruce R

    2008-10-01

    -analyses confirmed previously reported genes and helped identify genes (e.g. Tomosyn, Chitinase 5, Adar, Innexin 2, Transferrin 1, Sick, Oatp26F and Gene Ontology categories (e.g. purine nucleotide binding not previously associated with maturation in honey bees. Conclusion This study demonstrated that a combination of meta-analytical approaches best addresses the highly dimensional nature of genome-wide microarray studies. As expected, the integration of gene expression information from microarray studies using meta-analysis enhanced the characterization of the transcriptome of complex biological processes.

  5. A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features.

    Science.gov (United States)

    Adhikari, Kaustubh; Fontanil, Tania; Cal, Santiago; Mendoza-Revilla, Javier; Fuentes-Guajardo, Macarena; Chacón-Duque, Juan-Camilo; Al-Saadi, Farah; Johansson, Jeanette A; Quinto-Sanchez, Mirsha; Acuña-Alonzo, Victor; Jaramillo, Claudia; Arias, William; Barquera Lozano, Rodrigo; Macín Pérez, Gastón; Gómez-Valdés, Jorge; Villamil-Ramírez, Hugo; Hunemeier, Tábita; Ramallo, Virginia; Silva de Cerqueira, Caio C; Hurtado, Malena; Villegas, Valeria; Granja, Vanessa; Gallo, Carla; Poletti, Giovanni; Schuler-Faccini, Lavinia; Salzano, Francisco M; Bortolini, Maria-Cátira; Canizales-Quinteros, Samuel; Rothhammer, Francisco; Bedoya, Gabriel; Gonzalez-José, Rolando; Headon, Denis; López-Otín, Carlos; Tobin, Desmond J; Balding, David; Ruiz-Linares, Andrés

    2016-01-01

    We report a genome-wide association scan in over 6,000 Latin Americans for features of scalp hair (shape, colour, greying, balding) and facial hair (beard thickness, monobrow, eyebrow thickness). We found 18 signals of association reaching genome-wide significance (P values 5 × 10(-8) to 3 × 10(-119)), including 10 novel associations. These include novel loci for scalp hair shape and balding, and the first reported loci for hair greying, monobrow, eyebrow and beard thickness. A newly identified locus influencing hair shape includes a Q30R substitution in the Protease Serine S1 family member 53 (PRSS53). We demonstrate that this enzyme is highly expressed in the hair follicle, especially the inner root sheath, and that the Q30R substitution affects enzyme processing and secretion. The genome regions associated with hair features are enriched for signals of selection, consistent with proposals regarding the evolution of human hair. PMID:26926045

  6. Molecular profiling of indolent human prostate cancer:tackling technical challenges to achieve high-fidelity genome-wide data

    Institute of Scientific and Technical Information of China (English)

    Thomas A. Dunn; Helen L. Fedor; Angelo M. De Marzo; Jun Luo

    2012-01-01

    The contemporary problem of prostate cancer overtreatment can be partially attributed to the diagnosis of potentially indolent prostate cancers that pose low risk to aged men,and lack of sufficiently accurate risk stratification methods to reliably seek out men with indolent diseases.Since progressive acquisition and accumulation of genomic alterations,both genetic and epigenetic,is a defining feature of all human cancers at different stages of disease progression,it is hypothesized that RNA and DNA alterations characteristic of indolent prostate tumors may be different from those previously characterized in the setting of clinically significant prostate cancer.Approaches capable of detecting such alterations on a genome-wide level are the most promising.Such analysis may uncover molecular events defining early initiating stages along the natural history of prostate cancer progression,and ultimately lead to rational development of risk stratification methods for identification of men who can safely forego treatment.However,defining and characterizing indolent prostate cancer in a clinically relevant context remains a challenge,particularly when genome-wide approaches are employed to profile formalin-fixed paraffin-embedded (FFPE) tissue specimens.Here,we provide the conceptual basis underlying the importance of understanding indolent prostate cancer from molecular profiling studies,identify the key hurdles in sample acquisition and variables that affect molecular data derived from FFPE tissues,and highlight recent progresses in efforts to address these technical challenges.

  7. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci.

    Directory of Open Access Journals (Sweden)

    Ying Liu

    2008-03-01

    Full Text Available A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS and psoriatic arthritis (PSA, inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA were genotyped with 311,398 single nucleotide polymorphisms (SNPs, and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC. The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8x10(-11, GWA scan; P = 1.8x10(-30, replication; P = 1.8x10(-39, combined; U.K. PSA: P = 6.9x10(-11. However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13x10(-26 in U.S. cases yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively. This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4x10(-4; U.K. PSA: P = 8.0x10(-4; IL12B:rs6887695, U.S. PS, P = 5x10(-5 and U.K. PSA, P = 1.3x10(-3 and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001. Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP and conserved oligomeric golgi complex component 6 (COG6 genes on chromosome 13q13 (combined P = 2x10(-6 for rs7993214; OR = 0.71, the late cornified envelope gene cluster (LCE from the Epidermal Differentiation Complex (PSORS4 (combined P = 6.2x10(-5 for rs6701216; OR 1.45 and a region of LD at 15q21 (combined P = 2.9x10(-5 for rs

  8. A genome wide association study of alcohol dependence symptom counts in extended pedigrees identifies C15orf53

    OpenAIRE

    Wang, Jen-Chyong; Foroud, Tatiana; Hinrichs, Anthony L.; Le, Nhung XH; Bertelsen, Sarah; Budde, John P; Harari, Oscar; Koller, Daniel L.; Wetherill, Leah; Agrawal, Arpana; Almasy, Laura; Brooks, Andrew I; Bucholz, Kathleen; Dick, Danielle; Hesselbrock, Victor

    2012-01-01

    Several studies have identified genes associated with alcohol use disorders, but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome-wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism (COGA) to identify novel genes affecting risk for alcohol dependence. To maximize the power of the extended family design we used a quantitative endophenot...

  9. Genome Wide Association Study and Follow-Up Analysis of Adiposity Traits in Hispanic-Americans: the IRAS Family Study

    OpenAIRE

    Norris, Jill M.; Langefeld, Carl D.; Talbert, Matthew E.; Wing, Maria R; Haritunians, Talin; Fingerlin, Tasha E.; Hanley, Anthony J. G.; Ziegler, Julie T.; Taylor, Kent D.; Haffner, Steven M.; Chen, Yii-Der I.; Donald W Bowden; Wagenknecht, Lynne E.

    2009-01-01

    We investigated candidate genomic regions associated with computed tomography (CT)-derived measures of adiposity in Hispanic from the IRAS Family Study. In 1190 Hispanic individuals from 92 families from the San Luis Valley, CO and San Antonio, TX, we measured CT-derived visceral adipose tissue (VAT); subcutaneous adipose tissue (SAT); and visceral: subcutaneous ratio (VSR). A genome-wide association study (GWAS) was completed using the Illumina HumanHap 300 BeadChip (~317K single nucleotide ...

  10. Multibreed genome wide association can improve precision of mapping causative variants underlying milk production in dairy cattle

    OpenAIRE

    Raven, Lesley-Ann; Cocks, Benjamin G.; Hayes, Ben J

    2014-01-01

    Background Genome wide association studies (GWAS) in most cattle breeds result in large genomic intervals of significant associations making it difficult to identify causal mutations. This is due to the extensive, low-level linkage disequilibrium within a cattle breed. As there is less linkage disequilibrium across breeds, multibreed GWAS may improve precision of causal variant mapping. Here we test this hypothesis in a Holstein and Jersey cattle data set with 17,925 individuals with records ...

  11. Genome-wide identification of mRNAs associated with the translational regulator PUMILIO in Drosophila melanogaster

    OpenAIRE

    Gerber, André P.; Luschnig, Stefan; Krasnow, Mark A; Brown, Patrick O; Herschlag, Daniel

    2006-01-01

    Genome-wide identification of RNAs associated with RNA-binding proteins is crucial for deciphering posttranscriptional regulatory systems. PUMILIO is a member of the evolutionary conserved Puf-family of RNA-binding proteins that repress gene expression posttranscriptionally. We generated transgenic flies expressing affinity-tagged PUMILIO under the control of an ovary-specific promoter, and we purified PUMILIO from whole adult flies and embryos and analyzed associated mRNAs by using DNA micro...

  12. Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study

    OpenAIRE

    Cupples, L. Adrienne; D'Agostino, Ralph B.; Hwang, Shih-Jen; Ingellson, Erik; Liu, Chunyu; Murabito, Joanne M.; Polak, Joseph F.; Wolf, Philip A.; Demissie, Serkalem; O'Donnell, Christopher Joseph; Fox, Caroline; Hoffmann, Udo

    2007-01-01

    Introduction: Subclinical atherosclerosis (SCA) measures in multiple arterial beds are heritable phenotypes that are associated with increased incidence of cardiovascular disease. We conducted a genome-wide association study (GWAS) for SCA measurements in the community-based Framingham Heart Study. Methods: Over 100,000 single nucleotide polymorphisms (SNPs) were genotyped (Human 100K GeneChip, Affymetrix) in 1345 subjects from 310 families. We calculated sex-specific age-adjusted and multiva...

  13. Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study

    OpenAIRE

    Hwang Shih-Jen; Hoffmann Udo; Fox Caroline S; D'Agostino Ralph B; Cupples L Adrienne; O'Donnell Christopher J; Ingellson Erik; Liu Chunyu; Murabito Joanne M; Polak Joseph F; Wolf Philip A; Demissie Serkalem

    2007-01-01

    Abstract Introduction Subclinical atherosclerosis (SCA) measures in multiple arterial beds are heritable phenotypes that are associated with increased incidence of cardiovascular disease. We conducted a genome-wide association study (GWAS) for SCA measurements in the community-based Framingham Heart Study. Methods Over 100,000 single nucleotide polymorphisms (SNPs) were genotyped (Human 100K GeneChip, Affymetrix) in 1345 subjects from 310 families. We calculated sex-specific age-adjusted and ...

  14. Genome-wide association study of classical hodgkin lymphoma and epstein-barr virus status-defined subgroups

    OpenAIRE

    Urayama, Kevin Y.; Jarrett, Ruth F; Hjalgrim, Henrik; Diepstra, Arjan; Kamatani, Yoichiro; Chabrier, Amelie; Gaborieau, Valerie; Boland, Anne; Nieters, Alexandra; Becker, Nikolaus; Foretova, Lenka; Benavente, Yolanda; Maynadié, Marc; Staines, Anthony; Shield, Lesley

    2012-01-01

    Background Accumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein-Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification. Methods We conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status...

  15. Meta-analysis of genome-wide association for migraine in six population-based European cohorts

    OpenAIRE

    Ligthart, Lannie; de Vries, Boukje; Smith, Albert V; Ikram, M. Arfan; Amin, Najaf; Hottenga, Jouke-Jan; Koelewijn, Stephany C; Kattenberg, V. Mathijs; de Moor, Marleen HM; Janssens, A Cecile JW; Aulchenko, Yurii S.; Oostra, Ben A.; de Geus, Eco Jc; Smit, Johannes H; Zitman, Frans G

    2011-01-01

    Abstract Migraine is a common neurologic disorder with a genetically complex background. This paper describes a meta-analysis of genome-wide association (GWA) studies on migraine, performed by the Dutch-Icelandic migraine genetics (DICE) consortium, which brings together six population-based European migraine cohorts with a total sample size of 10,980 individuals (2446 cases and 8534 controls). A total of 32 SNPs showed marginal evidence for association at a p-value < 10-5. The bes...

  16. A Validated Genome Wide Association Study to Breed Cattle Adapted to an Environment Altered by Climate Change

    OpenAIRE

    Hayes, Ben J; Bowman, Phil J; Chamberlain, Amanda J.; Savin, Keith; Van Tassell, Curt P; Sonstegard, Tad S.; Goddard, Mike E.

    2009-01-01

    Continued production of food in areas predicted to be most affected by climate change, such as dairy farming regions of Australia, will be a major challenge in coming decades. Along with rising temperatures and water shortages, scarcity of inputs such as high energy feeds is predicted. With the motivation of selecting cattle adapted to these changing environments, we conducted a genome wide association study to detect DNA markers (single nucleotide polymorphisms) associated with the sensitivi...

  17. Phenotype–Genotype Integrator (PheGenI): synthesizing genome-wide association study (GWAS) data with existing genomic resources

    OpenAIRE

    Ramos, Erin M.; Hoffman, Douglas; Junkins, Heather A.; Maglott, Donna; Phan, Lon; Sherry, Stephen T.; Feolo, Mike; Hindorff, Lucia A

    2013-01-01

    Rapidly accumulating data from genome-wide association studies (GWASs) and other large-scale studies are most useful when synthesized with existing databases. To address this opportunity, we developed the Phenotype–Genotype Integrator (PheGenI), a user-friendly web interface that integrates various National Center for Biotechnology Information (NCBI) genomic databases with association data from the National Human Genome Research Institute GWAS Catalog and supports downloads of search results....

  18. Oncogenomic portals for the visualization and analysis of genome-wide cancer data.

    Science.gov (United States)

    Klonowska, Katarzyna; Czubak, Karol; Wojciechowska, Marzena; Handschuh, Luiza; Zmienko, Agnieszka; Figlerowicz, Marek; Dams-Kozlowska, Hanna; Kozlowski, Piotr

    2016-01-01

    Somatically acquired genomic alterations that drive oncogenic cellular processes are of great scientific and clinical interest. Since the initiation of large-scale cancer genomic projects (e.g., the Cancer Genome Project, The Cancer Genome Atlas, and the International Cancer Genome Consortium cancer genome projects), a number of web-based portals have been created to facilitate access to multidimensional oncogenomic data and assist with the interpretation of the data. The portals provide the visualization of small-size mutations, copy number variations, methylation, and gene/protein expression data that can be correlated with the available clinical, epidemiological, and molecular features. Additionally, the portals enable to analyze the gathered data with the use of various user-friendly statistical tools. Herein, we present a highly illustrated review of seven portals, i.e., Tumorscape, UCSC Cancer Genomics Browser, ICGC Data Portal, COSMIC, cBioPortal, IntOGen, and BioProfiling.de. All of the selected portals are user-friendly and can be exploited by scientists from different cancer-associated fields, including those without bioinformatics background. It is expected that the use of the portals will contribute to a better understanding of cancer molecular etiology and will ultimately accelerate the translation of genomic knowledge into clinical practice. PMID:26484415

  19. Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

    Directory of Open Access Journals (Sweden)

    Brandon L Pierce

    Full Text Available Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10(-8 for percentages of both monomethylarsonic acid (MMA and dimethylarsinic acid (DMA near the AS3MT gene (arsenite methyltransferase; 10q24.32, with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity and 1,794 controls, we show that one of these five variants (rs9527 is also associated with skin lesion risk (P = 0.0005. Using a subset of individuals with prospectively measured arsenic (n = 769, we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01. Expression quantitative trait locus (eQTL analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10(-12 and neighboring gene C10orf32 (P = 10(-44, which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical

  20. Genome-Wide Pattern of TCF7L2/TCF4 Chromatin Occupancy in Colorectal Cancer Cells▿ †

    OpenAIRE

    Hatzis, Pantelis; van der Flier, Laurens G.; van Driel, Marc A.; Guryev, Victor; Nielsen, Fiona; Denissov, Sergei; Nijman, Isaäc J; Koster, Jan; Santo, Evan E.; Welboren, Willem; Versteeg, Rogier; Cuppen, Edwin; van de Wetering, Marc; Clevers, Hans; Stunnenberg, Hendrik G.

    2008-01-01

    Wnt signaling activates gene expression through the induced formation of complexes between DNA-binding T-cell factors (TCFs) and the transcriptional coactivator β-catenin. In colorectal cancer, activating Wnt pathway mutations transform epithelial cells through the inappropriate activation of a TCF7L2/TCF4 target gene program. Through a DNA array-based genome-wide analysis of TCF4 chromatin occupancy, we have identified 6,868 high-confidence TCF4-binding sites in the LS174T colorectal cancer ...

  1. Genome-wide association study for biomarker identification of Rapamycin and Everolimus using a lymphoblastoid cell line system

    Directory of Open Access Journals (Sweden)

    Jing eJiang

    2013-08-01

    Full Text Available The mammalian target of rapamycin (mTOR inhibitors, a set of promising potential anti-cancer agents, has shown response variability among individuals. This study aimed to identify novel biomarkers and mechanisms that might influence the response to Rapamycin and Everolimus. Genome-wide association (GWA analyses involving single nucleotide polymorphisms (SNPs, mRNA and microRNAs microarray data were assessed for association with area under the cytotoxicity dose response curve (AUC of two mTOR inhibitors in 272 human lymphoblastoid cell lines (LCLs. Integrated analysis among SNPs, expression data, microRNA data and AUC values were also performed to help select candidate genes for further functional characterization. Functional validation of candidate genes using siRNA screening in multiple cell lines followed by MTS assays for the two mTOR inhibitors were performed. We found that 16 expression probe sets (genes that overlapped between the two drugs were associated with AUC values of two mTOR inhibitors. 127 and 100 SNPs had P<10-4, while 8 and 10 SNPs had P<10-5 with Rapamycin and Everolimus AUC, respectively. Functional studies indicated that 13 genes significantly altered cell sensitivity to either one or both drugs in at least one cell line. Additionally, one microRNA, miR-10a, was significantly associated with AUC values for both drugs and was shown to repress expression of genes that were associated with AUC and desensitize cells to both drugs. In summary, this study identified genes and a microRNA that might contribute to response to mTOR inhibitors.

  2. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Chuong B Do

    2011-06-01

    Full Text Available Although the causes of Parkinson's disease (PD are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls. We discovered two novel, genome-wide significant associations with PD-rs6812193 near SCARB2 (p = 7.6 × 10(-10, OR = 0.84 and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8, OR = 0.85-both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region, providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%-7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.

  3. A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13

    DEFF Research Database (Denmark)

    Cho, Michael H; Castaldi, Peter J; Wan, Emily S;

    2012-01-01

    The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through......KOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10......(-9)). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre...

  4. Genome-wide association study of response to cognitive-behavioural therapy in children with anxiety disorders

    DEFF Research Database (Denmark)

    Coleman, Jonathan R I; Lester, Kathryn J; Keers, Robert;

    2016-01-01

    BACKGROUND: Anxiety disorders are common, and cognitive-behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent. AIMS: To perform the first genome-wide association study (GWAS......) of psychological treatment response in children with anxiety disorders (n = 980). METHOD: Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using...... the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up. RESULTS: No variants passed a genome-wide significance threshold (P = 5×10(-8)) in either...

  5. Genome-wide diet-gene interaction analyses for risk of colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Jane C Figueiredo

    2014-04-01

    Full Text Available Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3 and processed meat consumption (OR = 1.17; p = 8.7E-09, which was consistently observed across studies (p heterogeneity = 0.78. The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively and null among those with the GG genotype (OR = 1.03. Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.

  6. Genome-wide association analysis identifies loci for left-sided displacement of the abomasum in German Holstein cattle.

    Science.gov (United States)

    Mömke, S; Sickinger, M; Lichtner, P; Doll, K; Rehage, J; Distl, O

    2013-06-01

    Left-sided displacement of the abomasum (LDA) is one of the most common disorders of the digestive system in many dairy breeds and particularly in Holstein dairy cows. We performed a genome-wide association study for 854 German Holstein cows, including 225 cases and 629 controls. All cows were genotyped using the Illumina Bovine SNP50 BeadChip (Illumina Inc., San Diego, CA). After quality control of genotypes, a total of 36,226 informative single nucleotide polymorphisms (SNP) were left for analysis. We used a mixed linear model approach for a genome-wide association study of LDA. In total, 36 SNP located on 17 bovine (Bos taurus) chromosomes (BTA) showed associations with LDA at nominal -log10P-values >3.0. Two of these SNP, located on BTA11 at 46.70 Mb and BTA20 at 16.67 Mb, showed genome-wide significant associations with LDA at -log10P-values >4.6. Pathway analyses indicated genes involved in calcium metabolism and insulin-dependent diabetes mellitus to be factors in the pathogenesis of LDA in German Holstein cows. PMID:23548285

  7. Trinculo: Bayesian and frequentist multinomial logistic regression for genome-wide association studies of multi-category phenotypes.

    OpenAIRE

    Jostins, L; McVean, G

    2016-01-01

    For many classes of disease the same genetic risk variants underly many related phenotypes or disease subtypes. Multinomial logistic regression provides an attractive framework to analyse multi-category phenotypes, and explore the genetic relationships between these phenotype categories. We introduce Trinculo, a program that implements a wide range of multinomial analyses in a single fast package that is designed to be easy to use by users of standard genome-wide association study software.An...

  8. Family-based Genome-wide Association Study of Frontal Theta Oscillations Identifies Potassium Channel Gene KCNJ6

    OpenAIRE

    Kang, Sun J.; Rangaswamy, Madhavi; Manz, Niklas; Wang, Jen-Chyong; Wetherill, Leah; Hinrichs, Tony; Almasy, Laura; Brooks, Andy; Chorlian, David B.; Dick, Danielle; Hesselbrock, Victor; Kramer, John; Kuperman, Sam; Nurnberger, John; Rice, John,

    2012-01-01

    Event-related oscillations (EROs) represent highly heritable neuroelectric correlates of cognitive processes that manifest deficits in alcoholics and in offspring at high risk to develop alcoholism. Theta ERO to targets in the visual oddball task has been shown to be an endophenotype for alcoholism. A family-based genome-wide association study was performed for the frontal theta ERO phenotype using 634583 autosomal single nucleotide polymorphisms (SNPs) genotyped in 1560 family members from 1...

  9. Genome-wide association mapping unravels the genetic control of seed germination and vigor in Brassica napus

    OpenAIRE

    Hatzig, Sarah V.; Frisch, Matthias; Breuer, Frank; Nesi, Nathalie; Ducournau, Sylvie; Wagner, Marie-Helene; Leckband, Gunhild; Abbadi, Amine; Snowdon, Rod J.

    2015-01-01

    Rapid and uniform seed germination is a crucial prerequisite for crop establishment and high yield levels in crop production. A disclosure of genetic factors contributing to adequate seed vigor would help to further increase yield potential and stability. Here we carried out a genome-wide association study in order to define genomic regions influencing seed germination and early seedling growth in oilseed rape (Brassica napus L.). A population of 248 genetically diverse winter-type B. napus a...

  10. Genome-wide association mapping revealed a diverse genetic basis of seed dormancy across subpopulations in rice (Oryza sativa L.)

    OpenAIRE

    Magwa, Risper Auma; Zhao, Hu; Xing, Yongzhong

    2016-01-01

    Background Seed dormancy is an adaptive trait employed by flowering plants to avoid harsh environmental conditions for the continuity of their next generations. In cereal crops, moderate seed dormancy could help prevent pre-harvest sprouting and improve grain yield and quality. We performed a genome wide association study (GWAS) for dormancy, based on seed germination percentage (GP) in freshly harvested seeds (FHS) and after-ripened seeds (ARS) in 350 worldwide accessions that were character...

  11. Local Genealogies in a Linear Mixed Model for Genome-Wide Association Mapping in Complex Pedigreed Populations

    OpenAIRE

    Sahana, Goutam; Mailund, Thomas; Lund, Mogens Sandø; Guldbrandtsen, Bernt

    2011-01-01

    Introduction: The state-of-the-art for dealing with multiple levels of relationship among the samples in genome-wide association studies (GWAS) is unified mixed model analysis (MMA). This approach is very flexible, can be applied to bothfamily-based and population-based samples, and can be extended to incorporate other effects in a straightforward and rigorous fashion. Here, we present a complementary approach, called ‘GENMIX (genealogy based mixed model)’ which combines advantages from two p...

  12. Genome-wide association and biological pathway analysis for milk-fat composition in Danish Holstein and Danish Jersey cattle

    OpenAIRE

    Buitenhuis, Bart; Janss, Luc L G; Poulsen, Nina Aagaard; Larsen, Lotte Bach; Larsen, Mette Krogh; Sørensen, Peter

    2014-01-01

    Background The milk fat profile of the Danish Holstein (DH) and Danish Jersey (DJ) show clear differences. Identification of the genomic regions, genes and biological pathways underlying the milk fat biosynthesis will improve the understanding of the biology underlying bovine milk fat production and may provide new possibilities to change the milk fat composition by selective breeding. In this study a genome wide association scan (GWAS) in the DH and DJ was performed for a detailed milk fatty...

  13. Genome-Wide Association Analysis and Genomic Prediction of Mycobacterium avium Subspecies paratuberculosis Infection in US Jersey Cattle

    OpenAIRE

    Zare, Yalda; Shook, George E.; Collins, Michael T.; Kirkpatrick, Brian W.

    2014-01-01

    Paratuberculosis (Johne’s disease), an enteric disorder in ruminants caused by Mycobacterium avium subspecies paratuberculosis (MAP), causes economic losses in excess of $200 million annually to the US dairy industry. To identify genomic regions underlying susceptibility to MAP infection in Jersey cattle, a case-control genome-wide association study (GWAS) was performed. Blood and fecal samples were collected from ∼5,000 mature cows in 30 commercial Jersey herds from across the US. Discovery ...

  14. Finding type 2 diabetes causal single nucleotide polymorphism combinations and functional modules from genome-wide association data

    OpenAIRE

    Kang, Chiyong; Yu, Hyeji; Yi, Gwan-Su

    2013-01-01

    Background Due to the low statistical power of individual markers from a genome-wide association study (GWAS), detecting causal single nucleotide polymorphisms (SNPs) for complex diseases is a challenge. SNP combinations are suggested to compensate for the low statistical power of individual markers, but SNP combinations from GWAS generate high computational complexity. Methods We aim to detect type 2 diabetes (T2D) causal SNP combinations from a GWAS dataset with optimal filtration and to di...

  15. Identification of Novel Susceptibility Loci for Kawasaki Disease in a Han Chinese Population by a Genome-Wide Association Study

    OpenAIRE

    Tsai, Fuu-Jen; Lee, Yi-Ching; Chang, Jeng-Sheng; Huang, Li-Min; Huang, Fu-Yuan; Chiu, Nan-Chang; Chen, Ming-Ren; CHI, Hsin; Lee, Yann-Jinn; Chang, Li-Ching; Liu, Yi-Min; Wang, Hsiang-Hua; Chen, Chien-Hsiun; Chen, Yuan-Tsong; Wu, Jer-Yuarn

    2011-01-01

    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 Ch...

  16. Genome-wide association implicates numerous genes and pleiotropy underlying ecological trait variation in natural populations of Populus trichocarpa

    Energy Technology Data Exchange (ETDEWEB)

    McKown, Athena [University of British Columbia, Vancouver; Klapste, Jaroslav [University of British Columbia, Vancouver; Guy, Robert [University of British Columbia, Vancouver; Geraldes, Armando [University of British Columbia, Vancouver; Porth, Ilga [University of British Columbia, Vancouver; Hannemann, Jan [University of Victoria, Canada; Friedmann, Michael [University of British Columbia, Vancouver; Muchero, Wellington [ORNL; Tuskan, Gerald A [ORNL; Ehlting, Juergen [University of Victoria, Canada; Cronk, Quentin [University of British Columbia, Vancouver; El-Kassaby, Yousry [University of British Columbia, Vancouver; Mansfield, Shawn [University of British Columbia, Vancouver; Douglas, Carl [University of British Columbia, Vancouver

    2014-01-01

    To uncover the genetic basis of phenotypic trait variation, we used 448 unrelated wild accessions of black cottonwood (Populus trichocarpa Torr. & Gray) from natural populations throughout western North America. Extensive information from large-scale trait phenotyping (with spatial and temporal replications within a common garden) and genotyping (with a 34K Populus SNP array) of all accessions were used for gene discovery in a genome-wide association study (GWAS).

  17. Rapid Testing of Gene-Gene Interactions in Genome-Wide Association Studies of Binary and Quantitative Phenotypes

    OpenAIRE

    Bhattacharya, Kanishka; McCarthy, Mark I; Morris, Andrew P