WorldWideScience

Sample records for genome-wide linkage analysis

  1. 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...

  2. Genome-wide linkage analysis for human longevity

    DEFF Research Database (Denmark)

    Beekman, Marian; Blanché, Hélène; Perola, Markus

    2013-01-01

    sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2...

  3. Meta-analysis of genome-wide linkage studies across autoimmune diseases

    Science.gov (United States)

    Forabosco, Paola; Bouzigon, Emmanuelle; Ng, Mandy Y; Hermanowski, Jane; Fisher, Sheila A; Criswell, Lindsey A; Lewis, Cathryn M

    2009-01-01

    Autoimmune diseases are chronic disorders initiated by a loss of immunologic tolerance to self-antigens. They cluster within families, and patients may be diagnosed with more than one disease, suggesting pleiotropic genes are involved in the aetiology of different diseases. To identify potential loci, which confer susceptibility to autoimmunity independent of disease phenotype, we pooled results from genome-wide linkage studies, using the genome scan meta-analysis method (GSMA). The meta-analysis included 42 independent studies for 11 autoimmune diseases, using 7350 families with 18 291 affected individuals. In addition to the HLA region, which showed highly significant genome-wide evidence for linkage, we obtained suggestive evidence for linkage on chromosome 16, with peak evidence at 10.0–19.8 Mb. This region may harbour a pleiotropic gene (or genes) conferring risk for several diseases, although no such gene has been identified through association studies. We did not identify evidence for linkage at several genes known to confer increased risk to different autoimmune diseases (PTPN22, CTLA4), even in subgroups of diseases consistently found to be associated with these genes. The relative risks conferred by variants in these genes are modest (<1.5 in most cases), and even a large study like this meta-analysis lacks power to detect linkage. This study illustrates the concept that linkage and association studies have power to identify very different types of disease-predisposing variants. PMID:18781189

  4. Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder

    NARCIS (Netherlands)

    Zhou, Kaixin; Dempfle, Astrid; Arcos-Burgos, Mauricio; Bakker, Steven C; Banaschewski, Tobias; Biederman, Joseph; Buitelaar, Jan; Castellanos, F Xavier; Doyle, Alysa; Ebstein, Richard P; Ekholm, Jenny; Forabosco, Paola; Franke, Barbara; Freitag, Christine; Friedel, Susann; Gill, Michael; Hebebrand, Johannes; Hinney, Anke; Jacob, Christian; Lesch, Klaus Peter; Loo, Sandra K; Lopera, Francisco; McCracken, James T; McGough, James J; Meyer, Jobst; Mick, Eric; Miranda, Ana; Muenke, Maximilian; Mulas, Fernando; Nelson, Stanley F; Nguyen, T Trang; Oades, Robert D; Ogdie, Matthew N; Palacio, Juan David; Pineda, David; Reif, Andreas; Renner, Tobias J; Roeyers, Herbert; Romanos, Marcel; Rothenberger, Aribert; Schäfer, Helmut; Sergeant, Joseph; Sinke, Richard J; Smalley, Susan L; Sonuga-Barke, Edmund; Steinhausen, Hans-Christoph; van der Meulen, Emma; Walitza, Susanne; Warnke, Andreas; Lewis, Cathryn M; Faraone, Stephen V; Asherson, Philip

    2008-01-01

    Genetic contribution to the development of attention deficit hyperactivity disorder (ADHD) is well established. Seven independent genome-wide linkage scans have been performed to map loci that increase the risk for ADHD. Although significant linkage signals were identified in some of the studies, th

  5. Genome-wide family-based linkage analysis of exome chip variants and cardiometabolic risk.

    Science.gov (United States)

    Hellwege, Jacklyn N; Palmer, Nicholette D; Raffield, Laura M; Ng, Maggie C Y; Hawkins, Gregory A; Long, Jirong; Lorenzo, Carlos; Norris, Jill M; Ida Chen, Y-D; Speliotes, Elizabeth K; Rotter, Jerome I; Langefeld, Carl D; Wagenknecht, Lynne E; Bowden, Donald W

    2014-05-01

    Linkage analysis of complex traits has had limited success in identifying trait-influencing loci. Recently, coding variants have been implicated as the basis for some biomedical associations. We tested whether coding variants are the basis for linkage peaks of complex traits in 42 African-American (n = 596) and 90 Hispanic (n = 1,414) families in the Insulin Resistance Atherosclerosis Family Study (IRASFS) using Illumina HumanExome Beadchips. A total of 92,157 variants in African Americans (34%) and 81,559 (31%) in Hispanics were polymorphic and tested using two-point linkage and association analyses with 37 cardiometabolic phenotypes. In African Americans 77 LOD scores greater than 3 were observed. The highest LOD score was 4.91 with the APOE SNP rs7412 (MAF = 0.13) with plasma apolipoprotein B (ApoB). This SNP was associated with ApoB (P-value = 4 × 10(-19)) and accounted for 16.2% of the variance in African Americans. In Hispanic families, 104 LOD scores were greater than 3. The strongest evidence of linkage (LOD = 4.29) was with rs5882 (MAF = 0.46) in CETP with HDL. CETP variants were strongly associated with HDL (0.00049 evidence of strong linkage in this genome wide survey of primarily coding variants was uncommon. Loci with strong evidence of linkage was characterized by large contributions to the variance, and, in these cases, are common variants. Less compelling evidence of linkage and association was observed with additional loci that may require larger family sets to confirm. © 2014 WILEY PERIODICALS, INC.

  6. Genome-Wide Linkage Analysis Identifies Loci for Physical Appearance Traits in Chickens.

    Science.gov (United States)

    Sun, Yanfa; Liu, Ranran; Zhao, Guiping; Zheng, Maiqing; Sun, Yan; Yu, Xiaoqiong; Li, Peng; Wen, Jie

    2015-08-06

    Physical appearance traits, such as feather-crested head, comb size and type, beard, wattles size, and feathered feet, are used to distinguish between breeds of chicken and also may be associated with economic traits. In this study, a genome-wide linkage analysis was used to identify candidate regions and genes for physical appearance traits and to potentially provide further knowledge of the molecular mechanisms that underlie these traits. The linkage analysis was conducted with an F2 population derived from Beijing-You chickens and a commercial broiler line. Single-nucleotide polymorphisms were analyzed using the Illumina 60K Chicken SNP Beadchip. The data were used to map quantitative trait loci and genes for six physical appearance traits. A 10-cM/0.51-Mb region (0.0-10.0 cM/0.00-0.51 Mb) with 1% genome-wide significant level on LGE22C19W28_E50C23 linkage group (LGE22) for crest trait was identified, which is likely very closely linked to the HOXC8. A QTL with 5% chromosome-wide significant level for comb weight, which partly overlaps with a region identified in a previous study, was identified at 74 cM/25.55 Mb on chicken (Gallus gallus; GG) chromosome 3 (i.e., GGA3). For beard and wattles traits, an identical region 11 cM/2.23 Mb (0.0-11.0 cM/0.00-2.23 Mb) including WNT3 and GH genes on GGA27 was identified. Two QTL with 1% genome-wide significant level for feathered feet trait, one 9-cM/2.80-Mb (48.0-57.0/13.40-16.20 Mb) region on GGA13, and another 12-cM/1.45-Mb (41.0-53.0 cM/11.37-12.82 Mb) region on GGA15 were identified. These candidate regions and genes provide important genetic information for the physical appearance traits in chicken. Copyright © 2015 Sun et al.

  7. Creative Activities in Music – A Genome-Wide Linkage Analysis

    Science.gov (United States)

    Oikkonen, Jaana; Kuusi, Tuire; Peltonen, Petri; Raijas, Pirre; Ukkola-Vuoti, Liisa; Karma, Kai; Onkamo, Päivi; Järvelä, Irma

    2016-01-01

    Creative activities in music represent a complex cognitive function of the human brain, whose biological basis is largely unknown. In order to elucidate the biological background of creative activities in music we performed genome-wide linkage and linkage disequilibrium (LD) scans in musically experienced individuals characterised for self-reported composing, arranging and non-music related creativity. The participants consisted of 474 individuals from 79 families, and 103 sporadic individuals. We found promising evidence for linkage at 16p12.1-q12.1 for arranging (LOD 2.75, 120 cases), 4q22.1 for composing (LOD 2.15, 103 cases) and Xp11.23 for non-music related creativity (LOD 2.50, 259 cases). Surprisingly, statistically significant evidence for linkage was found for the opposite phenotype of creative activity in music (neither composing nor arranging; NCNA) at 18q21 (LOD 3.09, 149 cases), which contains cadherin genes like CDH7 and CDH19. The locus at 4q22.1 overlaps the previously identified region of musical aptitude, music perception and performance giving further support for this region as a candidate region for broad range of music-related traits. The other regions at 18q21 and 16p12.1-q12.1 are also adjacent to the previously identified loci with musical aptitude. Pathway analysis of the genes suggestively associated with composing suggested an overrepresentation of the cerebellar long-term depression pathway (LTD), which is a cellular model for synaptic plasticity. The LTD also includes cadherins and AMPA receptors, whose component GSG1L was linked to arranging. These results suggest that molecular pathways linked to memory and learning via LTD affect music-related creative behaviour. Musical creativity is a complex phenotype where a common background with musicality and intelligence has been proposed. Here, we implicate genetic regions affecting music-related creative behaviour, which also include genes with neuropsychiatric associations. We also propose

  8. Creative Activities in Music--A Genome-Wide Linkage Analysis.

    Directory of Open Access Journals (Sweden)

    Jaana Oikkonen

    Full Text Available Creative activities in music represent a complex cognitive function of the human brain, whose biological basis is largely unknown. In order to elucidate the biological background of creative activities in music we performed genome-wide linkage and linkage disequilibrium (LD scans in musically experienced individuals characterised for self-reported composing, arranging and non-music related creativity. The participants consisted of 474 individuals from 79 families, and 103 sporadic individuals. We found promising evidence for linkage at 16p12.1-q12.1 for arranging (LOD 2.75, 120 cases, 4q22.1 for composing (LOD 2.15, 103 cases and Xp11.23 for non-music related creativity (LOD 2.50, 259 cases. Surprisingly, statistically significant evidence for linkage was found for the opposite phenotype of creative activity in music (neither composing nor arranging; NCNA at 18q21 (LOD 3.09, 149 cases, which contains cadherin genes like CDH7 and CDH19. The locus at 4q22.1 overlaps the previously identified region of musical aptitude, music perception and performance giving further support for this region as a candidate region for broad range of music-related traits. The other regions at 18q21 and 16p12.1-q12.1 are also adjacent to the previously identified loci with musical aptitude. Pathway analysis of the genes suggestively associated with composing suggested an overrepresentation of the cerebellar long-term depression pathway (LTD, which is a cellular model for synaptic plasticity. The LTD also includes cadherins and AMPA receptors, whose component GSG1L was linked to arranging. These results suggest that molecular pathways linked to memory and learning via LTD affect music-related creative behaviour. Musical creativity is a complex phenotype where a common background with musicality and intelligence has been proposed. Here, we implicate genetic regions affecting music-related creative behaviour, which also include genes with neuropsychiatric associations. We

  9. Creative Activities in Music--A Genome-Wide Linkage Analysis.

    Science.gov (United States)

    Oikkonen, Jaana; Kuusi, Tuire; Peltonen, Petri; Raijas, Pirre; Ukkola-Vuoti, Liisa; Karma, Kai; Onkamo, Päivi; Järvelä, Irma

    2016-01-01

    Creative activities in music represent a complex cognitive function of the human brain, whose biological basis is largely unknown. In order to elucidate the biological background of creative activities in music we performed genome-wide linkage and linkage disequilibrium (LD) scans in musically experienced individuals characterised for self-reported composing, arranging and non-music related creativity. The participants consisted of 474 individuals from 79 families, and 103 sporadic individuals. We found promising evidence for linkage at 16p12.1-q12.1 for arranging (LOD 2.75, 120 cases), 4q22.1 for composing (LOD 2.15, 103 cases) and Xp11.23 for non-music related creativity (LOD 2.50, 259 cases). Surprisingly, statistically significant evidence for linkage was found for the opposite phenotype of creative activity in music (neither composing nor arranging; NCNA) at 18q21 (LOD 3.09, 149 cases), which contains cadherin genes like CDH7 and CDH19. The locus at 4q22.1 overlaps the previously identified region of musical aptitude, music perception and performance giving further support for this region as a candidate region for broad range of music-related traits. The other regions at 18q21 and 16p12.1-q12.1 are also adjacent to the previously identified loci with musical aptitude. Pathway analysis of the genes suggestively associated with composing suggested an overrepresentation of the cerebellar long-term depression pathway (LTD), which is a cellular model for synaptic plasticity. The LTD also includes cadherins and AMPA receptors, whose component GSG1L was linked to arranging. These results suggest that molecular pathways linked to memory and learning via LTD affect music-related creative behaviour. Musical creativity is a complex phenotype where a common background with musicality and intelligence has been proposed. Here, we implicate genetic regions affecting music-related creative behaviour, which also include genes with neuropsychiatric associations. We also propose

  10. Combined genome-wide linkage and targeted association analysis of head circumference in autism spectrum disorder families.

    Science.gov (United States)

    Woodbury-Smith, M; Bilder, D A; Morgan, J; Jerominski, L; Darlington, T; Dyer, T; Paterson, A D; Coon, H

    2017-01-01

    It has long been recognized that there is an association between enlarged head circumference (HC) and autism spectrum disorder (ASD), but the genetics of HC in ASD is not well understood. In order to investigate the genetic underpinning of HC in ASD, we undertook a genome-wide linkage study of HC followed by linkage signal targeted association among a sample of 67 extended pedigrees with ASD. HC measurements on members of 67 multiplex ASD extended pedigrees were used as a quantitative trait in a genome-wide linkage analysis. The Illumina 6K SNP linkage panel was used, and analyses were carried out using the SOLAR implemented variance components model. Loci identified in this way formed the target for subsequent association analysis using the Illumina OmniExpress chip and imputed genotypes. A modification of the qTDT was used as implemented in SOLAR. We identified a linkage signal spanning 6p21.31 to 6p22.2 (maximum LOD = 3.4). Although targeted association did not find evidence of association with any SNP overall, in one family with the strongest evidence of linkage, there was evidence for association (rs17586672, p = 1.72E-07). Although this region does not overlap with ASD linkage signals in these same samples, it has been associated with other psychiatric risk, including ADHD, developmental dyslexia, schizophrenia, specific language impairment, and juvenile bipolar disorder. The genome-wide significant linkage signal represents the first reported observation of a potential quantitative trait locus for HC in ASD and may be relevant in the context of complex multivariate risk likely leading to ASD.

  11. Genome-Wide Linkage Analysis for Loci Affecting Pulse Pressure: The Family Blood Pressure Program

    National Research Council Canada - National Science Library

    Bielinski, Suzette J; Lynch, Amy I; Miller, Michael B; Weder, Alan; Cooper, Richard; Oberman, Albert; Chen, Yii-Der Ida; Turner, Stephen T; Fornage, Myriam; Province, Michael; Arnett, Donna K

    2005-01-01

    ... in sequential oligogenic linkage analysis routines. The analysis sample included 10 798 participants in 3320 families who were recruited as part of the Family Blood Pressure Program and were phenotyped with an oscillometric blood pressure measurement...

  12. Meta-analysis of genome-wide linkage studies in BMI and obesity

    NARCIS (Netherlands)

    Saunders, Catherine L.; Chiodini, Benedetta D.; Sham, Pak; Lewis, Cathryn M.; Abkevich, Victor; Adeyemo, Adebowale A.; de Andrade, Mariza; Arya, Rector; Berenson, Gerald S.; Blangero, John; Boehnke, Michael; Borecki, Ingrid B.; Chagnon, Yvon C.; Chen, Wei; Comuzzie, Anthony G.; Deng, Hong-Wen; Duggirala, Ravindranath; Feitosa, Mary F.; Froguel, Philippe; Hanson, Robert L.; Hebebrand, Johannes; Huezo-Dias, Patricia; Kissebah, Ahmed H.; Li, Weidong; Luke, Amy; Martin, Lisa J.; Nash, Matthew; Ohman, Muena; Palmer, Lyle J.; Peltonen, Leena; Perola, Markus; Price, R. Arlen; Redline, Susan; Srinivasan, Sathanur R.; Stern, Michael P.; Stone, Steven; Stringham, Heather; Turner, Stephen; Wijmenga, Cisca; Collier, David A.

    Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. Research Methods and Procedures: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000

  13. Meta-analysis of genome-wide linkage studies in BMI and obesity

    NARCIS (Netherlands)

    Saunders, Catherine L.; Chiodini, Benedetta D.; Sham, Pak; Lewis, Cathryn M.; Abkevich, Victor; Adeyemo, Adebowale A.; de Andrade, Mariza; Arya, Rector; Berenson, Gerald S.; Blangero, John; Boehnke, Michael; Borecki, Ingrid B.; Chagnon, Yvon C.; Chen, Wei; Comuzzie, Anthony G.; Deng, Hong-Wen; Duggirala, Ravindranath; Feitosa, Mary F.; Froguel, Philippe; Hanson, Robert L.; Hebebrand, Johannes; Huezo-Dias, Patricia; Kissebah, Ahmed H.; Li, Weidong; Luke, Amy; Martin, Lisa J.; Nash, Matthew; Ohman, Muena; Palmer, Lyle J.; Peltonen, Leena; Perola, Markus; Price, R. Arlen; Redline, Susan; Srinivasan, Sathanur R.; Stern, Michael P.; Stone, Steven; Stringham, Heather; Turner, Stephen; Wijmenga, Cisca; Collier, David A.

    2007-01-01

    Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. Research Methods and Procedures: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000

  14. Genome-wide linkage analysis of malaria infection intensity and mild disease.

    Directory of Open Access Journals (Sweden)

    Christian Timmann

    2007-03-01

    Full Text Available Although balancing selection with the sickle-cell trait and other red blood cell disorders has emphasized the interaction between malaria and human genetics, no systematic approach has so far been undertaken towards a comprehensive search for human genome variants influencing malaria. By screening 2,551 families in rural Ghana, West Africa, 108 nuclear families were identified who were exposed to hyperendemic malaria transmission and were homozygous wild-type for the established malaria resistance factors of hemoglobin (HbS, HbC, alpha(+ thalassemia, and glucose-6-phosphate-dehydrogenase deficiency. Of these families, 392 siblings aged 0.5-11 y were characterized for malaria susceptibility by closely monitoring parasite counts, malaria fever episodes, and anemia over 8 mo. An autosome-wide linkage analysis based on 10,000 single-nucleotide polymorphisms was conducted in 68 selected families including 241 siblings forming 330 sib pairs. Several regions were identified which showed evidence for linkage to the parasitological and clinical phenotypes studied, among them a prominent signal on Chromosome 10p15 obtained with malaria fever episodes (asymptotic z score = 4.37, empirical p-value = 4.0 x 10(-5, locus-specific heritability of 37.7%; 95% confidence interval, 15.7%-59.7%. The identification of genetic variants underlying the linkage signals may reveal as yet unrecognized pathways influencing human resistance to malaria.

  15. Nonlinear Analysis of Time Series in Genome-Wide Linkage Disequilibrium Data

    Science.gov (United States)

    Hernández-Lemus, Enrique; Estrada-Gil, Jesús K.; Silva-Zolezzi, Irma; Fernández-López, J. Carlos; Hidalgo-Miranda, Alfredo; Jiménez-Sánchez, Gerardo

    2008-02-01

    The statistical study of large scale genomic data has turned out to be a very important tool in population genetics. Quantitative methods are essential to understand and implement association studies in the biomedical and health sciences. Nevertheless, the characterization of recently admixed populations has been an elusive problem due to the presence of a number of complex phenomena. For example, linkage disequilibrium structures are thought to be more complex than their non-recently admixed population counterparts, presenting the so-called ancestry blocks, admixed regions that are not yet smoothed by the effect of genetic recombination. In order to distinguish characteristic features for various populations we have implemented several methods, some of them borrowed or adapted from the analysis of nonlinear time series in statistical physics and quantitative physiology. We calculate the main fractal dimensions (Kolmogorov's capacity, information dimension and correlation dimension, usually named, D0, D1 and D2). We also have made detrended fluctuation analysis and information based similarity index calculations for the probability distribution of correlations of linkage disequilibrium coefficient of six recently admixed (mestizo) populations within the Mexican Genome Diversity Project [1] and for the non-recently admixed populations in the International HapMap Project [2]. Nonlinear correlations showed up as a consequence of internal structure within the haplotype distributions. The analysis of these correlations as well as the scope and limitations of these procedures within the biomedical sciences are discussed.

  16. Genome-wide linkage analysis of inguinal hernia in pigs using affected sib pairs

    Directory of Open Access Journals (Sweden)

    Taubert Helge

    2006-05-01

    Full Text Available Abstract Background Inguinal and scrotal hernias are of great concern to pig producers, and lead to poor animal welfare and severe economic loss. Selection against these conditions is highly preferable, but at this time no gene, Quantitative Trait Loci (QTL, or mode of inheritance has been identified in pigs or in any other species. Therefore, a complete genome scan was performed in order to identify genomic regions affecting inguinal and scrotal hernias in pigs. Records from seedstock breeding farms were collected. No clinical examinations were executed on the pigs and there was therefore no distinction between inguinal and scrotal hernias. The genome scan utilised affected sib pairs (ASP, and the data was analysed using both an ASP test based on Non-parametric Linkage (NPL analysis, and a Transmission Disequilibrium Test (TDT. Results Significant QTLs (p Conclusion For the first time in any species, a genome scan has revealed suggestive QTLs for inguinal and scrotal hernias. While this study permitted the detection of chromosomal regions only, it is interesting to note that several promising candidate genes, including INSL3, MIS, and CGRP, are located within the highly significant QTL regions. Further studies are required in order to narrow down the suggestive QTL regions, investigate the candidate genes, and to confirm the suggestive QTLs in other populations. The haplotype associated with inguinal and scrotal hernias may help in achieving selection against the disorder.

  17. Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes.

    Science.gov (United States)

    Silverman, Edwin K; Mosley, Jonathan D; Palmer, Lyle J; Barth, Matthew; Senter, Jody M; Brown, Alison; Drazen, Jeffrey M; Kwiatkowski, David J; Chapman, Harold A; Campbell, Edward J; Province, Michael A; Rao, D C; Reilly, John J; Ginns, Leo C; Speizer, Frank E; Weiss, Scott T

    2002-03-15

    Familial aggregation of chronic obstructive pulmonary disease (COPD) has been demonstrated, but linkage analysis of COPD-related phenotypes has not been reported previously. An autosomal 10 cM genome-wide scan of short tandem repeat (STR) polymorphic markers was analyzed for linkage to COPD-related phenotypes in 585 members of 72 pedigrees ascertained through severe, early-onset COPD probands without severe alpha1-antitrypsin deficiency. Multipoint non-parametric linkage analysis (using the ALLEGRO program) was performed for qualitative phenotypes including moderate airflow obstruction [forced expiratory volume at one second (FEV(1)) < 60% predicted, FEV(1)/FVC < 90% predicted], mild airflow obstruction (FEV(1) < 80% predicted, FEV(1)/FVC < 90% predicted) and chronic bronchitis. The strongest evidence for linkage in all subjects was observed at chromosomes 12 (LOD = 1.70) and 19 (LOD = 1.54) for moderate airflow obstruction, chromosomes 8 (LOD = 1.36) and 19 (LOD = 1.09) for mild airflow obstruction and chromosomes 19 (LOD = 1.21) and 22 (LOD = 1.37) for chronic bronchitis. Restricting analysis to cigarette smokers only provided increased evidence for linkage of mild airflow obstruction and chronic bronchitis to several genomic regions; for mild airflow obstruction in smokers only, the maximum LOD was 1.64 at chromosome 19, whereas for chronic bronchitis in smokers only, the maximum LOD was 2.08 at chromosome 22. On chromosome 12p, 12 additional STR markers were genotyped, which provided additional support for an airflow obstruction locus in that region with a non-parametric multipoint approach for moderate airflow obstruction (LOD = 2.13) and mild airflow obstruction (LOD = 1.43). Using a dominant model with the STR markers on 12p, two point parametric linkage analysis of all subjects demonstrated a maximum LOD score of 2.09 for moderate airflow obstruction and 2.61 for mild airflow obstruction. In smokers only, the maximum two point LOD score for mild airflow

  18. Parent-Of-Origin Effects in Autism Identified through Genome-Wide Linkage Analysis of 16,000 SNPs

    OpenAIRE

    Delphine Fradin; Keely Cheslack-Postava; Christine Ladd-Acosta; Craig Newschaffer; Aravinda Chakravarti; Arking, Dan E.; Andrew Feinberg; M Daniele Fallin

    2010-01-01

    BACKGROUND: Autism is a common heritable neurodevelopmental disorder with complex etiology. Several genome-wide linkage and association scans have been carried out to identify regions harboring genes related to autism or autism spectrum disorders, with mixed results. Given the overlap in autism features with genetic abnormalities known to be associated with imprinting, one possible reason for lack of consistency would be the influence of parent-of-origin effects that may mask the ability to d...

  19. Parent-of-origin effects in autism identified through genome-wide linkage analysis of 16,000 SNPs.

    Directory of Open Access Journals (Sweden)

    Delphine Fradin

    Full Text Available BACKGROUND: Autism is a common heritable neurodevelopmental disorder with complex etiology. Several genome-wide linkage and association scans have been carried out to identify regions harboring genes related to autism or autism spectrum disorders, with mixed results. Given the overlap in autism features with genetic abnormalities known to be associated with imprinting, one possible reason for lack of consistency would be the influence of parent-of-origin effects that may mask the ability to detect linkage and association. METHODS AND FINDINGS: We have performed a genome-wide linkage scan that accounts for potential parent-of-origin effects using 16,311 SNPs among families from the Autism Genetic Resource Exchange (AGRE and the National Institute of Mental Health (NIMH autism repository. We report parametric (GH, Genehunter and allele-sharing linkage (Aspex results using a broad spectrum disorder case definition. Paternal-origin genome-wide statistically significant linkage was observed on chromosomes 4 (LOD(GH = 3.79, empirical p<0.005 and LOD(Aspex = 2.96, p = 0.008, 15 (LOD(GH = 3.09, empirical p<0.005 and LOD(Aspex = 3.62, empirical p = 0.003 and 20 (LOD(GH = 3.36, empirical p<0.005 and LOD(Aspex = 3.38, empirical p = 0.006. CONCLUSIONS: These regions may harbor imprinted sites associated with the development of autism and offer fruitful domains for molecular investigation into the role of epigenetic mechanisms in autism.

  20. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

    DEFF Research Database (Denmark)

    Leu, Costin; de Kovel, Carolien G F; Zara, Federico

    2012-01-01

    Purpose: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1...... ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared...... Findings: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all...

  1. Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham study

    OpenAIRE

    2007-01-01

    Abstract Background Brain magnetic resonance imaging (MRI) and cognitive tests can identify heritable endophenotypes associated with an increased risk of developing stroke, dementia and Alzheimer's disease (AD). We conducted a genome-wide association (GWA) and linkage analysis exploring the genetic basis of these endophenotypes in a community-based sample. Methods A total of 705 stroke- and dementia-free Framingham participants (age 62 +9 yrs, 50% male) who underwent volumetric brain MRI and ...

  2. Five blood pressure loci identified by an updated genome-wide linkage scan: meta-analysis of the Family Blood Pressure Program.

    Science.gov (United States)

    Simino, Jeannette; Shi, Gang; Kume, Rezart; Schwander, Karen; Province, Michael A; Gu, C Charles; Kardia, Sharon; Chakravarti, Aravinda; Ehret, Georg; Olshen, Richard A; Turner, Stephen T; Ho, Low-Tone; Zhu, Xiaofeng; Jaquish, Cashell; Paltoo, Dina; Cooper, Richard S; Weder, Alan; Curb, J David; Boerwinkle, Eric; Hunt, Steven C; Rao, Dabeeru C

    2011-03-01

    A preliminary genome-wide linkage analysis of blood pressure in the Family Blood Pressure Program (FBPP) was reported previously. We harnessed the power and ethnic diversity of the final pooled FBPP dataset to identify novel loci for blood pressure thereby enhancing localization of genes containing less common variants with large effects on blood pressure levels and hypertension. We performed one overall and 4 race-specific meta-analyses of genome-wide blood pressure linkage scans using data on 4,226 African-American, 2,154 Asian, 4,229 Caucasian, and 2,435 Mexican-American participants (total N = 13,044). Variance components models were fit to measured (raw) blood pressure levels and two types of antihypertensive medication adjusted blood pressure phenotypes within each of 10 subgroups defined by race and network. A modified Fisher's method was used to combine the P values for each linkage marker across the 10 subgroups. Five quantitative trait loci (QTLs) were detected on chromosomes 6p22.3, 8q23.1, 20q13.12, 21q21.1, and 21q21.3 based on significant linkage evidence (defined by logarithm of odds (lod) score ≥3) in at least one meta-analysis and lod scores ≥1 in at least 2 subgroups defined by network and race. The chromosome 8q23.1 locus was supported by Asian-, Caucasian-, and Mexican-American-specific meta-analyses. The new QTLs reported justify new candidate gene studies. They may help support results from genome-wide association studies (GWAS) that fall in these QTL regions but fail to achieve the genome-wide significance.

  3. Identification of a glutamic acid repeat polymorphism of ALMS1 as a novel genetic risk marker for early-onset myocardial infarction by genome-wide linkage analysis.

    Science.gov (United States)

    Ichihara, Sahoko; Yamamoto, Ken; Asano, Hiroyuki; Nakatochi, Masahiro; Sukegawa, Mayo; Ichihara, Gaku; Izawa, Hideo; Hirashiki, Akihiro; Takatsu, Fumimaro; Umeda, Hisashi; Iwase, Mitsunori; Inagaki, Haruo; Hirayama, Haruo; Sone, Takahito; Nishigaki, Kazuhiko; Minatoguchi, Shinya; Cho, Myeong-Chan; Jang, Yangsoo; Kim, Hyo-Soo; Park, Jeong E; Tada-Oikawa, Saeko; Kitajima, Hidetoshi; Matsubara, Tatsuaki; Sunagawa, Kenji; Shimokawa, Hiroaki; Kimura, Akinori; Lee, Jong-Young; Murohara, Toyoaki; Inoue, Ituro; Yokota, Mitsuhiro

    2013-12-01

    Myocardial infarction (MI) is a leading cause of death worldwide. Given that a family history is an independent risk factor for coronary artery disease, genetic variants are thought to contribute directly to the development of this condition. The identification of susceptibility genes for coronary artery disease or MI may thus help to identify high-risk individuals and offer the opportunity for disease prevention. We designed a 5-step protocol, consisting of a genome-wide linkage study followed by association analysis, to identify novel genetic variants that confer susceptibility to coronary artery disease or MI. A genome-wide affected sib-pair linkage study with 221 Japanese families with coronary artery disease yielded a statistically significant logarithm of the odds score of 3.44 for chromosome 2p13 and MI. Further association analysis implicated Alström syndrome 1 gene (ALMS1) as a candidate gene within the linkage region. Validation association analysis revealed that representative single-nucleotide polymorphisms of the ALMS1 promoter region were significantly associated with early-onset MI in both Japanese and Korean populations. Moreover, direct sequencing of the ALMS1 coding region identified a glutamic acid repeat polymorphism in exon 1, which was subsequently found to be associated with early-onset MI. The glutamic acid repeat polymorphism of ALMS1 identified in the present study may provide insight into the pathogenesis of early-onset MI.

  4. A Genome-Wide SNP Linkage Analysis Suggests a Susceptibility Locus on 6p21 for Ankylosing Spondylitis and Inflammatory Back Pain Trait

    Science.gov (United States)

    Zhang, Yanli; Liao, Zetao; Wei, Qiujing; Pan, Yunfeng; Wang, Xinwei; Cao, Shuangyan; Guo, Zishi; Wu, Yuqiong; Rong, Ju; Jin, Ou; Xu, Manlong; Gu, Jieruo

    2016-01-01

    Objectives To screen susceptibility loci for ankylosing spondylitis (AS) using an affected-only linkage analysis based on high-density single nucleotide polymorphisms (SNPs) in a genome-wide manner. Patients and Methods AS patients from ten families with Cantonese origin of China were enrolled in the study. Blood samples were genotyped using genomic DNA derived from peripheral blood leukocytes by Illumina HumanHap 610-Quad SNP Chip. Genotype data were generated using the Illumina BeadStudio 3.2 software. PLINK package was used to remove non-autosomal SNPs and to further eliminate markers of typing errors. An affected-only linkage analysis was carried out using both non-parametric and parametric linkage analyses, as implemented in MERLIN. Result Seventy-eight AS patients (48 males and 30 females, mean age: 39±16 years) were enrolled in the study. The mean age of onset was 23±10 years and mean duration of disease was 16.7±12.2 years. Iritis (2/76, 2.86%), dactylitis (5/78, 6.41%), hip joint involvement (9/78, 11.54%), peripheral arthritis (22/78, 28.21%), inflammatory back pain (IBP) (69/78, 88.46%) and HLA-B27 positivity (70/78, 89.74%) were observed in these patients. Using non-parameter linkage analysis, we found one susceptibility locus for AS, IBP and HLA-B27 in 6p21 respectively, spanning about 13.5Mb, 20.9Mb and 21.2Mb, respectively No significant results were found in the other clinical trait groups including dactylitis, hip involved and arthritis. The identical susceptibility locus region spanning above 9.44Mb was detected in AS IBP and HLA-B27 by the parametric linkage analysis. Conclusion Our genome-wide SNP linkage analysis in ten families with ankylosing spondylitis suggests a susceptibility locus on 6p21 in AS, which is a risk locus for IBP in AS patients. PMID:27973620

  5. Genome-wide Linkage Disequilibrium Linkage Analysis (LDLA) of Body Fat Traits in an F2 Porcine Model for Human Obesity

    DEFF Research Database (Denmark)

    Pant, Sameer Dinkar; Karlskov-Mortensen, Peter; Cirera Salicio, Susanna;

    , body composition was determined at about two months of age (64 ± 11 days) via dual-energy xray absorptiometry (DXA) scanning. All pigs were genotyped using Illumina Porcine 60k SNP Beadchip and a combined LDLA approach was used to perform genomewide linkage and association analysis for body fat traits...

  6. Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype.

    Science.gov (United States)

    Khan, A O; Budde, B S; Nürnberg, P; Kawalia, A; Lenzner, S; Bolz, H J

    2017-03-30

    To uncover the genotype underlying early-onset cone-rod dystrophy and central nummular macular atrophic lesion in 2 siblings from an endogamous Arab family, we performed targeted next-generation sequencing (NGS) of 44 retinal dystrophy genes, whole-exome sequencing (WES) and genome-wide linkage analysis. Targeted NGS and WES in the index patient highlighted 2 homozygous variants, a CCDC66 frameshift deletion and a novel missense NMNAT1 variant, c.500G>A (p.Asn167Ser). Linkage and segregation analysis excluded the CCDC66 variant and confirmed the NMNAT1 mutation. Biallelic NMNAT1 mutations cause Leber congenital amaurosis with a central nummular macular atrophic lesion (LCA9). The NMNAT1 mutation reported here underlied cone-rod dystrophy rather than LCA but the fundus lesion was compatible with that of LCA9 patients, highlighting that such a fundus appearance should raise suspicion for biallelic mutations in NMNAT1 when in the context of any retinal dystrophy. Although Ccdc66 mutations have been proposed to cause retinal disease in dogs, our results and public databases challenge CCDC66 as a candidate gene for human retinal dystrophy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Genome-wide linkage and copy number variation analysis reveals 710 kb duplication on chromosome 1p31.3 responsible for autosomal dominant omphalocele

    Science.gov (United States)

    Radhakrishna, Uppala; Nath, Swapan K; McElreavey, Ken; Ratnamala, Uppala; Sun, Celi; Maiti, Amit K; Gagnebin, Maryline; Béna, Frédérique; Newkirk, Heather L; Sharp, Andrew J; Everman, David B; Murray, Jeffrey C; Schwartz, Charles E; Antonarakis, Stylianos E; Butler, Merlin G

    2017-01-01

    Background Omphalocele is a congenital birth defect characterised by the presence of internal organs located outside of the ventral abdominal wall. The purpose of this study was to identify the underlying genetic mechanisms of a large autosomal dominant Caucasian family with omphalocele. Methods and findings A genetic linkage study was conducted in a large family with an autosomal dominant transmission of an omphalocele using a genome-wide single nucleotide polymorphism (SNP) array. The analysis revealed significant evidence of linkage (non-parametric NPL = 6.93, p=0.0001; parametric logarithm of odds (LOD) = 2.70 under a fully penetrant dominant model) at chromosome band 1p31.3. Haplotype analysis narrowed the locus to a 2.74 Mb region between markers rs2886770 (63014807 bp) and rs1343981 (65757349 bp). Molecular characterisation of this interval using array comparative genomic hybridisation followed by quantitative microsphere hybridisation analysis revealed a 710 kb duplication located at 63.5–64.2 Mb. All affected individuals who had an omphalocele and shared the haplotype were positive for this duplicated region, while the duplication was absent from all normal individuals of this family. Multipoint linkage analysis using the duplication as a marker yielded a maximum LOD score of 3.2 at 1p31.3 under a dominant model. The 710 kb duplication at 1p31.3 band contains seven known genes including FOXD3, ALG6, ITGB3BP, KIAA1799, DLEU2L, PGM1, and the proximal portion of ROR1. Importantly, this duplication is absent from the database of genomic variants. Conclusions The present study suggests that development of an omphalocele in this family is controlled by overexpression of one or more genes in the duplicated region. To the authors’ knowledge, this is the first reported association of an inherited omphalocele condition with a chromosomal rearrangement. PMID:22499347

  8. Genome-wide linkage analysis of longitudinal phenotypes using sigma(2)(A) random effects (SSARs) fitted by Gibbs sampling

    NARCIS (Netherlands)

    Palmer, LJ; Scurrah, KJ; Tobin, M; Patel, [No Value; Celedon, JC; Burton, PR; Weiss, ST

    2003-01-01

    The study of change in intermediate phenotypes over time is important in genetics. In this paper we explore a new approach to phenotype definition in the genetic analysis of longitudinal phenotypes. We utilized data from the longitudinal Framingham Heart Study Family Cohort to investigate the famili

  9. Genome-wide linkage analysis of QTL for growth and body composition employing the PorcineSNP60 BeadChip

    Directory of Open Access Journals (Sweden)

    Fernández Ana I

    2012-05-01

    Full Text Available Abstract Background The traditional strategy to map QTL is to use linkage analysis employing a limited number of markers. These analyses report wide QTL confidence intervals, making very difficult to identify the gene and polymorphisms underlying the QTL effects. The arrival of genome-wide panels of SNPs makes available thousands of markers increasing the information content and therefore the likelihood of detecting and fine mapping QTL regions. The aims of the current study are to confirm previous QTL regions for growth and body composition traits in different generations of an Iberian x Landrace intercross (IBMAP and especially identify new ones with narrow confidence intervals by employing the PorcineSNP60 BeadChip in linkage analyses. Results Three generations (F3, Backcross 1 and Backcross 2 of the IBMAP and their related animals were genotyped with PorcineSNP60 BeadChip. A total of 8,417 SNPs equidistantly distributed across autosomes were selected after filtering by quality, position and frequency to perform the QTL scan. The joint and separate analyses of the different IBMAP generations allowed confirming QTL regions previously identified in chromosomes 4 and 6 as well as new ones mainly for backfat thickness in chromosomes 4, 5, 11, 14 and 17 and shoulder weight in chromosomes 1, 2, 9 and 13; and many other to the chromosome-wide signification level. In addition, most of the detected QTLs displayed narrow confidence intervals, making easier the selection of positional candidate genes. Conclusions The use of higher density of markers has allowed to confirm results obtained in previous QTL scans carried out with microsatellites. Moreover several new QTL regions have been now identified in regions probably not covered by markers in previous scans, most of these QTLs displayed narrow confidence intervals. Finally, prominent putative biological and positional candidate genes underlying those QTL effects are listed based on recent porcine

  10. Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham study

    Science.gov (United States)

    Seshadri, Sudha; DeStefano, Anita L; Au, Rhoda; Massaro, Joseph M; Beiser, Alexa S; Kelly-Hayes, Margaret; Kase, Carlos S; D'Agostino, Ralph B; DeCarli, Charles; Atwood, Larry D; Wolf, Philip A

    2007-01-01

    Background Brain magnetic resonance imaging (MRI) and cognitive tests can identify heritable endophenotypes associated with an increased risk of developing stroke, dementia and Alzheimer's disease (AD). We conducted a genome-wide association (GWA) and linkage analysis exploring the genetic basis of these endophenotypes in a community-based sample. Methods A total of 705 stroke- and dementia-free Framingham participants (age 62 +9 yrs, 50% male) who underwent volumetric brain MRI and cognitive testing (1999–2002) were genotyped. We used linear models adjusting for first degree relationships via generalized estimating equations (GEE) and family based association tests (FBAT) in additive models to relate qualifying single nucleotide polymorphisms (SNPs, 70,987 autosomal on Affymetrix 100K Human Gene Chip with minor allele frequency ≥ 0.10, genotypic call rate ≥ 0.80, and Hardy-Weinberg equilibrium p-value ≥ 0.001) to multivariable-adjusted residuals of 9 MRI measures including total cerebral brain (TCBV), lobar, ventricular and white matter hyperintensity (WMH) volumes, and 6 cognitive factors/tests assessing verbal and visuospatial memory, visual scanning and motor speed, reading, abstract reasoning and naming. We determined multipoint identity-by-descent utilizing 10,592 informative SNPs and 613 short tandem repeats and used variance component analyses to compute LOD scores. Results The strongest gene-phenotype association in FBAT analyses was between SORL1 (rs1131497; p = 3.2 × 10-6) and abstract reasoning, and in GEE analyses between CDH4 (rs1970546; p = 3.7 × 10-8) and TCBV. SORL1 plays a role in amyloid precursor protein processing and has been associated with the risk of AD. Among the 50 strongest associations (25 each by GEE and FBAT) were other biologically interesting genes. Polymorphisms within 28 of 163 candidate genes for stroke, AD and memory impairment were associated with the endophenotypes studied at p < 0.001. We confirmed our previously

  11. A genome-wide screen and linkage mapping for a large pedigree with episodic ataxia.

    Science.gov (United States)

    Cader, M Z; Steckley, J L; Dyment, D A; McLachlan, R S; Ebers, G C

    2005-07-12

    Episodic ataxias are ion channel disorders characterized by attacks of incoordination. The authors performed a genome-wide screen in a large pedigree segregating a novel episodic ataxia and found significant linkage on 1q42 with a multipoint lod score of 3.65. Haplotype analysis and fine mapping yielded a peak 2-point lod score of 4.14 and indicated a 4-cM region on 1q42 that is likely to harbor an episodic ataxia gene.

  12. Genome-wide distribution of genetic diversity and linkage disequilibrium in elite sugar beet germplasm

    Directory of Open Access Journals (Sweden)

    Weißleder Knuth

    2011-10-01

    Full Text Available Abstract Background Characterization of population structure and genetic diversity of germplasm is essential for the efficient organization and utilization of breeding material. The objectives of this study were to (i explore the patterns of population structure in the pollen parent heterotic pool using different methods, (ii investigate the genome-wide distribution of genetic diversity, and (iii assess the extent and genome-wide distribution of linkage disequilibrium (LD in elite sugar beet germplasm. Results A total of 264 and 238 inbred lines from the yield type and sugar type inbreds of the pollen parent heterotic gene pools, respectively, which had been genotyped with 328 SNP markers, were used in this study. Two distinct subgroups were detected based on different statistical methods within the elite sugar beet germplasm set, which was in accordance with its breeding history. MCLUST based on principal components, principal coordinates, or lapvectors had high correspondence with the germplasm type information as well as the assignment by STRUCTURE, which indicated that these methods might be alternatives to STRUCTURE for population structure analysis. Gene diversity and modified Roger's distance between the examined germplasm types varied considerably across the genome, which might be due to artificial selection. This observation indicates that population genetic approaches could be used to identify candidate genes for the traits under selection. Due to the fact that r2 >0.8 is required to detect marker-phenotype association explaining less than 1% of the phenotypic variance, our observation of a low proportion of SNP loci pairs showing such levels of LD suggests that the number of markers has to be dramatically increased for powerful genome-wide association mapping. Conclusions We provided a genome-wide distribution map of genetic diversity and linkage disequilibrium for the elite sugar beet germplasm, which is useful for the application of

  13. A genome-wide linkage analysis for the personality trait neuroticism in the Irish affected sib-pair study of alcohol dependence.

    Science.gov (United States)

    Kuo, Po-Hsiu; Neale, Michael C; Riley, Brien P; Patterson, Diana G; Walsh, Dermot; Prescott, Carol A; Kendler, Kenneth S

    2007-06-05

    Neuroticism is a personality trait which reflects individual differences in emotional stability and vulnerability to stress and anxiety. Consistent evidence shows substantial genetic influences on variation in this trait. The present study seeks to identify regions containing susceptibility loci for neuroticism using a selected sib-pair sample from Ireland. Using Merlin regress, we conducted a 4 cM whole-genome linkage analysis on 714 sib-pairs. Evidence for linkage to neuroticism was found on chromosomes 11p, 12q, and 15q. The highest linkage peak was on 12q at marker D12S1638 with a Lod score of 2.13 (-log p = 2.76, empirical P-value neuroticism, with male specific linkage regions on chromosomes 1, 4, 11, 12, 15, 16, and 22, and female specific linkage regions on chromosomes 2, 4, 9, 12, 13, and 18. Some genome regions reported in the present study replicate findings from previous linkage studies of neuroticism. These results, together with prior studies, indicate several potential regions for quantitative trait loci for neuroticism that warrant further study.

  14. Genome-wide Analysis of Gene Regulation

    DEFF Research Database (Denmark)

    Chen, Yun

    cells are capable of regulating their gene expression, so that each cell can only express a particular set of genes yielding limited numbers of proteins with specialized functions. Therefore a rigid control of differential gene expression is necessary for cellular diversity. On the other hand, aberrant...... gene regulation will disrupt the cell’s fundamental processes, which in turn can cause disease. Hence, understanding gene regulation is essential for deciphering the code of life. Along with the development of high throughput sequencing (HTS) technology and the subsequent large-scale data analysis......, genome-wide assays have increased our understanding of gene regulation significantly. This thesis describes the integration and analysis of HTS data across different important aspects of gene regulation. Gene expression can be regulated at different stages when the genetic information is passed from gene...

  15. Genome-Wide Linkage Analysis of Hemodynamic Parameters Under Mental and Physical Stress in Extended Omani Arab Pedigrees : The Oman Family Study

    NARCIS (Netherlands)

    Hassan, Mohammed O.; Jaju, Deepali; Voruganti, V. Saroja; Bayoumi, Riad A.; Albarwani, Sulayma; Al-Yahyaee, Saeed; Aslani, Afshin; Snieder, Harold; Lopez-Alvarenga, Juan C.; Al-Anqoudi, Zahir M.; Alizadeh, Behrooz Z.; Comuzzie, Anthony G.

    2011-01-01

    Background: We performed a genome-wide scan in a homogeneous Arab population to identify genomic regions linked to blood pressure (BP) and its intermediate phenotypes during mental and physical stress tests. Methods: The Oman Family Study subjects (N = 1277) were recruited from five extended familie

  16. Genome-wide linkage analysis of hemodynamic parameters under mental and physical stress in extended Omani Arab pedigrees : the Oman Family Study

    NARCIS (Netherlands)

    Hassan, Mohammed O; Jaju, Deepali; Voruganti, V Saroja; Bayoumi, Riad A; Albarwani, Sulayma; Al-Yahyaee, Saeed; Aslani, Afshin; Snieder, Harold; Lopez-Alvarenga, Juan C; Al-Anqoudi, Zahir M; Alizadeh, Behrooz Z; Comuzzie, Anthony G

    2011-01-01

    BACKGROUND: We performed a genome-wide scan in a homogeneous Arab population to identify genomic regions linked to blood pressure (BP) and its intermediate phenotypes during mental and physical stress tests. METHODS: The Oman Family Study subjects (N = 1277) were recruited from five extended familie

  17. Genome-wide association and linkage analyses localize a progressive retinal atrophy locus in Persian cats.

    Science.gov (United States)

    Alhaddad, Hasan; Gandolfi, Barbara; Grahn, Robert A; Rah, Hyung-Chul; Peterson, Carlyn B; Maggs, David J; Good, Kathryn L; Pedersen, Niels C; Lyons, Leslie A

    2014-08-01

    Hereditary eye diseases of animals serve as excellent models of human ocular disorders and assist in the development of gene and drug therapies for inherited forms of blindness. Several primary hereditary eye conditions affecting various ocular tissues and having different rates of progression have been documented in domestic cats. Gene therapy for canine retinopathies has been successful, thus the cat could be a gene therapy candidate for other forms of retinal degenerations. The current study investigates a hereditary, autosomal recessive, retinal degeneration specific to Persian cats. A multi-generational pedigree segregating for this progressive retinal atrophy was genotyped using a 63 K SNP array and analyzed via genome-wide linkage and association methods. A multi-point parametric linkage analysis localized the blindness phenotype to a ~1.75 Mb region with significant LOD scores (Z ≈ 14, θ = 0.00) on cat chromosome E1. Genome-wide TDT, sib-TDT, and case-control analyses also consistently supported significant association within the same region on chromosome E1, which is homologous to human chromosome 17. Using haplotype analysis, a ~1.3 Mb region was identified as highly associated for progressive retinal atrophy in Persian cats. Several candidate genes within the region are reasonable candidates as a potential causative gene and should be considered for molecular analyses.

  18. Unidimensional nonnegative scaling for genome-wide linkage disequilibrium maps.

    Science.gov (United States)

    Liao, Haiyong; Ng, Michael; Fung, Eric; Sham, Pak C

    2008-01-01

    The main aim of this paper is to propose and develop a unidimensional nonnegative scaling model to construct Linkage Disequilibrium (LD) maps. The proposed constrained scaling model can be efficiently solved by transforming it to an unconstrained model. The method is implemented in PC Clusters at Hong Kong Baptist University. The LD maps are constructed for four populations from Hapmap data sets with chromosomes of several ten thousand Single Nucleotide Polymorphisms (SNPs). The similarities and dissimilarities of the LD maps are studied and analysed. Computational results are also reported to show the effectiveness of the method using parallel computation.

  19. Genome-wide analysis correlates Ayurveda Prakriti.

    Science.gov (United States)

    Govindaraj, Periyasamy; Nizamuddin, Sheikh; Sharath, Anugula; Jyothi, Vuskamalla; Rotti, Harish; Raval, Ritu; Nayak, Jayakrishna; Bhat, Balakrishna K; Prasanna, B V; Shintre, Pooja; Sule, Mayura; Joshi, Kalpana S; Dedge, Amrish P; Bharadwaj, Ramachandra; Gangadharan, G G; Nair, Sreekumaran; Gopinath, Puthiya M; Patwardhan, Bhushan; Kondaiah, Paturu; Satyamoorthy, Kapaettu; Valiathan, Marthanda Varma Sankaran; Thangaraj, Kumarasamy

    2015-10-29

    The practice of Ayurveda, the traditional medicine of India, is based on the concept of three major constitutional types (Vata, Pitta and Kapha) defined as "Prakriti". To the best of our knowledge, no study has convincingly correlated genomic variations with the classification of Prakriti. In the present study, we performed genome-wide SNP (single nucleotide polymorphism) analysis (Affymetrix, 6.0) of 262 well-classified male individuals (after screening 3416 subjects) belonging to three Prakritis. We found 52 SNPs (p ≤ 1 × 10(-5)) were significantly different between Prakritis, without any confounding effect of stratification, after 10(6) permutations. Principal component analysis (PCA) of these SNPs classified 262 individuals into their respective groups (Vata, Pitta and Kapha) irrespective of their ancestry, which represent its power in categorization. We further validated our finding with 297 Indian population samples with known ancestry. Subsequently, we found that PGM1 correlates with phenotype of Pitta as described in the ancient text of Caraka Samhita, suggesting that the phenotypic classification of India's traditional medicine has a genetic basis; and its Prakriti-based practice in vogue for many centuries resonates with personalized medicine.

  20. A genome-wide linkage study of individuals with high scores on NEO personality traits.

    Science.gov (United States)

    Amin, N; Schuur, M; Gusareva, E S; Isaacs, A; Aulchenko, Y S; Kirichenko, A V; Zorkoltseva, I V; Axenovich, T I; Oostra, B A; Janssens, A C J W; van Duijn, C M

    2012-10-01

    The NEO-Five-Factor Inventory divides human personality traits into five dimensions: neuroticism, extraversion, openness, conscientiousness and agreeableness. In this study, we sought to identify regions harboring genes with large effects on the five NEO personality traits by performing genome-wide linkage analysis of individuals scoring in the extremes of these traits (>90th percentile). Affected-only linkage analysis was performed using an Illumina 6K linkage array in a family-based study, the Erasmus Rucphen Family study. We subsequently determined whether distinct, segregating haplotypes found with linkage analysis were associated with the trait of interest in the population. Finally, a dense single-nucleotide polymorphism genotyping array (Illumina 318K) was used to search for copy number variations (CNVs) in the associated regions. In the families with extreme phenotype scores, we found significant evidence of linkage for conscientiousness to 20p13 (rs1434789, log of odds (LOD)=5.86) and suggestive evidence of linkage (LOD >2.8) for neuroticism to 19q, 21q and 22q, extraversion to 1p, 1q, 9p and12q, openness to 12q and 19q, and agreeableness to 2p, 6q, 17q and 21q. Further analysis determined haplotypes in 21q22 for neuroticism (P-values = 0.009, 0.007), in 17q24 for agreeableness (marginal P-value = 0.018) and in 20p13 for conscientiousness (marginal P-values = 0.058, 0.038) segregating in families with large contributions to the LOD scores. No evidence for CNVs in any of the associated regions was found. Our findings imply that there may be genes with relatively large effects involved in personality traits, which may be identified with next-generation sequencing techniques.

  1. Genome-wide linkage scan identifies two novel genetic loci for coronary artery disease: in GeneQuest families.

    Science.gov (United States)

    Gao, Hanxiang; Li, Lin; Rao, Shaoqi; Shen, Gongqing; Xi, Quansheng; Chen, Shenghan; Zhang, Zheng; Wang, Kai; Ellis, Stephen G; Chen, Qiuyun; Topol, Eric J; Wang, Qing K

    2014-01-01

    Coronary artery disease (CAD) is the leading cause of death worldwide. Recent genome-wide association studies (GWAS) identified >50 common variants associated with CAD or its complication myocardial infarction (MI), but collectively they account for missing heritability". Rare variants with large effects may account for a large portion of missing heritability. Genome-wide linkage studies of large families and follow-up fine mapping and deep sequencing are particularly effective in identifying rare variants with large effects. Here we show results from a genome-wide linkage scan for CAD in multiplex GeneQuest families with early onset CAD and MI. Whole genome genotyping was carried out with 408 markers that span the human genome by every 10 cM and linkage analyses were performed using the affected relative pair analysis implemented in GENEHUNTER. Affected only nonparametric linkage (NPL) analysis identified two novel CAD loci with highly significant evidence of linkage on chromosome 3p25.1 (peak NPL  = 5.49) and 3q29 (NPL  = 6.84). We also identified four loci with suggestive linkage on 9q22.33, 9q34.11, 17p12, and 21q22.3 (NPL  = 3.18-4.07). These results identify novel loci for CAD and provide a framework for fine mapping and deep sequencing to identify new susceptibility genes and novel variants associated with risk of CAD.

  2. Critical reasoning on causal inference in genome-wide linkage and association studies

    NARCIS (Netherlands)

    Li, Yang; Tesson, Bruno M.; Churchill, Gary A.; Jansen, Ritsert C.

    2010-01-01

    Genome-wide linkage and association studies of tens of thousands of clinical and molecular traits are currently underway, offering rich data for inferring causality between traits and genetic variation. However, the inference process is based on discovering subtle patterns in the correlation between

  3. Genome-wide linkage scan for the metabolic syndrome: the GENNID study.

    Science.gov (United States)

    Edwards, Karen L; Hutter, Carolyn M; Wan, Jia Yin; Kim, Helen; Monks, Stephanie A

    2008-07-01

    In the United States, the metabolic syndrome (MetS) constitutes a major public health problem with over 47 million persons meeting clinical criteria for MetS. Numerous studies have suggested genetic susceptibility to MetS. The goals of this study were (i) to identify susceptibility loci for MetS in well-characterized families with type 2 diabetes (T2D) in four ethnic groups and (ii) to determine whether evidence for linkage varies across the four groups. The GENNID study (Genetics of NIDDM) is a multicenter study established by the American Diabetes Association in 1993 and comprises a comprehensive, well-characterized resource of T2D families from four ethnic groups (whites, Mexican Americans, African Americans, and Japanese Americans). Principal component factor analysis (PCFA) was used to define quantitative phenotypes of the MetS. Variance components linkage analysis was conducted using microsatellite markers from a 10-cM genome-wide linkage scan, separately in each of the four ethnic groups. Three quantitative MetS factors were identified by PCFA and used as phenotypes for MetS: (i) a weight/waist factor, (ii) a blood pressure factor, and (iii) a lipid factor. Evidence for linkage to each of these factors was observed. For each ethnic group, our results suggest that several regions harbor susceptibility genes for the MetS. The strongest evidence for linkage for MetS phenotypes was observed on chromosome 2 (2q12.1-2q13) in the white sample and on chromosome 3 (3q26.1-3q29) in the Mexican-American sample. In conclusion, the results suggest that several regions harbor MetS susceptibility genes and that heterogeneity may exist across groups.

  4. Genome-Wide Association Mapping for Intelligence in Military Working Dogs: Canine Cohort, Canine Intelligence Assessment Regimen, Genome-Wide Single Nucleotide Polymorphism (SNP) Typing, and Unsupervised Classification Algorithm for Genome-Wide Association Data Analysis

    Science.gov (United States)

    2011-09-01

    Almasy, L, Blangero, J. (2009) Human QTL linkage mapping. Genetica 136:333-340. Amos, CI. (2007) Successful design and conduct of genome-wide...quantitative trait loci. Genetica 136:237-243. Skol AD, Scott LJ, Abecasis GR, Boehnke M. (2006) Joint analysis is more efficient than replication

  5. Genome wide linkage disequilibrium in Chinese asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm: implications for domestication history and genome wide association studies.

    Science.gov (United States)

    Xu, P; Wu, X; Wang, B; Luo, J; Liu, Y; Ehlers, J D; Close, T J; Roberts, P A; Lu, Z; Wang, S; Li, G

    2012-07-01

    Association mapping of important traits of crop plants relies on first understanding the extent and patterns of linkage disequilibrium (LD) in the particular germplasm being investigated. We characterize here the genetic diversity, population structure and genome wide LD patterns in a set of asparagus bean (Vigna. unguiculata ssp. sesquipedialis) germplasm from China. A diverse collection of 99 asparagus bean and normal cowpea accessions were genotyped with 1127 expressed sequence tag-derived single nucleotide polymorphism markers (SNPs). The proportion of polymorphic SNPs across the collection was relatively low (39%), with an average number of SNPs per locus of 1.33. Bayesian population structure analysis indicated two subdivisions within the collection sampled that generally represented the 'standard vegetable' type (subgroup SV) and the 'non-standard vegetable' type (subgroup NSV), respectively. Level of LD (r(2)) was higher and extent of LD persisted longer in subgroup SV than in subgroup NSV, whereas LD decayed rapidly (0-2 cM) in both subgroups. LD decay distance varied among chromosomes, with the longest (≈ 5 cM) five times longer than the shortest (≈ 1 cM). Partitioning of LD variance into within- and between-subgroup components coupled with comparative LD decay analysis suggested that linkage group 5, 7 and 10 may have undergone the most intensive epistatic selection toward traits favorable for vegetable use. This work provides a first population genetic insight into domestication history of asparagus bean and demonstrates the feasibility of mapping complex traits by genome wide association study in asparagus bean using a currently available cowpea SNPs marker platform.

  6. Genome-wide linkage scan identifies two novel genetic loci for coronary artery disease: in GeneQuest families.

    Directory of Open Access Journals (Sweden)

    Hanxiang Gao

    Full Text Available Coronary artery disease (CAD is the leading cause of death worldwide. Recent genome-wide association studies (GWAS identified >50 common variants associated with CAD or its complication myocardial infarction (MI, but collectively they account for <20% of heritability, generating a phenomena of "missing heritability". Rare variants with large effects may account for a large portion of missing heritability. Genome-wide linkage studies of large families and follow-up fine mapping and deep sequencing are particularly effective in identifying rare variants with large effects. Here we show results from a genome-wide linkage scan for CAD in multiplex GeneQuest families with early onset CAD and MI. Whole genome genotyping was carried out with 408 markers that span the human genome by every 10 cM and linkage analyses were performed using the affected relative pair analysis implemented in GENEHUNTER. Affected only nonparametric linkage (NPL analysis identified two novel CAD loci with highly significant evidence of linkage on chromosome 3p25.1 (peak NPL  = 5.49 and 3q29 (NPL  = 6.84. We also identified four loci with suggestive linkage on 9q22.33, 9q34.11, 17p12, and 21q22.3 (NPL  = 3.18-4.07. These results identify novel loci for CAD and provide a framework for fine mapping and deep sequencing to identify new susceptibility genes and novel variants associated with risk of CAD.

  7. A novel statistic for genome-wide interaction analysis.

    Science.gov (United States)

    Wu, Xuesen; Dong, Hua; Luo, Li; Zhu, Yun; Peng, Gang; Reveille, John D; Xiong, Momiao

    2010-09-23

    Although great progress in genome-wide association studies (GWAS) has been made, the significant SNP associations identified by GWAS account for only a few percent of the genetic variance, leading many to question where and how we can find the missing heritability. There is increasing interest in genome-wide interaction analysis as a possible source of finding heritability unexplained by current GWAS. However, the existing statistics for testing interaction have low power for genome-wide interaction analysis. To meet challenges raised by genome-wide interactional analysis, we have developed a novel statistic for testing interaction between two loci (either linked or unlinked). The null distribution and the type I error rates of the new statistic for testing interaction are validated using simulations. Extensive power studies show that the developed statistic has much higher power to detect interaction than classical logistic regression. The results identified 44 and 211 pairs of SNPs showing significant evidence of interactions with FDRanalysis is a valuable tool for finding remaining missing heritability unexplained by the current GWAS, and the developed novel statistic is able to search significant interaction between SNPs across the genome. Real data analysis showed that the results of genome-wide interaction analysis can be replicated in two independent studies.

  8. Genome-wide Analysis of Gene Regulation

    DEFF Research Database (Denmark)

    Chen, Yun

    IP-seq and small RNA-seq, we delineated the landscape of the promoters with bidirectional transcriptions that yield steady-state RNA in only one directions (Paper III). A subsequent motif analysis enabled us to uncover specific DNA signals – early polyA sites – that make RNA on the reverse strand sensitive...... they regulated or if the sites had global elevated usage rates by multiple TFs. Using RNA-seq, 5’end-seq in combination with depletion of 5’exonuclease as well as nonsensemediated decay (NMD) factors, we systematically analyzed NMD substrates as well as their degradation intermediates in human cells (Paper V......). Gene enrichment analysis on the detected NMD substrates revealed an unappreciated NMD-based regulatory mechanism of the genes hosting multiple intronic snoRNAs, which can facilitate differential expression of individual snoRNAs from a single host gene locus. Finally, supported by RNA-seq and small RNA-seq...

  9. A novel statistic for genome-wide interaction analysis.

    Directory of Open Access Journals (Sweden)

    Xuesen Wu

    2010-09-01

    Full Text Available Although great progress in genome-wide association studies (GWAS has been made, the significant SNP associations identified by GWAS account for only a few percent of the genetic variance, leading many to question where and how we can find the missing heritability. There is increasing interest in genome-wide interaction analysis as a possible source of finding heritability unexplained by current GWAS. However, the existing statistics for testing interaction have low power for genome-wide interaction analysis. To meet challenges raised by genome-wide interactional analysis, we have developed a novel statistic for testing interaction between two loci (either linked or unlinked. The null distribution and the type I error rates of the new statistic for testing interaction are validated using simulations. Extensive power studies show that the developed statistic has much higher power to detect interaction than classical logistic regression. The results identified 44 and 211 pairs of SNPs showing significant evidence of interactions with FDR<0.001 and 0.001genome-wide interaction analysis is a valuable tool for finding remaining missing heritability unexplained by the current GWAS, and the developed novel statistic is able to search significant interaction between SNPs across the genome. Real data analysis showed that the results of genome-wide interaction analysis can be replicated in two independent studies.

  10. Genome-wide linkage scan for loci associated with epilepsy in Belgian shepherd dogs

    Directory of Open Access Journals (Sweden)

    Regan Kelly R

    2010-05-01

    Full Text Available Abstract Background Idiopathic epilepsy in the Belgian shepherd dog is known to have a substantial genetic component. The objective of this study was to identify genomic regions associated with the expression of generalized seizures in the Belgian Tervuren and Sheepdog. Results DNA from 366 dogs, of which 74 were classified as epileptic, representing two extended families were subjected to a genome-wide linkage scan using 410 microsatellite markers yielding informative coverage averaging 5.95 ± 0.21 Mb. Though previous studies based on pedigree analyses proposed a major gene of influence, the present study demonstrated the trait to be highly polygenic. Studies of complex disorders in humans indicate that a liberal composite evaluation of genetic linkage is needed to identify underlying quantitative trait loci (QTLs. Four chromosomes yielded tentative linkage based upon LOD scores in excess of 1.0. Possible QTLs within these regions were supported also by analyses of multipoint linkage, allele frequency, TDT, and transmission of haplotype blocks. Conclusions Taken together the data tentatively indicate six QTLs, three on CFA 2, and one on each of CFA 6, 12, and 37, that support fine mapping for mutations associated with epilepsy in the Belgian shepherd. The study also underscores the complexity of genomic linkage studies for polygenic disorders.

  11. Improved statistics for genome-wide interaction analysis.

    Science.gov (United States)

    Ueki, Masao; Cordell, Heather J

    2012-01-01

    Recently, Wu and colleagues [1] proposed two novel statistics for genome-wide interaction analysis using case/control or case-only data. In computer simulations, their proposed case/control statistic outperformed competing approaches, including the fast-epistasis option in PLINK and logistic regression analysis under the correct model; however, reasons for its superior performance were not fully explored. Here we investigate the theoretical properties and performance of Wu et al.'s proposed statistics and explain why, in some circumstances, they outperform competing approaches. Unfortunately, we find minor errors in the formulae for their statistics, resulting in tests that have higher than nominal type 1 error. We also find minor errors in PLINK's fast-epistasis and case-only statistics, although theory and simulations suggest that these errors have only negligible effect on type 1 error. We propose adjusted versions of all four statistics that, both theoretically and in computer simulations, maintain correct type 1 error rates under the null hypothesis. We also investigate statistics based on correlation coefficients that maintain similar control of type 1 error. Although designed to test specifically for interaction, we show that some of these previously-proposed statistics can, in fact, be sensitive to main effects at one or both loci, particularly in the presence of linkage disequilibrium. We propose two new "joint effects" statistics that, provided the disease is rare, are sensitive only to genuine interaction effects. In computer simulations we find, in most situations considered, that highest power is achieved by analysis under the correct genetic model. Such an analysis is unachievable in practice, as we do not know this model. However, generally high power over a wide range of scenarios is exhibited by our joint effects and adjusted Wu statistics. We recommend use of these alternative or adjusted statistics and urge caution when using Wu et al

  12. Genome-wide gene expression analysis of anguillid herpesvirus 1

    NARCIS (Netherlands)

    Beurden, van S.J.; Peeters, B.P.H.; Rottier, P.J.M.; Davison, A.A.; Engelsma, M.Y.

    2013-01-01

    Background Whereas temporal gene expression in mammalian herpesviruses has been studied extensively, little is known about gene expression in fish herpesviruses. Here we report a genome-wide transcription analysis of a fish herpesvirus, anguillid herpesvirus 1, in cell culture, studied during the

  13. Genome-Wide Association Analysis in Primary Sclerosing Cholangitis

    NARCIS (Netherlands)

    T.H. Karlsen; A. Franke; E. Melum; A.. Kaser; J.R. Hov; T. Balschun; B.A. Lie; A. Bergquist; C. Schramm; T.J. Weismüller; D. Gotthardt; C. Rust; E.E.R. Philipp; T. Fritz; L. Henckaerts; R. Weersma; P. Stokkers; C.Y. Ponsioen; C. Wijmenga; M. Sterneck; M. Nothnagel; J. Hampe; A. Teufel; H. Runz; P. Rosenstiel; A. Stiehl; S. Vermeire; U. Beuers; M. Manns; E. Schrumpf; K.M. Boberg; S. Schreiber

    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

  14. Genome-wide linkage scan for primary open angle glaucoma: influences of ancestry and age at diagnosis.

    Directory of Open Access Journals (Sweden)

    Kristy R Crooks

    Full Text Available Primary open-angle glaucoma (POAG is the most common form of glaucoma and one of the leading causes of vision loss worldwide. The genetic etiology of POAG is complex and poorly understood. The purpose of this work is to identify genomic regions of interest linked to POAG. This study is the largest genetic linkage study of POAG performed to date: genomic DNA samples from 786 subjects (538 Caucasian ancestry, 248 African ancestry were genotyped using either the Illumina GoldenGate Linkage 4 Panel or the Illumina Infinium Human Linkage-12 Panel. A total of 5233 SNPs was analyzed in 134 multiplex POAG families (89 Caucasian ancestry, 45 African ancestry. Parametric and non-parametric linkage analyses were performed on the overall dataset and within race-specific datasets (Caucasian ancestry and African ancestry. Ordered subset analysis was used to stratify the data on the basis of age of glaucoma diagnosis. Novel linkage regions were identified on chromosomes 1 and 20, and two previously described loci-GLC1D on chromosome 8 and GLC1I on chromosome 15--were replicated. These data will prove valuable in the context of interpreting results from genome-wide association studies for POAG.

  15. A comparison in association and linkage genome-wide scans for alcoholism susceptibility genes using single-nucleotide polymorphisms.

    Science.gov (United States)

    Chiu, Yen-Feng; Liu, Su-Yun; Tsai, Ya-Yu

    2005-12-30

    We conducted genome-wide linkage scans using both microsatellite and single-nucleotide polymorphism (SNP) markers. Regions showing the strongest evidence of linkage to alcoholism susceptibility genes were identified. Haplotype analyses using a sliding-window approach for SNPs in these regions were performed. In addition, we performed a genome-wide association scan using SNP data. SNPs in these regions with evidence of association (P alcoholism (the most significant SNP had a p-value of 0.030) as those identified from association genomic screening (the most significant SNP had a p-value of 2.0 x 10(-8)).

  16. Genome wide copy number analysis of single cells

    Science.gov (United States)

    Baslan, Timour; Kendall, Jude; Rodgers, Linda; Cox, Hilary; Riggs, Mike; Stepansky, Asya; Troge, Jennifer; Ravi, Kandasamy; Esposito, Diane; Lakshmi, B.; Wigler, Michael; Navin, Nicholas; Hicks, James

    2016-01-01

    Summary Copy number variation (CNV) is increasingly recognized as an important contributor to phenotypic variation in health and disease. Most methods for determining CNV rely on admixtures of cells, where information regarding genetic heterogeneity is lost. Here, we present a protocol that allows for the genome wide copy number analysis of single nuclei isolated from mixed populations of cells. Single nucleus sequencing (SNS), combines flow sorting of single nuclei based on DNA content, whole genome amplification (WGA), followed by next generation sequencing to quantize genomic intervals in a genome wide manner. Multiplexing of single cells is discussed. Additionally, we outline informatic approaches that correct for biases inherent in the WGA procedure and allow for accurate determination of copy number profiles. All together, the protocol takes ~3 days from flow cytometry to sequence-ready DNA libraries. PMID:22555242

  17. Genome-Wide Detection and Analysis of Multifunctional Genes

    Science.gov (United States)

    Pritykin, Yuri; Ghersi, Dario; Singh, Mona

    2015-01-01

    Many genes can play a role in multiple biological processes or molecular functions. Identifying multifunctional genes at the genome-wide level and studying their properties can shed light upon the complexity of molecular events that underpin cellular functioning, thereby leading to a better understanding of the functional landscape of the cell. However, to date, genome-wide analysis of multifunctional genes (and the proteins they encode) has been limited. Here we introduce a computational approach that uses known functional annotations to extract genes playing a role in at least two distinct biological processes. We leverage functional genomics data sets for three organisms—H. sapiens, D. melanogaster, and S. cerevisiae—and show that, as compared to other annotated genes, genes involved in multiple biological processes possess distinct physicochemical properties, are more broadly expressed, tend to be more central in protein interaction networks, tend to be more evolutionarily conserved, and are more likely to be essential. We also find that multifunctional genes are significantly more likely to be involved in human disorders. These same features also hold when multifunctionality is defined with respect to molecular functions instead of biological processes. Our analysis uncovers key features about multifunctional genes, and is a step towards a better genome-wide understanding of gene multifunctionality. PMID:26436655

  18. Genome-wide SNP-based linkage scan identifies a locus on 8q24 for an age-related hearing impairment trait

    DEFF Research Database (Denmark)

    Huyghe, J.R.; Laer, L. Van; Hendrickx, J.J.

    2008-01-01

    the results of a cross-sectional family-based genetic study employing audiometric data. By using principal component analysis, we were able to reduce the dimensionality of this multivariate phenotype while capturing most of the variation and retaining biologically important features of the audiograms. We...... conducted a genome-wide association as well as a linkage scan with high-density SNP microarrays. Because of the presence of genetic population substructure, association testing was stratified after which evidence was combined by meta-analysis. No association signals reaching genome-wide significance were...

  19. Three novel quantitative trait loci for skin thickness in swine identified by linkage and genome-wide association studies.

    Science.gov (United States)

    Ai, Huashui; Xiao, Shijun; Zhang, Zhiyan; Yang, Bin; Li, Lin; Guo, Yuanmei; Lin, Guoshan; Ren, Jun; Huang, Lusheng

    2014-08-01

    Skin is the largest organ in the pig body and plays a key role in protecting the body against pathogens and excessive water loss. Deciphering the genetic basis of swine skin thickness would enrich our knowledge about the skin. To identify the loci for porcine skin thickness, we first performed a genome scan with 194 microsatellite markers in a White Duroc × Erhualian F2 intercross. We identified three genome-wide significant QTL on pig chromosomes (SSC) 4, 7 and 15 using linkage analysis. The most significant QTL was found on SSC7 with a small confidence interval of ~5 cM, explaining 23.9 percent of phenotypic variance. Further, we conducted a genome-wide association study (GWAS) using Illumina PorcineSNP60 Beadchips for the F2 pedigree and a population of Chinese Sutai pigs. We confirmed significant QTL in the F2 pedigree and replicated QTL on SSC15 in Chinese Sutai pigs. A meta-analysis of GWASs on both populations detected a genomic region associated with skin thickness on SSC4. GWAS results were generally consistent with QTL mapping. Identical-by-descent analysis defined QTL on SSC7 in a 683-kb region harboring an interesting candidate gene: HMGA1. On SSC15, the linkage disequilibrium analysis showed a haplotype block of 2.20 Mb that likely harbors the gene responsible for skin thickness. Our findings provide novel insights into the genetic basis of swine skin thickness, which would benefit further understanding of porcine skin function.

  20. Genome-wide linkage, exome sequencing and functional analyses identify ABCB6 as the pathogenic gene of dyschromatosis universalis hereditaria.

    Directory of Open Access Journals (Sweden)

    Hong Liu

    Full Text Available BACKGROUND: As a genetic disorder of abnormal pigmentation, the molecular basis of dyschromatosis universalis hereditaria (DUH had remained unclear until recently when ABCB6 was reported as a causative gene of DUH. METHODOLOGY: We performed genome-wide linkage scan using Illumina Human 660W-Quad BeadChip and exome sequencing analyses using Agilent SureSelect Human All Exon Kits in a multiplex Chinese DUH family to identify the pathogenic mutations and verified the candidate mutations using Sanger sequencing. Quantitative RT-PCR and Immunohistochemistry was performed to verify the expression of the pathogenic gene, Zebrafish was also used to confirm the functional role of ABCB6 in melanocytes and pigmentation. RESULTS: Genome-wide linkage (assuming autosomal dominant inheritance mode and exome sequencing analyses identified ABCB6 as the disease candidate gene by discovering a coding mutation (c.1358C>T; p.Ala453Val that co-segregates with the disease phenotype. Further mutation analysis of ABCB6 in four other DUH families and two sporadic cases by Sanger sequencing confirmed the mutation (c.1358C>T; p.Ala453Val and discovered a second, co-segregating coding mutation (c.964A>C; p.Ser322Lys in one of the four families. Both mutations were heterozygous in DUH patients and not present in the 1000 Genome Project and dbSNP database as well as 1,516 unrelated Chinese healthy controls. Expression analysis in human skin and mutagenesis interrogation in zebrafish confirmed the functional role of ABCB6 in melanocytes and pigmentation. Given the involvement of ABCB6 mutations in coloboma, we performed ophthalmological examination of the DUH carriers of ABCB6 mutations and found ocular abnormalities in them. CONCLUSION: Our study has advanced our understanding of DUH pathogenesis and revealed the shared pathological mechanism between pigmentary DUH and ocular coloboma.

  1. Genome-wide evaluation of genetic diversity and linkage disequilibrium in winter and spring triticale (x Triticosecale Wittmack

    Directory of Open Access Journals (Sweden)

    Alheit Katharina V

    2012-06-01

    Full Text Available Abstract Background Recent advances in genotyping with high-density markers nowadays enable genome-wide genomic analyses in crops. A detailed characterisation of the population structure and linkage disequilibrium (LD is essential for the application of genomic approaches and consequently for knowledge-based breeding. In this study we used the triticale-specific DArT array to analyze population structure, genetic diversity, and LD in a worldwide set of 161 winter and spring triticale lines. Results The principal coordinate analysis revealed that the first principal coordinate divides the triticale population into two clusters according to their growth habit. The density distributions of the first ten principal coordinates revealed that several show a distribution indicative of population structure. In addition, we observed relatedness within growth habits which was higher among the spring types than among the winter types. The genome-wide analysis of polymorphic information content (PIC showed that the PIC is variable among and along chromosomes and that especially the R genome of spring types possesses a reduced genetic diversity. We also found that several chromosomes showed regions of high genetic distance between the two growth habits, indicative of divergent selection. Regarding linkage disequilibrium, the A and B genomes showed a similar LD of 0.24 for closely linked markers and a decay within approximately 12 cM. LD in the R genome was lower with 0.19 and decayed within a shorter map distance of approximately 5 cM. The extent of LD was generally higher for the spring types compared to the winter types. In addition, we observed strong variability of LD along the chromosomes. Conclusions Our results confirm winter and spring growth habit are the major contributors to population structure in triticale, and a family structure exists in both growth types. The specific patterns of genetic diversity observed within these types, such as the

  2. Arabidopsis transcription factors: genome-wide comparative analysis among eukaryotes.

    Science.gov (United States)

    Riechmann, J L; Heard, J; Martin, G; Reuber, L; Jiang, C; Keddie, J; Adam, L; Pineda, O; Ratcliffe, O J; Samaha, R R; Creelman, R; Pilgrim, M; Broun, P; Zhang, J Z; Ghandehari, D; Sherman, B K; Yu, G

    2000-12-15

    The completion of the Arabidopsis thaliana genome sequence allows a comparative analysis of transcriptional regulators across the three eukaryotic kingdoms. Arabidopsis dedicates over 5% of its genome to code for more than 1500 transcription factors, about 45% of which are from families specific to plants. Arabidopsis transcription factors that belong to families common to all eukaryotes do not share significant similarity with those of the other kingdoms beyond the conserved DNA binding domains, many of which have been arranged in combinations specific to each lineage. The genome-wide comparison reveals the evolutionary generation of diversity in the regulation of transcription.

  3. A genome-wide linkage study of bipolar disorder and co-morbid migraine

    DEFF Research Database (Denmark)

    Oedegaard, K. J.; Greenwood, T. A.; Lunde, Asger

    2010-01-01

    on chromosome 4q24 for migraine (but not BPAD) with a peak LOD of 2.26. This region has previously been implicated in two independent migraine linkage studies. In additionwe identified a locus on chromosome 20p11 with overlapping elevated LOD scores for both migraine (LOD=1.95) and BPAD (LOD=1.67) phenotypes...... Genetics Initiative wave 4 data set. In this analysis we selected only those families in which at least two members were diagnosed with migraine by a doctor according to patients' reports. Nonparametric linkage analysis performed on 31 families segregating both BPAD and migraine identified a linkage signal...... osome 4 (not co-segregating with BPAD) in a sample of BPAD families with comorbid migraine, and suggest a susceptibility locus on chromosome 20, harboring a gene for the migraine/BPAD phenotype. Together these data suggest that some genes may predispose to both bipolar disorder and migraine....

  4. A genome-wide linkage study of bipolar disorder and co-morbid migraine

    DEFF Research Database (Denmark)

    Oedegaard, K. J.; Greenwood, T. A.; Lunde, Asger

    2010-01-01

    Migraine and Bipolar Disorder (BPAD) are clinically heterogeneous disorders of the brain with a significant, but complex, genetic component. Epidemiological and clinical studies have demonstrated a high degree of co-morbidity between migraine and BPAD. Several genomewide linkage studies in BPAD...... that using migraine comorbidity to look at subsets of BPAD families in a genetic linkage analysis would prove useful in identifying genetic susceptibility regions in both of these disorders. We used BPAD with comorbid migraine as an alternative phenotype definition in a re-analysis of the NIMH Bipolar...... osome 4 (not co-segregating with BPAD) in a sample of BPAD families with comorbid migraine, and suggest a susceptibility locus on chromosome 20, harboring a gene for the migraine/BPAD phenotype. Together these data suggest that some genes may predispose to both bipolar disorder and migraine....

  5. High-Resolution Genome-Wide Linkage Mapping Identifies Susceptibility Loci for BMI in the Chinese Population

    DEFF Research Database (Denmark)

    Zhang, Dong Feng; Pang, Zengchang; Li, Shuxia

    2012-01-01

    The genetic loci affecting the commonly used BMI have been intensively investigated using linkage approaches in multiple populations. This study aims at performing the first genome-wide linkage scan on BMI in the Chinese population in mainland China with hypothesis that heterogeneity in genetic...... in western countries. Multiple loci showing suggestive linkage were found on chromosome 1 (lod score 2.38 at 242 cM), chromosome 8 (2.48 at 95 cM), and chromosome 14 (2.2 at 89.4 cM). The strong linkage identified in the Chinese subjects that is consistent with that found in populations of European origin...... could suggest the existence of evolutionarily preserved genetic mechanisms for BMI whereas the multiple suggestive loci could represent genetic effect from gene-environment interaction as a result of population-specific environmental adaptation....

  6. Systematic, genome-wide, sex-specific linkage of cardiovascular traits in French Canadians.

    Science.gov (United States)

    Seda, Ondrej; Tremblay, Johanne; Gaudet, Daniel; Brunelle, Pierre-Luc; Gurau, Alexandru; Merlo, Ettore; Pilote, Louise; Orlov, Sergei N; Boulva, Francis; Petrovich, Milan; Kotchen, Theodore A; Cowley, Allen W; Hamet, Pavel

    2008-04-01

    The sexual dimorphism of cardiovascular traits, as well as susceptibility to a variety of related diseases, has long been recognized, yet their sex-specific genomic determinants are largely unknown. We systematically assessed the sex-specific heritability and linkage of 539 hemodynamic, metabolic, anthropometric, and humoral traits in 120 French-Canadian families from the Saguenay-Lac-St-Jean region of Quebec, Canada. We performed multipoint linkage analysis using microsatellite markers followed by peak-wide linkage scan based on Affymetrix Human Mapping 50K Array Xba240 single nucleotide polymorphism genotypes in 3 settings, including the entire sample and then separately in men and women. Nearly one half of the traits were age and sex independent, one quarter were both age and sex dependent, and one eighth were exclusively age or sex dependent. Sex-specific phenotypes are most frequent in heart rate and blood pressure categories, whereas sex- and age-independent determinants are predominant among humoral and biochemical parameters. Twenty sex-specific loci passing multiple testing criteria were corroborated by 2-point single nucleotide polymorphism linkage. Several resting systolic blood pressure measurements showed significant genotype-by-sex interaction, eg, male-specific locus at chromosome 12 (male-female logarithm of odds difference: 4.16; interaction P=0.0002), which was undetectable in the entire population, even after adjustment for sex. Detailed interrogation of this locus revealed a 220-kb block overlapping parts of TAO-kinase 3 and SUDS3 genes. In summary, a large number of complex cardiovascular traits display significant sexual dimorphism, for which we have demonstrated genomic determinants at the haplotype level. Many of these would have been missed in a traditional, sex-adjusted setting.

  7. Natural selection on functional modules, a genome-wide analysis.

    Science.gov (United States)

    Serra, François; Arbiza, Leonardo; Dopazo, Joaquín; Dopazo, Hernán

    2011-03-01

    Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA), a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species.

  8. Natural selection on functional modules, a genome-wide analysis.

    Directory of Open Access Journals (Sweden)

    François Serra

    2011-03-01

    Full Text Available Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA, a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species.

  9. Genome-Wide Analysis of DNA Methylation in Human Amnion

    Directory of Open Access Journals (Sweden)

    Jinsil Kim

    2013-01-01

    Full Text Available The amnion is a specialized tissue in contact with the amniotic fluid, which is in a constantly changing state. To investigate the importance of epigenetic events in this tissue in the physiology and pathophysiology of pregnancy, we performed genome-wide DNA methylation profiling of human amnion from term (with and without labor and preterm deliveries. Using the Illumina Infinium HumanMethylation27 BeadChip, we identified genes exhibiting differential methylation associated with normal labor and preterm birth. Functional analysis of the differentially methylated genes revealed biologically relevant enriched gene sets. Bisulfite sequencing analysis of the promoter region of the oxytocin receptor (OXTR gene detected two CpG dinucleotides showing significant methylation differences among the three groups of samples. Hypermethylation of the CpG island of the solute carrier family 30 member 3 (SLC30A3 gene in preterm amnion was confirmed by methylation-specific PCR. This work provides preliminary evidence that DNA methylation changes in the amnion may be at least partially involved in the physiological process of labor and the etiology of preterm birth and suggests that DNA methylation profiles, in combination with other biological data, may provide valuable insight into the mechanisms underlying normal and pathological pregnancies.

  10. Genome-wide transcriptome analysis of 150 cell samples†

    Science.gov (United States)

    Russom, Aman; Xiao, Wenzhong; Wilhelmy, Julie; Wang, Shenglong; Heath, Joe Don; Kurn, Nurith; Tompkins, Ronald G.; Davis, Ronald W.; Toner, Mehmet

    2013-01-01

    A major challenge in molecular biology is interrogating the human transcriptome on a genome wide scale when only a limited amount of biological sample is available for analysis. Current methodologies using microarray technologies for simultaneously monitoring mRNA transcription levels require nanogram amounts of total RNA. To overcome the sample size limitation of current technologies, we have developed a method to probe the global gene expression in biological samples as small as 150 cells, or the equivalent of approximately 300 pg total RNA. The new method employs microfluidic devices for the purification of total RNA from mammalian cells and ultra-sensitive whole transcriptome amplification techniques. We verified that the RNA integrity is preserved through the isolation process, accomplished highly reproducible whole transcriptome analysis, and established high correlation between repeated isolations of 150 cells and the same cell culture sample. We validated the technology by demonstrating that the combined microfluidic and amplification protocol is capable of identifying biological pathways perturbed by stimulation, which are consistent with the information recognized in bulk-isolated samples. PMID:20023796

  11. Genome-wide transcriptome analysis of 150 cell samples.

    Science.gov (United States)

    Irimia, Daniel; Mindrinos, Michael; Russom, Aman; Xiao, Wenzhong; Wilhelmy, Julie; Wang, Shenglong; Heath, Joe Don; Kurn, Nurith; Tompkins, Ronald G; Davis, Ronald W; Toner, Mehmet

    2009-01-01

    A major challenge in molecular biology is interrogating the human transcriptome on a genome wide scale when only a limited amount of biological sample is available for analysis. Current methodologies using microarray technologies for simultaneously monitoring mRNA transcription levels require nanogram amounts of total RNA. To overcome the sample size limitation of current technologies, we have developed a method to probe the global gene expression in biological samples as small as 150 cells, or the equivalent of approximately 300 pg total RNA. The new method employs microfluidic devices for the purification of total RNA from mammalian cells and ultra-sensitive whole transcriptome amplification techniques. We verified that the RNA integrity is preserved through the isolation process, accomplished highly reproducible whole transcriptome analysis, and established high correlation between repeated isolations of 150 cells and the same cell culture sample. We validated the technology by demonstrating that the combined microfluidic and amplification protocol is capable of identifying biological pathways perturbed by stimulation, which are consistent with the information recognized in bulk-isolated samples.

  12. Comparative analysis of methods for genome-wide nucleosome cartography.

    Science.gov (United States)

    Quintales, Luis; Vázquez, Enrique; Antequera, Francisco

    2015-07-01

    Nucleosomes contribute to compacting the genome into the nucleus and regulate the physical access of regulatory proteins to DNA either directly or through the epigenetic modifications of the histone tails. Precise mapping of nucleosome positioning across the genome is, therefore, essential to understanding the genome regulation. In recent years, several experimental protocols have been developed for this purpose that include the enzymatic digestion, chemical cleavage or immunoprecipitation of chromatin followed by next-generation sequencing of the resulting DNA fragments. Here, we compare the performance and resolution of these methods from the initial biochemical steps through the alignment of the millions of short-sequence reads to a reference genome to the final computational analysis to generate genome-wide maps of nucleosome occupancy. Because of the lack of a unified protocol to process data sets obtained through the different approaches, we have developed a new computational tool (NUCwave), which facilitates their analysis, comparison and assessment and will enable researchers to choose the most suitable method for any particular purpose. NUCwave is freely available at http://nucleosome.usal.es/nucwave along with a step-by-step protocol for its use. © The Author 2014. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  13. Genome-Wide Analysis of DNA Methylation in Human Amnion

    Science.gov (United States)

    Kim, Jinsil; Pitlick, Mitchell M.; Christine, Paul J.; Schaefer, Amanda R.; Saleme, Cesar; Comas, Belén; Cosentino, Viviana; Gadow, Enrique; Murray, Jeffrey C.

    2013-01-01

    The amnion is a specialized tissue in contact with the amniotic fluid, which is in a constantly changing state. To investigate the importance of epigenetic events in this tissue in the physiology and pathophysiology of pregnancy, we performed genome-wide DNA methylation profiling of human amnion from term (with and without labor) and preterm deliveries. Using the Illumina Infinium HumanMethylation27 BeadChip, we identified genes exhibiting differential methylation associated with normal labor and preterm birth. Functional analysis of the differentially methylated genes revealed biologically relevant enriched gene sets. Bisulfite sequencing analysis of the promoter region of the oxytocin receptor (OXTR) gene detected two CpG dinucleotides showing significant methylation differences among the three groups of samples. Hypermethylation of the CpG island of the solute carrier family 30 member 3 (SLC30A3) gene in preterm amnion was confirmed by methylation-specific PCR. This work provides preliminary evidence that DNA methylation changes in the amnion may be at least partially involved in the physiological process of labor and the etiology of preterm birth and suggests that DNA methylation profiles, in combination with other biological data, may provide valuable insight into the mechanisms underlying normal and pathological pregnancies. PMID:23533356

  14. Power analysis for genome-wide association studies

    Directory of Open Access Journals (Sweden)

    Klein Robert J

    2007-08-01

    Full Text Available Abstract Background Genome-wide association studies are a promising new tool for deciphering the genetics of complex diseases. To choose the proper sample size and genotyping platform for such studies, power calculations that take into account genetic model, tag SNP selection, and the population of interest are required. Results The power of genome-wide association studies can be computed using a set of tag SNPs and a large number of genotyped SNPs in a representative population, such as available through the HapMap project. As expected, power increases with increasing sample size and effect size. Power also depends on the tag SNPs selected. In some cases, more power is obtained by genotyping more individuals at fewer SNPs than fewer individuals at more SNPs. Conclusion Genome-wide association studies should be designed thoughtfully, with the choice of genotyping platform and sample size being determined from careful power calculations.

  15. GLIDERS - A web-based search engine for genome-wide linkage disequilibrium between HapMap SNPs

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    Broxholme John

    2009-10-01

    Full Text Available Abstract Background A number of tools for the examination of linkage disequilibrium (LD patterns between nearby alleles exist, but none are available for quickly and easily investigating LD at longer ranges (>500 kb. We have developed a web-based query tool (GLIDERS: Genome-wide LInkage DisEquilibrium Repository and Search engine that enables the retrieval of pairwise associations with r2 ≥ 0.3 across the human genome for any SNP genotyped within HapMap phase 2 and 3, regardless of distance between the markers. Description GLIDERS is an easy to use web tool that only requires the user to enter rs numbers of SNPs they want to retrieve genome-wide LD for (both nearby and long-range. The intuitive web interface handles both manual entry of SNP IDs as well as allowing users to upload files of SNP IDs. The user can limit the resulting inter SNP associations with easy to use menu options. These include MAF limit (5-45%, distance limits between SNPs (minimum and maximum, r2 (0.3 to 1, HapMap population sample (CEU, YRI and JPT+CHB combined and HapMap build/release. All resulting genome-wide inter-SNP associations are displayed on a single output page, which has a link to a downloadable tab delimited text file. Conclusion GLIDERS is a quick and easy way to retrieve genome-wide inter-SNP associations and to explore LD patterns for any number of SNPs of interest. GLIDERS can be useful in identifying SNPs with long-range LD. This can highlight mis-mapping or other potential association signal localisation problems.

  16. An efficient hierarchical generalized linear mixed model for pathway analysis of genome-wide association studies.

    Science.gov (United States)

    Wang, Lily; Jia, Peilin; Wolfinger, Russell D; Chen, Xi; Grayson, Britney L; Aune, Thomas M; Zhao, Zhongming

    2011-03-01

    In genome-wide association studies (GWAS) of complex diseases, genetic variants having real but weak associations often fail to be detected at the stringent genome-wide significance level. Pathway analysis, which tests disease association with combined association signals from a group of variants in the same pathway, has become increasingly popular. However, because of the complexities in genetic data and the large sample sizes in typical GWAS, pathway analysis remains to be challenging. We propose a new statistical model for pathway analysis of GWAS. This model includes a fixed effects component that models mean disease association for a group of genes, and a random effects component that models how each gene's association with disease varies about the gene group mean, thus belongs to the class of mixed effects models. The proposed model is computationally efficient and uses only summary statistics. In addition, it corrects for the presence of overlapping genes and linkage disequilibrium (LD). Via simulated and real GWAS data, we showed our model improved power over currently available pathway analysis methods while preserving type I error rate. Furthermore, using the WTCCC Type 1 Diabetes (T1D) dataset, we demonstrated mixed model analysis identified meaningful biological processes that agreed well with previous reports on T1D. Therefore, the proposed methodology provides an efficient statistical modeling framework for systems analysis of GWAS. The software code for mixed models analysis is freely available at http://biostat.mc.vanderbilt.edu/LilyWang.

  17. Genome-wide analysis of alternative splicing in Chlamydomonas reinhardtii

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    Thomas Julie

    2010-02-01

    Full Text Available Abstract Background Genome-wide computational analysis of alternative splicing (AS in several flowering plants has revealed that pre-mRNAs from about 30% of genes undergo AS. Chlamydomonas, a simple unicellular green alga, is part of the lineage that includes land plants. However, it diverged from land plants about one billion years ago. Hence, it serves as a good model system to study alternative splicing in early photosynthetic eukaryotes, to obtain insights into the evolution of this process in plants, and to compare splicing in simple unicellular photosynthetic and non-photosynthetic eukaryotes. We performed a global analysis of alternative splicing in Chlamydomonas reinhardtii using its recently completed genome sequence and all available ESTs and cDNAs. Results Our analysis of AS using BLAT and a modified version of the Sircah tool revealed AS of 498 transcriptional units with 611 events, representing about 3% of the total number of genes. As in land plants, intron retention is the most prevalent form of AS. Retained introns and skipped exons tend to be shorter than their counterparts in constitutively spliced genes. The splice site signals in all types of AS events are weaker than those in constitutively spliced genes. Furthermore, in alternatively spliced genes, the prevalent splice form has a stronger splice site signal than the non-prevalent form. Analysis of constitutively spliced introns revealed an over-abundance of motifs with simple repetitive elements in comparison to introns involved in intron retention. In almost all cases, AS results in a truncated ORF, leading to a coding sequence that is around 50% shorter than the prevalent splice form. Using RT-PCR we verified AS of two genes and show that they produce more isoforms than indicated by EST data. All cDNA/EST alignments and splice graphs are provided in a website at http://combi.cs.colostate.edu/as/chlamy. Conclusions The extent of AS in Chlamydomonas that we observed is much

  18. A genome-wide search for linkage of estimated glomerular filtration rate (eGFR in the Family Investigation of Nephropathy and Diabetes (FIND.

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    Farook Thameem

    Full Text Available OBJECTIVE: Estimated glomerular filtration rate (eGFR, a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL that influence eGFR. METHODS: Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND study. This study included 954 African Americans (AA, 781 American Indians (AI, 614 European Americans (EA and 1,611 Mexican Americans (MA. A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD formula. RESULTS: The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4 × 10(-5 in MA and chromosome 15q12 (LOD = 2.84; P = 1.5 × 10(-4 in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5 × 10(-4 at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome. CONCLUSION: The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses

  19. Linkage disequilibrium and genome-wide association mapping in tetraploid wheat (Triticum turgidum L.).

    Science.gov (United States)

    Laidò, Giovanni; Marone, Daniela; Russo, Maria A; Colecchia, Salvatore A; Mastrangelo, Anna M; De Vita, Pasquale; Papa, Roberto

    2014-01-01

    Association mapping is a powerful tool for the identification of quantitative trait loci through the exploitation of the differential decay of linkage disequilibrium (LD) between marker loci and genes of interest in natural and domesticated populations. Using a sample of 230 tetraploid wheat lines (Triticum turgidum ssp), which included naked and hulled accessions, we analysed the pattern of LD considering 26 simple sequence repeats and 970 mostly mapped diversity array technology loci. In addition, to validate the potential for association mapping in durum wheat, we evaluated the same genotypes for plant height, heading date, protein content, and thousand-kernel weight. Molecular and phenotypic data were used to: (i) investigate the genetic and phenotypic diversity; (ii) study the dynamics of LD across the durum wheat genome, by investigating the patterns of LD decay; and (iii) test the potential of our panel to identify marker-trait associations through the analysis of four quantitative traits of major agronomic importance. Moreover, we compared and validated the association mapping results with outlier detection analysis based on population divergence. Overall, in tetraploid wheat, the pattern of LD is extremely population dependent and is related to the domestication and breeding history of durum wheat. Comparing our data with several other studies in wheat, we confirm the position of many major genes and quantitative trait loci for the traits considered. Finally, the analysis of the selection signature represents a very useful complement to validate marker-trait associations.

  20. Population structure and linkage disequilibrium in oat (Avena sativa L.): implications for genome-wide association studies.

    Science.gov (United States)

    Newell, M A; Cook, D; Tinker, N A; Jannink, J-L

    2011-02-01

    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 a high-throughput, high-density marker system. The objectives of this research were to survey the level of population structure and the extent of LD in oat germplasm and determine their implications for GWAS. In total, 1,205 lines and 402 diversity array technology (DArT) markers were used to explore population structure. Principal component analysis and model-based cluster analysis of these data indicated that, for the lines used in this study, relatively weak population structure exists. To explore LD decay, map distances of 2,225 linked DArT marker pairs were compared with LD (estimated as r²). Results showed that LD between linked markers decayed rapidly to r² = 0.2 for marker pairs with a map distance of 1.0 centi-Morgan (cM). For GWAS, we suggest a minimum of one marker every cM, but higher densities of markers should increase marker-QTL association and therefore detection power. Additionally, it was found that LD was relatively consistent across the majority of germplasm clusters. These findings suggest that GWAS in oat can include germplasm with diverse origins and backgrounds. The results from this research demonstrate the feasibility of GWAS and related analyses in oat.

  1. A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease

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    Wilson Alexander F

    2010-06-01

    Full Text Available Abstract Background The inability of aspirin (ASA to adequately suppress platelet aggregation is associated with future risk of coronary artery disease (CAD. Heritability studies of agonist-induced platelet function phenotypes suggest that genetic variation may be responsible for ASA responsiveness. In this study, we leverage independent information from genome-wide linkage and association data to determine loci controlling platelet phenotypes before and after treatment with ASA. Methods Clinical data on 37 agonist-induced platelet function phenotypes were evaluated before and after a 2-week trial of ASA (81 mg/day in 1231 European American and 846 African American healthy subjects with a family history of premature CAD. Principal component analysis was performed to minimize the number of independent factors underlying the covariance of these various phenotypes. Multi-point sib-pair based linkage analysis was performed using a microsatellite marker set, and single-SNP association tests were performed using markers from the Illumina 1 M genotyping chip from deCODE Genetics, Inc. All analyses were performed separately within each ethnic group. Results Several genomic regions appear to be linked to ASA response factors: a 10 cM region in African Americans on chromosome 5q11.2 had several STRs with suggestive (p-value -4 and significant (p-value -5 linkage to post aspirin platelet response to ADP, and ten additional factors had suggestive evidence for linkage (p-value -4 to thirteen genomic regions. All but one of these factors were aspirin response variables. While the strength of genome-wide SNP association signals for factors showing evidence for linkage is limited, especially at the strict thresholds of genome-wide criteria (N = 9 SNPs for 11 factors, more signals were considered significant when the association signal was weighted by evidence for linkage (N = 30 SNPs. Conclusions Our study supports the hypothesis that platelet phenotypes in

  2. Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand.

    Science.gov (United States)

    Phasukkijwatana, Nopasak; Kunhapan, Bussaraporn; Stankovich, Jim; Chuenkongkaew, Wanicha L; Thomson, Russell; Thornton, Timothy; Bahlo, Melanie; Mushiroda, Taisei; Nakamura, Yusuke; Mahasirimongkol, Surakameth; Tun, Aung Win; Srisawat, Chatchawan; Limwongse, Chanin; Peerapittayamongkol, Chayanon; Sura, Thanyachai; Suthammarak, Wichit; Lertrit, Patcharee

    2010-07-01

    Leber hereditary optic neuropathy (LHON) is the most common mitochondrially inherited disease causing blindness, preferentially in young adult males. Most of the patients carry the G11778A mitochondrial DNA (mtDNA) mutation. However, the marked incomplete penetrance and the gender bias indicate some additional genetic and/or environmental factors to disease expression. Herein, we first conducted a genome-wide linkage scan with 400 microsatellite markers in 9 large Thai LHON G11778A pedigrees. Using an affecteds-only nonparametric linkage analysis, 4 regions on chromosomes 3, 12, 13 and 18 showed Zlr scores greater than 2 (P 2 in 10 of 16 allele sharing models tested) was then expanded to include the region 3q26.2-3q28 covering SLC7A14 (3q26.2), MFN1 (3q26.32), MRPL47 (3q26.33), MCCC1 (3q27.1), PARL (3q27.1) and OPA1 (3q28-q29). All of these candidate genes were selected from the Maestro database and had known to be localized in mitochondria. Sixty tag SNPs were genotyped in 86 cases, 211 of their relatives and 32 unrelated Thai controls, by multiplex-PCR-based Invader assay. Analyses using a powerful association testing tool that adjusts for relatedness (the M(QLS) statistic) showed the most evidence of association between two SNPs, rs3749446 and rs1402000 (located in PARL presenilins-associated rhomboid-like) and LHON expression (both P = 8.8 x 10(-5)). The mitochondrial PARL protease has been recently known to play a role with a dynamin-related OPA1 protein in preventing apoptotic events by slowing down the release of cytochrome c out of mitochondrial cristae junctions. Moreover, PARL is required to activate the intramembranous proteolyses resulting in the degradation of an accumulated pro-apoptotic protein in the outer mitochondrial membrane. Under these circumstances, variants of PARL are suggested to influence cell death by apoptosis which has long been believed to intrigue the neurodegeneration of LHON.

  3. Genome-wide linkage and association mapping identify susceptibility alleles in ABCC4 for Kawasaki disease

    NARCIS (Netherlands)

    Khor, Chiea Chuen; Davila, Sonia; Shimizu, Chisato; Sheng, Stephanie; Matsubara, Tomoyo; Suzuki, Yasuo; Newburger, Jane W.; Baker, Annette; Burgner, David; Breunis, Willemijn; Kuijpers, Taco; Wright, Victoria J.; Levin, Michael; Hibberd, Martin L.; Burns, Jane C.

    Background Kawasaki disease (KD) is a self limited vasculitis in which host genetics plays a prominent role. To further the understanding of the role of host genetics in KD, a three-stage genetic study was conducted that began with a family linkage study and ultimately involved more than 3000

  4. Genome-wide linkage and association mapping identify susceptibility alleles in ABCC4 for Kawasaki disease

    NARCIS (Netherlands)

    Khor, C.C.; Davila, S.; Shimizu, C.; Sheng, S.; Matsubara, T.; Suzuki, Y.; Newburger, J.W.; Baker, A.; Burgner, D.; Breunis, W.; Kuijpers, T.; Wright, V.J.; Levin, M.; Hibberd, M.L.; Burns, J.C.

    2011-01-01

    Kawasaki disease (KD) is a self limited vasculitis in which host genetics plays a prominent role. To further the understanding of the role of host genetics in KD, a three-stage genetic study was conducted that began with a family linkage study and ultimately involved more than 3000 individuals to

  5. Genome-wide linkage and association mapping identify susceptibility alleles in ABCC4 for Kawasaki disease

    NARCIS (Netherlands)

    Khor, C.C.; Davila, S.; Shimizu, C.; Sheng, S.; Matsubara, T.; Suzuki, Y.; Newburger, J.W.; Baker, A.; Burgner, D.; Breunis, W.; Kuijpers, T.; Wright, V.J.; Levin, M.; Hibberd, M.L.; Burns, J.C.

    2011-01-01

    Kawasaki disease (KD) is a self limited vasculitis in which host genetics plays a prominent role. To further the understanding of the role of host genetics in KD, a three-stage genetic study was conducted that began with a family linkage study and ultimately involved more than 3000 individuals to id

  6. Genome-wide linkage and association mapping identify susceptibility alleles in ABCC4 for Kawasaki disease

    NARCIS (Netherlands)

    Khor, Chiea Chuen; Davila, Sonia; Shimizu, Chisato; Sheng, Stephanie; Matsubara, Tomoyo; Suzuki, Yasuo; Newburger, Jane W.; Baker, Annette; Burgner, David; Breunis, Willemijn; Kuijpers, Taco; Wright, Victoria J.; Levin, Michael; Hibberd, Martin L.; Burns, Jane C.

    2011-01-01

    Background Kawasaki disease (KD) is a self limited vasculitis in which host genetics plays a prominent role. To further the understanding of the role of host genetics in KD, a three-stage genetic study was conducted that began with a family linkage study and ultimately involved more than 3000 indivi

  7. Genome-wide linkage screen for testicular germ cell tumour susceptibility loci

    NARCIS (Netherlands)

    Crockford, GP; Linger, R; Hockley, S; Dudakia, D; Johnson, L; Huddart, R; Tucker, K; Friedlander, M; Phillips, KA; Hogg, D; Jewett, MAS; Lohynska, R; Daugaard, G; Richard, S; Chompret, A; Bonaiti-Pellie, C; Heidenreich, A; Albers, P; Olah, E; Geczi, L; Bodrogi, [No Value; Ormiston, WJ; Daly, PA; Guilford, P; Fossa, SD; Heimdal, K; Tjulandin, SA; Liubchenko, L; Stoll, H; Weber, W; Forman, D; Oliver, T; Einhorn, L; McMaster, M; Kramer, J; Greene, MH; Weber, BL; Nathanson, KL; Cortessis, [No Value; Easton, DF; Bishop, DT; Stratton, MR; Rapley, EA

    2006-01-01

    A family history of disease is a strong risk factor for testicular germ cell tumour (TGCT). In order to identify the location of putative TGCT susceptibility gene(s) we conducted a linkage search in 237 pedigrees with two or more cases of TGCT. One hundred and seventy-nine pedigrees were evaluated g

  8. Dating the age of admixture via wavelet transform analysis of genome-wide data

    NARCIS (Netherlands)

    I. Pugach (Irina); R. Matveyev (Rostislav); A. Wollstein (Andreas); M.H. Kayser (Manfred); M. Stoneking (Mark)

    2011-01-01

    textabstractWe describe a PCA-based genome scan approach to analyze genome-wide admixture structure, and introduce wavelet transform analysis as a method for estimating the time of admixture. We test the wavelet transform method with simulations and apply it to genome-wide SNP data from eight admixe

  9. 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…

  10. 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…

  11. Genome-wide linkage scan to identify loci associated with type 2 diabetes and blood lipid phenotypes in the Sikh Diabetes Study.

    Directory of Open Access Journals (Sweden)

    Dharambir K Sanghera

    Full Text Available In this investigation, we have carried out an autosomal genome-wide linkage analysis to map genes associated with type 2 diabetes (T2D and five quantitative traits of blood lipids including total cholesterol, high-density lipoprotein (HDL cholesterol, low-density lipoprotein (LDL cholesterol, very low-density lipoprotein (VLDL cholesterol, and triglycerides in a unique family-based cohort from the Sikh Diabetes Study (SDS. A total of 870 individuals (526 male/344 female from 321 families were successfully genotyped using 398 polymorphic microsatellite markers with an average spacing of 9.26 cM on the autosomes. Results of non-parametric multipoint linkage analysis using S(all statistics (implemented in Merlin did not reveal any chromosomal region to be significantly associated with T2D in this Sikh cohort. However, linkage analysis for lipid traits using QTL-ALL analysis revealed promising linkage signals with p≤0.005 for total cholesterol, LDL cholesterol, and HDL cholesterol at chromosomes 5p15, 9q21, 10p11, 10q21, and 22q13. The most significant signal (p = 0.0011 occurred at 10q21.2 for HDL cholesterol. We also observed linkage signals for total cholesterol at 22q13.32 (p = 0.0016 and 5p15.33 (p = 0.0031 and for LDL cholesterol at 10p11.23 (p = 0.0045. Interestingly, some of linkage regions identified in this Sikh population coincide with plausible candidate genes reported in recent genome-wide association and meta-analysis studies for lipid traits. Our study provides the first evidence of linkage for loci associated with quantitative lipid traits at four chromosomal regions in this Asian Indian population from Punjab. More detailed examination of these regions with more informative genotyping, sequencing, and functional studies should lead to rapid detection of novel targets of therapeutic importance.

  12. Genome-wide characterization and linkage mapping of simple sequence repeats in mei (Prunus mume Sieb. et Zucc..

    Directory of Open Access Journals (Sweden)

    Lidan Sun

    Full Text Available Because of its popularity as an ornamental plant in East Asia, mei (Prunus mume Sieb. et Zucc. has received increasing attention in genetic and genomic research with the recent shotgun sequencing of its genome. Here, we performed the genome-wide characterization of simple sequence repeats (SSRs in the mei genome and detected a total of 188,149 SSRs occurring at a frequency of 794 SSR/Mb. Mononucleotide repeats were the most common type of SSR in genomic regions, followed by di- and tetranucleotide repeats. Most of the SSRs in coding sequences (CDS were composed of tri- or hexanucleotide repeat motifs, but mononucleotide repeats were always the most common in intergenic regions. Genome-wide comparison of SSR patterns among the mei, strawberry (Fragaria vesca, and apple (Malus×domestica genomes showed mei to have the highest density of SSRs, slightly higher than that of strawberry (608 SSR/Mb and almost twice as high as that of apple (398 SSR/Mb. Mononucleotide repeats were the dominant SSR motifs in the three Rosaceae species. Using 144 SSR markers, we constructed a 670 cM-long linkage map of mei delimited into eight linkage groups (LGs, with an average marker distance of 5 cM. Seventy one scaffolds covering about 27.9% of the assembled mei genome were anchored to the genetic map, depending on which the macro-colinearity between the mei genome and Prunus T×E reference map was identified. The framework map of mei constructed provides a first step into subsequent high-resolution genetic mapping and marker-assisted selection for this ornamental species.

  13. Genome-Wide Analysis of Human MicroRNA Stability

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    Yang Li

    2013-01-01

    Full Text Available Increasing studies have shown that microRNA (miRNA stability plays important roles in physiology. However, the global picture of miRNA stability remains largely unknown. Here, we had analyzed genome-wide miRNA stability across 10 diverse cell types using miRNA arrays. We found that miRNA stability shows high dynamics and diversity both within individual cells and across cell types. Strikingly, we observed a negative correlation between miRNA stability and miRNA expression level, which is different from current findings on other biological molecules such as proteins and mRNAs that show positive and not negative correlations between stability and expression level. This finding indicates that miRNA has a distinct action mode, which we called “rapid production, rapid turnover; slow production, slow turnover.” This mode further suggests that high expression miRNAs normally degrade fast and may endow the cell with special properties that facilitate cellular status-transition. Moreover, we revealed that the stability of miRNAs is affected by cohorts of factors that include miRNA targets, transcription factors, nucleotide content, evolution, associated disease, and environmental factors. Together, our results provided an extensive description of the global landscape, dynamics, and distinct mode of human miRNA stability, which provide help in investigating their functions in physiology and pathophysiology.

  14. Genome-wide and fine-resolution association analysis of malaria in West Africa

    OpenAIRE

    Jallow, Muminatou; Teo, Yik Ying; Kerrin S Small; Kirk A Rockett; Deloukas, Panos; Taane G Clark; Kivinen, Katja; Kalifa A Bojang; Conway, David J.; Pinder, Margaret; Sirugo, Giorgio; Sisay-Joof, Fatou; Usen, Stanley; Auburn, Sarah; Suzannah J Bumpstead

    2009-01-01

    We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible sol...

  15. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

    OpenAIRE

    Stahl, Eli A; Raychaudhuri, Soumya; Remmers, Elaine F.; Xie, Gang; Eyre, Stephen; Thomson, Brian P.; Li, Yonghong; Kurreeman, Fina A. S.; Zhernakova, Alexandra; Hinks, Anne; Guiducci, Candace; Chen, Robert; Alfredsson, Lars; Amos, Christopher I.; Ardlie, Kristin G.

    2010-01-01

    To identify novel genetic risk factors for rheumatoid arthritis (RA), we conducted a genome-wide association study (GWAS) meta-analysis of 5,539 autoantibody positive RA cases and 20,169 controls of European descent, followed by replication in an independent set of 6,768 RA cases and 8,806 controls. Of 34 SNPs selected for replication, 7 novel RA risk alleles were identified at genome-wide significance (P

  16. A genome-wide 20 K citrus microarray for gene expression analysis

    OpenAIRE

    Martinez-Godoy, M Angeles; Mauri, Nuria; Juarez, Jose; Marques, M Carmen; Santiago, Julia; Forment, Javier; Gadea, Jose

    2008-01-01

    Background Understanding of genetic elements that contribute to key aspects of citrus biology will impact future improvements in this economically important crop. Global gene expression analysis demands microarray platforms with a high genome coverage. In the last years, genome-wide EST collections have been generated in citrus, opening the possibility to create new tools for functional genomics in this crop plant. Results We have designed and constructed a publicly available genome-wide cDNA...

  17. Identifying Loci for the Overlap between Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Using a Genome-Wide QTL Linkage Approach

    Science.gov (United States)

    Nijmeijer, Judith S.; Arias-Vasquez, Alejandro; Rommelse, Nanda N. J.; Altink, Marieke E.; Anney, Richard J. L.; Asherson, Philip; Banaschewski, Tobias; Buschgens, Cathelijne J. M.; Fliers, Ellen A.; Gill, Michael; Minderaa, Ruud B.; Poustka, Luise; Sergeant, Joseph A.; Buitelaar, Jan K.; Franke, Barbara; Ebstein, Richard P.; Miranda, Ana; Mulas, Fernando; Oades, Robert D.; Roeyers, Herbert; Rothenberger, Aribert; Sonuga-Barke, Edmund J. S.; Steinhausen, Hans-Christoph; Faraone, Stephen V.; Hartman, Catharina A.; Hoekstra, Pieter J.

    2010-01-01

    Objective: The genetic basis for autism spectrum disorder (ASD) symptoms in children with attention-deficit/hyperactivity disorder (ADHD) was addressed using a genome-wide linkage approach. Method: Participants of the International Multi-Center ADHD Genetics study comprising 1,143 probands with ADHD and 1,453 siblings were analyzed. The total and…

  18. Identifying Loci for the Overlap Between Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder Using a Genome-wide QTL Linkage Approach

    NARCIS (Netherlands)

    Nijmeijer, Judith S.; Arias-Vasquez, Alejandro; Rommelse, Nanda N. J.; Altink, Marieke E.; Anney, Richard J. L.; Asherson, Philip; Banaschewski, Tobias; Buschgens, Cathelijne J. M.; Fliers, Ellen A.; Gill, Michael; Minderaa, Ruud B.; Poustka, Luise; Sergeant, Joseph A.; Buitelaar, Jan K.; Franke, Barbara; Ebstein, Richard P.; Miranda, Ana; Mulas, Fernando; Oades, Robert D.; Roeyers, Herbert; Rothenberger, Aribert; Sonuga-Barke, Edmund J. S.; Steinhausen, Hans-Christoph; Faraone, Stephen. V.; Hartman, Catharina A.; Hoekstra, Pieter J.

    Objective: The genetic basis for autism spectrum disorder (ASD) symptoms in children with attention-deficit/hyperactivity disorder (ADHD) was addressed using a genome-wide linkage approach. Method: Participants of the International Multi-Center ADHD Genetics study comprising 1,143 probands with ADHD

  19. BioMet Toolbox: genome-wide analysis of metabolism

    DEFF Research Database (Denmark)

    Cvijovic, M.; Olivares Hernandez, Roberto; Agren, R.

    2010-01-01

    models. Systematic analysis of biological processes by means of modelling and simulations has made the identification of metabolic networks and prediction of metabolic capabilities under different conditions possible. For facilitating such systemic analysis, we have developed the BioMet Toolbox, a web......-based resource for stoichiometric analysis and for integration of transcriptome and interactome data, thereby exploiting the capabilities of genome-scale metabolic models. The BioMet Toolbox provides an effective user-friendly way to perform linear programming simulations towards maximized or minimized growth...... rates, substrate uptake rates and metabolic production rates by detecting relevant fluxes, simulate single and double gene deletions or detect metabolites around which major transcriptional changes are concentrated. These tools can be used for high-throughput in silico screening and allows fully...

  20. BioMet Toolbox: genome-wide analysis of metabolism

    OpenAIRE

    Cvijovic, M.; R. Olivares-Hernandez; Agren, R.; Dahr, N.; Vongsangnak, W.; Nookaew, I.; K. R. Patil; Nielsen, J.

    2010-01-01

    The rapid progress of molecular biology tools for directed genetic modifications, accurate quantitative experimental approaches, high-throughput measurements, together with development of genome sequencing has made the foundation for a new area of metabolic engineering that is driven by metabolic models. Systematic analysis of biological processes by means of modelling and simulations has made the identification of metabolic networks and prediction of metabolic capabilities under different co...

  1. Genome-wide analysis of promoter architecture in Drosophila melanogaster

    Energy Technology Data Exchange (ETDEWEB)

    Hoskins, Roger A.; Landolin, Jane M.; Brown, James B.; Sandler, Jeremy E.; Takahashi, Hazuki; Lassmann, Timo; Yu, Charles; Booth, Benjamin W.; Zhang, Dayu; Wan, Kenneth H.; Yang, Li; Boley, Nathan; Andrews, Justen; Kaufman, Thomas C.; Graveley, Brenton R.; Bickel, Peter J.; Carninci, Piero; Carlson, Joseph W.; Celniker, Susan E.

    2010-10-20

    Core promoters are critical regions for gene regulation in higher eukaryotes. However, the boundaries of promoter regions, the relative rates of initiation at the transcription start sites (TSSs) distributed within them, and the functional significance of promoter architecture remain poorly understood. We produced a high-resolution map of promoters active in the Drosophila melanogaster embryo by integrating data from three independent and complementary methods: 21 million cap analysis of gene expression (CAGE) tags, 1.2 million RNA ligase mediated rapid amplification of cDNA ends (RLMRACE) reads, and 50,000 cap-trapped expressed sequence tags (ESTs). We defined 12,454 promoters of 8037 genes. Our analysis indicates that, due to non-promoter-associated RNA background signal, previous studies have likely overestimated the number of promoter-associated CAGE clusters by fivefold. We show that TSS distributions form a complex continuum of shapes, and that promoters active in the embryo and adult have highly similar shapes in 95% of cases. This suggests that these distributions are generally determined by static elements such as local DNA sequence and are not modulated by dynamic signals such as histone modifications. Transcription factor binding motifs are differentially enriched as a function of promoter shape, and peaked promoter shape is correlated with both temporal and spatial regulation of gene expression. Our results contribute to the emerging view that core promoters are functionally diverse and control patterning of gene expression in Drosophila and mammals.

  2. Genome wide analysis of blood pressure variability and ischemic stroke

    Science.gov (United States)

    Khan, Muhammad S; Nalls, Michael A; Bevan, Steve; Cheng, Yu-Ching; Chen, Wei-Min; Malik, Rainer; McCarthy, Nina S; Holliday, Elizabeth G; Speed, Douglas; Hasan, Nazeeha; Pucek, Mateusz; Rinne, Paul E.; Sever, Peter; Stanton, Alice; Shields, Denis C; Maguire, Jane M; McEvoy, Mark; Scott, Rodney J; Ferrucci, Luigi; Macleod, Mary J; Attia, John; Markus, Hugh S; Sale, Michele M; Worrall, Bradford B; Mitchell, Braxton D; Dichgans, Martin; Sudlow, Cathy; Meschia, James F; Rothwell, Peter M

    2013-01-01

    Background and Purpose Visit-to-visit variability in BP is associated with ischemic stroke. We sought to determine whether such variability has a genetic aetiology and whether genetic variants associated with BP variability are also associated with ischemic stroke. Methods A GWAS for loci influencing BP variability was undertaken in 3,802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study where long-term visit-to-visit and within visit BP measures were available. Since BP variability is strongly associated with ischemic stroke, we genotyped the sentinel SNP in an independent ischemic stroke population comprising of 8,624 cases and 12,722 controls and in 3,900 additional (Scandinavian) participants from the ASCOT study in order to replicate our findings. Results The ASCOT discovery GWAS identified a cluster of 17 correlated SNPs within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 (p=1.4×10−8). Conditional analysis on rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in ischemic stroke patients found no association for overall stroke (OR 1.02; 95% CI 0.97-1.07; p=0.52) or its sub-types: CE (OR 1.07; 95% CI 0.97-1.16; p=0.17), LVD (OR 0.98; 95% 0.89-1.07; p=0.60) and SVD (OR 1.07; 95% CI 0.97-1.17; p=0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants (p=0.18). Conclusions We identified a cluster of SNPs at the NLGN1 locus showing significant association with BP variability. Follow up analyses did not support an association with risk of ischemic stroke and its subtypes. PMID:23929743

  3. Genome wide linkage study, using a 250K SNP map, of Plasmodium falciparum infection and mild malaria attack in a Senegalese population.

    Directory of Open Access Journals (Sweden)

    Jacqueline Milet

    Full Text Available Multiple factors are involved in the variability of host's response to P. falciparum infection, like the intensity and seasonality of malaria transmission, the virulence of parasite and host characteristics like age or genetic make-up. Although admitted nowadays, the involvement of host genetic factors remains unclear. Discordant results exist, even concerning the best-known malaria resistance genes that determine the structure or function of red blood cells. Here we report on a genome-wide linkage and association study for P. falciparum infection intensity and mild malaria attack among a Senegalese population of children and young adults from 2 to 18 years old. A high density single nucleotide polymorphisms (SNP genome scan (Affimetrix GeneChip Human Mapping 250K-nsp was performed for 626 individuals: i.e. 249 parents and 377 children out of the 504 ones included in the follow-up. The population belongs to a unique ethnic group and was closely followed-up during 3 years. Genome-wide linkage analyses were performed on four clinical and parasitological phenotypes and association analyses using the family based association tests (FBAT method were carried out in regions previously linked to malaria phenotypes in literature and in the regions for which we identified a linkage peak. Analyses revealed three strongly suggestive evidences for linkage: between mild malaria attack and both the 6p25.1 and the 12q22 regions (empirical p-value=5x10(-5 and 9x10(-5 respectively, and between the 20p11q11 region and the prevalence of parasite density in asymptomatic children (empirical p-value=1.5x10(-4. Family based association analysis pointed out one significant association between the intensity of plasmodial infection and a polymorphism located in ARHGAP26 gene in the 5q31-q33 region (p-value=3.7x10(-5. This study identified three candidate regions, two of them containing genes that could point out new pathways implicated in the response to malaria infection

  4. Genome-wide analysis of TCP family in tobacco.

    Science.gov (United States)

    Chen, L; Chen, Y Q; Ding, A M; Chen, H; Xia, F; Wang, W F; Sun, Y H

    2016-05-23

    The TCP family is a transcription factor family, members of which are extensively involved in plant growth and development as well as in signal transduction in the response against many physiological and biochemical stimuli. In the present study, 61 TCP genes were identified in tobacco (Nicotiana tabacum) genome. Bioinformatic methods were employed for predicting and analyzing the gene structure, gene expression, phylogenetic analysis, and conserved domains of TCP proteins in tobacco. The 61 NtTCP genes were divided into three diverse groups, based on the division of TCP genes in tomato and Arabidopsis, and the results of the conserved domain and sequence analyses further confirmed the classification of the NtTCP genes. The expression pattern of NtTCP also demonstrated that majority of these genes play important roles in all the tissues, while some special genes exercise their functions only in specific tissues. In brief, the comprehensive and thorough study of the TCP family in other plants provides sufficient resources for studying the structure and functions of TCPs in tobacco.

  5. Genome-wide linkage study suggests a susceptibility locus for isolated bilateral microtia on 4p15.32-4p16.2.

    Directory of Open Access Journals (Sweden)

    Xin Li

    Full Text Available Microtia is a congenital deformity where the external ear is underdeveloped. Genetic investigations have identified many susceptibility genes of microtia-related syndromes. However, no causal genes were reported for isolated microtia, the main form of microtia. We conducted a genome-wide linkage analysis on a 5-generation Chinese pedigree with isolated bilateral microtia. We identified a suggestive linkage locus on 4p15.32-4p16.2 with parametric LOD score of 2.70 and nonparametric linkage score (Zmean of 12.28 (simulated occurrence per genome scan equal to 0.46 and 0.47, respectively. Haplotype reconstruction analysis of the 4p15.32-4p16.2 region further confined the linkage signal to a 10-Mb segment located between rs12505562 and rs12649803 (9.65-30.24 cM; 5.54-15.58 Mb. Various human organ developmental genes reside in this 10-Mb susceptibility region, such as EVC, EVC2, SLC2A9, NKX3-2, and HMX1. The coding regions of three genes, EVC known for cartilage development and NKX3-2, HMX1 involved in microtia, were selected for sequencing with 5 individuals from the pedigree. Of the 38 identified sequence variants, none segregates along with the disease phenotype. Other genes or DNA sequences of the 10-Mb region warrant for further investigation. In conclusion, we report a susceptibility locus of isolated microtia, and this finding will encourage future studies on the genetic basis of ear deformity.

  6. Genome-wide linkage study suggests a susceptibility locus for isolated bilateral microtia on 4p15.32-4p16.2.

    Science.gov (United States)

    Li, Xin; Hu, Jintian; Zhang, Jiao; Jin, Qian; Wang, Duen-Mei; Yu, Jun; Zhang, Qingguo; Zhang, Yong-Biao

    2014-01-01

    Microtia is a congenital deformity where the external ear is underdeveloped. Genetic investigations have identified many susceptibility genes of microtia-related syndromes. However, no causal genes were reported for isolated microtia, the main form of microtia. We conducted a genome-wide linkage analysis on a 5-generation Chinese pedigree with isolated bilateral microtia. We identified a suggestive linkage locus on 4p15.32-4p16.2 with parametric LOD score of 2.70 and nonparametric linkage score (Zmean) of 12.28 (simulated occurrence per genome scan equal to 0.46 and 0.47, respectively). Haplotype reconstruction analysis of the 4p15.32-4p16.2 region further confined the linkage signal to a 10-Mb segment located between rs12505562 and rs12649803 (9.65-30.24 cM; 5.54-15.58 Mb). Various human organ developmental genes reside in this 10-Mb susceptibility region, such as EVC, EVC2, SLC2A9, NKX3-2, and HMX1. The coding regions of three genes, EVC known for cartilage development and NKX3-2, HMX1 involved in microtia, were selected for sequencing with 5 individuals from the pedigree. Of the 38 identified sequence variants, none segregates along with the disease phenotype. Other genes or DNA sequences of the 10-Mb region warrant for further investigation. In conclusion, we report a susceptibility locus of isolated microtia, and this finding will encourage future studies on the genetic basis of ear deformity.

  7. Genome-wide DNA methylation analysis in permanent atrial fibrillation.

    Science.gov (United States)

    Zhao, Guochang; Zhou, Jian; Gao, Jie; Liu, Yan; Gu, Song; Zhang, Xitao; Su, Pixiong

    2017-10-01

    Atrial fibrillation (AF) is a highly heterogeneous genetic disease; however, the pathogenesis of AF cannot be explained by genetic variants alone. DNA methylation is a heritable method of gene expression regulation, and may be a potential regulatory mechanism in AF. Therefore, in the present study, the genome‑wide DNA methylation pattern in cells derived from the left atrium of patients with permanent AF (n=7) was compared with that of healthy heart donors (n=4) with a normal sinus rhythm (SR). Enriched biological functions of the differentially methylated genes were assessed. Integrated analysis of genome‑wide methylation and mRNA expression profiles was performed, and reverse transcription quantitative‑polymerase chain reaction (RT‑qPCR) was used to determine the expression levels of four selected genes. A total of 417 differentially methylated CpG sites were identified in the fibrillating atrium (P0.17); the majority of which were located in gene‑body and intergenic regions outside of CpG islands. Aberrantly methylated genes participated in the activation of inflammation, sodium and potassium ion transport, fibrosis and the reduction of lipid metabolism. Hypermethylation in the AF susceptible loci, paired‑like homeodomain transcription factor 2 (chromosome 4q25) and coiled‑coil domain containing 141 (chromosome 2q31), as well as hypomethylation in the calcium voltage‑gated channel subunit α1C (chromosome 12p13) locus, were identified in all patients with AF. Of the 420 upregulated and 567 downregulated genes previously identified in patients with AF relative to those with normal SR (fold‑change >2.0; P≤0.05), 12 genes were hypomethylated and eight genes were hypermethylated in each group, respectively (|β|>0.2: Peffect of DNA methylation on gene expression. These results suggest that DNA methylation‑mediated regulation of gene expression may serve an important role in AF pathogenesis, and several susceptible AF CpG loci were

  8. An across-breed genome wide association analysis of susceptibility to paratuberculosis in dairy cattle.

    Science.gov (United States)

    Sallam, Ahmed M; Zare, Yalda; Alpay, Fazli; Shook, George E; Collins, Michael T; Alsheikh, Samir; Sharaby, Mahmoud; Kirkpatrick, Brian W

    2017-02-01

    Paratuberculosis is a chronic disease of ruminants caused by Mycobacterium avium subspecies paratuberculosis (MAP). It occurs worldwide and causes a significant loss in the animal production industry. There is no cure for MAP infection and vaccination is problematic. Identification of genetics of susceptibility could be a useful adjunct for programs that focus on management, testing and culling of diseased animals. A case-control, genome-wide association study (GWAS) was conducted using Holstein and Jersey cattle in a combined analysis in order to identify markers and chromosomal regions associated with susceptibility to MAP infection across-breed. A mixed-model method (GRAMMAR-GC) implemented in the GenABEL R package and a Bayes C analysis implemented in GenSel software were used as alternative approaches to conduct GWAS analysis focused on single SNPs and chromosomal segments, respectively. After conducting quality control, 22 406 SNPs from 2157 individuals were available for the GRAMMAR-GC (Bayes C) analysis and 45 640 SNPs from 2199 individuals were available for the Bayes C analysis. One SNP located on BTA27 (8·6 Mb) was identified as moderately associated (P < 5 × 10-5, FDR = 0·44) in the GRAMMAR-GC analysis of the combined breed data. Nine 1 Mb windows located on BTA 2, 3 (3 windows), 6, 8, 25, 27 and 29 each explained ≥1% of the total proportion of genetic variance in the Bayes C analysis. In an analysis ignoring differences in linkage phase, two moderately significantly associated SNPs were identified; ARS-BFGL-NGS-19381 on BTA23 (32 Mb) and Hapmap40994-BTA-46361 on BTA19 (61 Mb). New common genomic regions and candidate genes have been identified from the across-breed analysis that might be involved in the immune response and susceptibility to MAP infection.

  9. A genome-wide linkage and association scan reveals novel loci for hypertension and blood pressure traits.

    Directory of Open Access Journals (Sweden)

    Youling Guo

    Full Text Available Hypertension is caused by the interaction of environmental and genetic factors. The condition which is very common, with about 18% of the adult Hong Kong Chinese population and over 50% of older individuals affected, is responsible for considerable morbidity and mortality. To identify genes influencing hypertension and blood pressure, we conducted a combined linkage and association study using over 500,000 single nucleotide polymorphisms (SNPs genotyped in 328 individuals comprising 111 hypertensive probands and their siblings. Using a family-based association test, we found an association with SNPs on chromosome 5q31.1 (rs6596140; P<9 × 10(-8 for hypertension. One candidate gene, PDC, was replicated, with rs3817586 on 1q31.1 attaining P = 2.5 × 10(-4 and 2.9 × 10(-5 in the within-family tests for DBP and MAP, respectively. We also identified regions of significant linkage for systolic and diastolic blood pressure on chromosomes 2q22 and 5p13, respectively. Further family-based association analysis of the linkage peak on chromosome 5 yielded a significant association (rs1605685, P<7 × 10(-5 for DBP. This is the first combined linkage and association study of hypertension and its related quantitative traits with Chinese ancestry. The associations reported here account for the action of common variants whereas the discovery of linkage regions may point to novel targets for rare variant screening.

  10. A genome-wide linkage and association scan reveals novel loci for hypertension and blood pressure traits.

    Science.gov (United States)

    Guo, Youling; Tomlinson, Brian; Chu, Tanya; Fang, Yu Jing; Gui, Hongsheng; Tang, Clara S; Yip, Benjamin H; Cherny, Stacey S; Hur, Yoon-Mi; Sham, Pak Chung; Lam, Tai Hing; Thomas, Neil G

    2012-01-01

    Hypertension is caused by the interaction of environmental and genetic factors. The condition which is very common, with about 18% of the adult Hong Kong Chinese population and over 50% of older individuals affected, is responsible for considerable morbidity and mortality. To identify genes influencing hypertension and blood pressure, we conducted a combined linkage and association study using over 500,000 single nucleotide polymorphisms (SNPs) genotyped in 328 individuals comprising 111 hypertensive probands and their siblings. Using a family-based association test, we found an association with SNPs on chromosome 5q31.1 (rs6596140; Ppressure on chromosomes 2q22 and 5p13, respectively. Further family-based association analysis of the linkage peak on chromosome 5 yielded a significant association (rs1605685, Prelated quantitative traits with Chinese ancestry. The associations reported here account for the action of common variants whereas the discovery of linkage regions may point to novel targets for rare variant screening.

  11. A genome-wide linkage and association study of musical aptitude identifies loci containing genes related to inner ear development and neurocognitive functions

    Science.gov (United States)

    Oikkonen, J.; Huang, Y.; Onkamo, P.; Ukkola-Vuoti, L.; Raijas, P.; Karma, K.; Vieland, V. J.; Järvelä, I.

    2014-01-01

    Humans have developed the perception, production and processing of sounds into the art of music. A genetic contribution to these skills of musical aptitude has long been suggested. We performed a genome-wide scan in 76 pedigrees (767 individuals) characterized for the ability to discriminate pitch (SP), duration (ST) and sound patterns (KMT), which are primary capacities for music perception. Using the Bayesian linkage and association approach implemented in program package KELVIN, especially designed for complex pedigrees, several SNPs near genes affecting the functions of the auditory pathway and neurocognitive processes were identified. The strongest association was found at 3q21.3 (rs9854612) with combined SP, ST and KMT test scores (COMB). This region is located a few dozen kilobases upstream of the GATA binding protein 2 (GATA2) gene. GATA2 regulates the development of cochlear hair cells and the inferior colliculus (IC), which are important in tonotopic mapping. The highest probability of linkage was obtained for phenotype SP at 4p14, located next to the region harboring the protocadherin 7 gene, PCDH7. Two SNPs rs13146789 and rs13109270 of PCDH7 showed strong association. PCDH7 has been suggested to play a role in cochlear and amygdaloid complexes. Functional class analysis showed that inner ear and schizophrenia related genes were enriched inside the linked regions. This study is the first to show the importance of auditory pathway genes in musical aptitude. PMID:24614497

  12. Genome-wide identification and analysis of the MADS-box gene family in sesame.

    Science.gov (United States)

    Wei, Xin; Wang, Linhai; Yu, Jingyin; Zhang, Yanxin; Li, Donghua; Zhang, Xiurong

    2015-09-10

    MADS-box genes encode transcription factors that play crucial roles in plant growth and development. Sesame (Sesamum indicum L.) is an oil crop that contributes to the daily oil and protein requirements of almost half of the world's population; therefore, a genome-wide analysis of the MADS-box gene family is needed. Fifty-seven MADS-box genes were identified from 14 linkage groups of the sesame genome. Analysis of phylogenetic relationships with Arabidopsis thaliana, Utricularia gibba and Solanum lycopersicum MADS-box genes was performed. Sesame MADS-box genes were clustered into four groups: 28 MIKC(c)-type, 5 MIKC(⁎)-type, 14 Mα-type and 10 Mγ-type. Gene structure analysis revealed from 1 to 22 exons of sesame MADS-box genes. The number of exons in type II MADS-box genes greatly exceeded the number in type I genes. Motif distribution analysis of sesame MADS-box genes also indicated that type II MADS-box genes contained more motifs than type I genes. These results suggested that type II sesame MADS-box genes had more complex structures. By analyzing expression profiles of MADS-box genes in seven sesame transcriptomes, we determined that MIKC(C)-type MADS-box genes played significant roles in sesame flower and seed development. Although most MADS-box genes in the same clade showed similar expression features, some gene functions were diversified from the orthologous Arabidopsis genes. This research will contribute to uncovering the role of MADS-box genes in sesame development. Copyright © 2015 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

    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 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 (I2 = 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. PMID:17332845

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

    Science.gov (United States)

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

    2007-02-07

    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. 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). 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.

  15. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

    NARCIS (Netherlands)

    Stahl, Eli A.; Raychaudhuri, Soumya; Remmers, Elaine F.; Xie, Gang; Eyre, Stephen; Thomson, Brian P.; Li, Yonghong; Kurreeman, Fina A. S.; Zhernakova, Alexandra; Hinks, Anne; Guiducci, Candace; Chen, Robert; Alfredsson, Lars; Amos, Christopher I.; Ardlie, Kristin G.; Barton, Anne; Bowes, John; Brouwer, Elisabeth; Burtt, Noel P.; Catanese, Joseph J.; Coblyn, Jonathan; Coenen, Marieke J. H.; Costenbader, Karen H.; Criswell, Lindsey A.; Crusius, J. Bart A.; Cui, Jing; de Bakker, Paul I. W.; De Jager, Philip L.; Ding, Bo; Emery, Paul; Flynn, Edward; Harrison, Pille; Hocking, Lynne J.; Huizinga, Tom W. J.; Kastner, Daniel L.; Ke, Xiayi; Lee, Annette T.; Liu, Xiangdong; Martin, Paul; Morgan, Ann W.; Padyukov, Leonid; Posthumus, Marcel D.; Radstake, Timothy R. D. J.; Reid, David M.; Seielstad, Mark; Seldin, Michael F.; Shadick, Nancy A.; Steer, Sophia; Tak, Paul P.; Thomson, Wendy; van der Helm-van Mil, Annette H. M.; van der Horst-Bruinsma, Irene E.; van der Schoot, C. Ellen; van Riel, Piet L. C. M.; Weinblatt, Michael E.; Wilson, Anthony G.; Wolbink, Gert Jan; Wordsworth, B. Paul; Wijmenga, Cisca; Karlson, Elizabeth W.; Toes, Rene E. M.; de Vries, Niek; Begovich, Ann B.; Worthington, Jane; Siminovitch, Katherine A.; Gregersen, Peter K.; Klareskog, Lars; Plenge, Robert M.

    2010-01-01

    To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheum

  16. Genome-wide meta-analysis identifies new susceptibility loci for migraine

    NARCIS (Netherlands)

    Anttila, Verneri; Winsvold, Bendik S.; Gormley, Padhraig; Kurth, Tobias; Bettella, Francesco; McMahon, George; Kallela, Mikko; Malik, Rainer; de Vries, Boukje; Terwindt, Gisela; Medland, Sarah E.; Todt, Unda; McArdle, Wendy L.; Quaye, Lydia; Koiranen, Markku; Ikram, M. Arfan; Lehtimaki, Terho; Stam, Anine H.; Ligthart, Lannie; Wedenoja, Juho; Dunham, Ian; Neale, Benjamin M.; Palta, Priit; Hamalainen, Eija; Schuerks, Markus; Rose, Lynda M.; Buring, Julie E.; Ridker, Paul M.; Steinberg, Stacy; Stefansson, Hreinn; Jakobsson, Finnbogi; Lawlor, Debbie A.; Evans, David M.; Ring, Susan M.; Farkkila, Markus; Artto, Ville; Kaunisto, Mari A.; Freilinger, Tobias; Schoenen, Jean; Frants, Rune R.; Pelzer, Nadine; Weller, Claudia M.; Zielman, Ronald; Heath, Andrew C.; Madden, Pamela A. F.; Montgomery, Grant W.; Martin, Nicholas G.; Borck, Guntram; Goebel, Hartmut; Heinze, Axel; Heinze-Kuhn, Katja; Williams, Frances M. K.; Hartikainen, Anna-Liisa; Pouta, Anneli; van den Ende, Joyce; Uitterlinden, Andre G.; Hofman, Albert; Amin, Najaf; Hottenga, Jouke-Jan; Vink, Jacqueline M.; Heikkila, Kauko; Alexander, Michael; Muller-Myhsok, Bertram; Schreiber, Stefan; Meitinger, Thomas; Wichmann, Heinz Erich; Aromaa, Arpo; Eriksson, Johan G.; Traynor, Bryan J.; Trabzuni, Daniah; Rossin, Elizabeth; Lage, Kasper; Jacobs, Suzanne B. R.; Gibbs, J. Raphael; Birney, Ewan; Kaprio, Jaakko; Penninx, Brenda W.; Boomsma, Dorret I.; van Duijn, Cornelia; Raitakari, Olli; Jarvelin, Marjo-Riitta; Zwart, John-Anker; Cherkas, Lynn; Strachan, David P.; Kubisch, Christian; Ferrari, Michel D.; van den Maagdenberg, Arn M. J. M.; Dichgans, Martin; Wessman, Maija; Smith, George Davey; Stefansson, Kari; Daly, Mark J.; Nyholt, Dale R.; Chasman, Daniel I.; Palotie, Aarno

    2013-01-01

    Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 9

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

    NARCIS (Netherlands)

    Berndt, Sonja I; Camp, Nicola J; Skibola, Christine F; Vijai, Joseph; Wang, Zhaoming; Gu, Jian; Nieters, Alexandra; Kelly, Rachel S; Smedby, Karin E; Monnereau, Alain; Cozen, Wendy; Cox, Angela; Wang, Sophia S; Lan, Qing; Teras, Lauren R; Machado, Moara; Yeager, Meredith; Brooks-Wilson, Angela R; Hartge, Patricia; Purdue, Mark P; Birmann, Brenda M; Vajdic, Claire M; Cocco, Pierluigi; Zhang, Yawei; Giles, Graham G; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Montalvan, Rebecca; Burdett, Laurie; Hutchinson, Amy; Ye, Yuanqing; Call, Timothy G; Shanafelt, Tait D; Novak, Anne J; Kay, Neil E; Liebow, Mark; Cunningham, Julie M; Allmer, Cristine; Hjalgrim, Henrik; Adami, Hans-Olov; Melbye, Mads; Glimelius, Bengt; Chang, Ellen T; Glenn, Martha; Curtin, Karen; Cannon-Albright, Lisa A; Diver, W Ryan; Link, Brian K; Weiner, George J; Conde, Lucia; Bracci, Paige M; Riby, Jacques; Arnett, Donna K; Zhi, Degui; Leach, Justin M; Holly, Elizabeth A; Jackson, Rebecca D; Tinker, Lesley F; Benavente, Yolanda; Sala, Núria; Casabonne, Delphine; Becker, Nikolaus; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; McKay, James; Staines, Anthony; Chaffee, Kari G; Achenbach, Sara J; Vachon, Celine M; Goldin, Lynn R; Strom, Sara S; Leis, Jose F; Weinberg, J Brice; Caporaso, Neil E; Norman, Aaron D; De Roos, Anneclaire J; Morton, Lindsay M; Severson, Richard K; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Masala, Giovanna; Weiderpass, Elisabete; Chirlaque, María-Dolores; Vermeulen, Roel C H|info:eu-repo/dai/nl/216532620; Travis, Ruth C; Southey, Melissa C; Milne, Roger L; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Clavel, Jacqueline; Zheng, Tongzhang; Holford, Theodore R; Villano, Danylo J; Maria, Ann; Spinelli, John J; Gascoyne, Randy D; Connors, Joseph M; Bertrand, Kimberly A; Giovannucci, Edward; Kraft, Peter; Kricker, Anne; Turner, Jenny; Ennas, Maria Grazia; Ferri, Giovanni M; Miligi, Lucia; Liang, Liming; Ma, Baoshan; Huang, Jinyan; Crouch, Simon; Park, Ju-Hyun; Chatterjee, Nilanjan; North, Kari E; Snowden, John A; Wright, Josh; Fraumeni, Joseph F; Offit, Kenneth; Wu, Xifeng; de Sanjose, Silvia; Cerhan, James R; Chanock, Stephen J; Rothman, Nathaniel; Slager, Susan L

    2016-01-01

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

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

    NARCIS (Netherlands)

    Melum, Espen; Franke, Andre; Schramm, Christoph; Weismueller, Tobias J.; Gotthardt, Daniel Nils; Offner, Felix A.; Juran, Brian D.; Laerdahl, Jon K.; Labi, Verena; Bjoernsson, 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, Bjoern; 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.

    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

  19. 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.

    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

  20. 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); 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 (Cock); 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)

  1. 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.; Magi, 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.; Rooij, F.J. van; 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., Jr.; 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.; Doring, 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.; Tonjes, 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.; Hypponen, E.; Jarvelin, M.R.; Cupples, L.A.; Franks, P.W.; Ridker, P.M.; Duijn, C.M. van; Heiss, G.; Metspalu, A.; North, K.E.; Ingelsson, E.; Nettleton, J.A.; Dam, R.M. van; 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

  2. Genome-wide Association Analysis of Kernel Weight in Hard Winter Wheat

    Science.gov (United States)

    Wheat kernel weight is an important and heritable component of wheat grain yield and a key predictor of flour extraction. Genome-wide association analysis was conducted to identify genomic regions associated with kernel weight and kernel weight environmental response in 8 trials of 299 hard winter ...

  3. 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

  4. A mega-analysis of genome-wide association studies for major depressive disorder

    NARCIS (Netherlands)

    Sullivan, Patrick F.; Daly, Mark J.; Ripke, Stephan; Lewis, Cathryn M.; Lin, Dan-Yu; Wray, Naomi R.; Neale, Benjamin; Levinson, Douglas F.; Breen, Gerome; Byrne, Enda M.; Wray, Naomi R.; Levinson, Douglas F.; Rietschel, Marcella; Hoogendijk, Witte; Ripke, Stephan; Sullivan, Patrick F.; Hamilton, Steven P.; Levinson, Douglas F.; Lewis, Cathryn M.; Ripke, Stephan; Weissman, Myrna M.; Wray, Naomi R.; Breuer, Rene; Cichon, Sven; Degenhardt, Franziska; Frank, Josef; Gross, Magdalena; Herms, Stefan; Hoefels, Susanne; Maier, Wolfgang; Mattheisen, Manuel; Noeethen, Markus M.; Rietschel, Marcella; Schulze, Thomas G.; Steffens, Michael; Treutlein, Jens; Boomsma, Dorret I.; De Geus, Eco J.; Hoogendijk, Witte; Hottenga, Jouke Jan; Jung-Ying, Tzeng; Lin, Dan-Yu; Middeldorp, Christel M.; Nolen, Willem A.; Penninx, Brenda P.; Smit, Johannes H.; Sullivan, Patrick F.; van Grootheest, Gerard; Willemsen, Gonneke; Zitman, Frans G.; Coryell, William H.; Knowles, James A.; Lawson, William B.; Levinson, Douglas F.; Potash, James B.; Scheftner, William A.; Shi, Jianxin; Weissman, Myrna M.; Holsboer, Florian; Muglia, Pierandrea; Tozzi, Federica; Blackwood, Douglas H. R.; Boomsma, Dorret I.; De Geus, Eco J.; Hottenga, Jouke Jan; MacIntyre, Donald J.; McIntosh, Andrew; McLean, Alan; Middeldorp, Christel M.; Penninx, Brenda P.; Ripke, Stephan; Smit, Johannes H.; Sullivan, Patrick F.; van Grootheest, Gerard; Willemsen, Gonneke; Zitman, Frans G.; van den Oord, Edwin J. C. G.; Holsboer, Florian; Lucae, Susanne; Binder, Elisabeth; Mueller-Myhsok, Bertram; Ripke, Stephan; Czamara, Darina; Kohli, Martin A.; Ising, Marcus; Uhr, Manfred; Bettecken, Thomas; Barnes, Michael R.; Breen, Gerome; Craig, Ian W.; Farmer, Anne E.; Lewis, Cathryn M.; McGuffin, Peter; Muglia, Pierandrea; Byrne, Enda; Gordon, Scott D.; Heath, Andrew C.; Henders, Anjali K.; Hickie, Ian B.; Madden, Pamela A. F.; Martin, Nicholas G.; Montgomery, Grant M.; Nyholt, Dale R.; Pergadia, Michele L.; Wray, Naomi R.; Hamilton, Steven P.; McGrath, Patrick J.; Shyn, Stanley I.; Slager, Susan L.; Oskarsson, Hoegni; Sigurdsson, Engilbert; Stefansson, Hreinn; Stefansson, Kari; Steinberg, Stacy; Thorgeirsson, Thorgeir; Levinson, Douglas F.; Potash, James B.; Shi, Jianxin; Weissman, Myrna M.; Guipponi, Michel; Lewis, Glyn; O'Donovan, Michael; Tansey, Katherine E.; Uher, Rudolf; Coryell, William H.; Knowles, James A.; Lawson, William B.; Levinson, Douglas F.; Potash, James B.; Scheftner, William A.; Shi, Jianxin; Weissman, Myrna M.; Castro, Victor M.; Churchill, Susanne E.; Fava, Maurizio; Gainer, Vivian S.; Gallagher, Patience J.; Goryachev, Sergey; Iosifescu, Dan V.; Kohane, Isaac S.; Murphy, Shawn N.; Perlis, Roy H.; Smoller, Jordan W.; Weilburg, Jeffrey B.; Kutalik, Zoltan; Preisig, Martin; Grabe, Hans J.; Nauck, Matthias; Schulz, Andrea; Teumer, Alexander; Voelzke, Henry; Landen, Mikael; Lichtenstein, Paul; Magnusson, Patrik; Pedersen, Nancy; Viktorin, Alexander

    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

  5. 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...

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

    NARCIS (Netherlands)

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

    2016-01-01

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

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

    NARCIS (Netherlands)

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

    2015-01-01

    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 in

  8. A mega-analysis of genome-wide association studies for major depressive disorder

    NARCIS (Netherlands)

    Sullivan, Patrick F.; Daly, Mark J.; Ripke, Stephan; Lewis, Cathryn M.; Lin, Dan-Yu; Wray, Naomi R.; Neale, Benjamin; Levinson, Douglas F.; Breen, Gerome; Byrne, Enda M.; Wray, Naomi R.; Levinson, Douglas F.; Rietschel, Marcella; Hoogendijk, Witte; Ripke, Stephan; Sullivan, Patrick F.; Hamilton, Steven P.; Levinson, Douglas F.; Lewis, Cathryn M.; Ripke, Stephan; Weissman, Myrna M.; Wray, Naomi R.; Breuer, Rene; Cichon, Sven; Degenhardt, Franziska; Frank, Josef; Gross, Magdalena; Herms, Stefan; Hoefels, Susanne; Maier, Wolfgang; Mattheisen, Manuel; Noeethen, Markus M.; Rietschel, Marcella; Schulze, Thomas G.; Steffens, Michael; Treutlein, Jens; Boomsma, Dorret I.; De Geus, Eco J.; Hoogendijk, Witte; Hottenga, Jouke Jan; Jung-Ying, Tzeng; Lin, Dan-Yu; Middeldorp, Christel M.; Nolen, Willem A.; Penninx, Brenda P.; Smit, Johannes H.; Sullivan, Patrick F.; van Grootheest, Gerard; Willemsen, Gonneke; Zitman, Frans G.; Coryell, William H.; Knowles, James A.; Lawson, William B.; Levinson, Douglas F.; Potash, James B.; Scheftner, William A.; Shi, Jianxin; Weissman, Myrna M.; Holsboer, Florian; Muglia, Pierandrea; Tozzi, Federica; Blackwood, Douglas H. R.; Boomsma, Dorret I.; De Geus, Eco J.; Hottenga, Jouke Jan; MacIntyre, Donald J.; McIntosh, Andrew; McLean, Alan; Middeldorp, Christel M.; Penninx, Brenda P.; Ripke, Stephan; Smit, Johannes H.; Sullivan, Patrick F.; van Grootheest, Gerard; Willemsen, Gonneke; Zitman, Frans G.; van den Oord, Edwin J. C. G.; Holsboer, Florian; Lucae, Susanne; Binder, Elisabeth; Mueller-Myhsok, Bertram; Ripke, Stephan; Czamara, Darina; Kohli, Martin A.; Ising, Marcus; Uhr, Manfred; Bettecken, Thomas; Barnes, Michael R.; Breen, Gerome; Craig, Ian W.; Farmer, Anne E.; Lewis, Cathryn M.; McGuffin, Peter; Muglia, Pierandrea; Byrne, Enda; Gordon, Scott D.; Heath, Andrew C.; Henders, Anjali K.; Hickie, Ian B.; Madden, Pamela A. F.; Martin, Nicholas G.; Montgomery, Grant M.; Nyholt, Dale R.; Pergadia, Michele L.; Wray, Naomi R.; Hamilton, Steven P.; McGrath, Patrick J.; Shyn, Stanley I.; Slager, Susan L.; Oskarsson, Hoegni; Sigurdsson, Engilbert; Stefansson, Hreinn; Stefansson, Kari; Steinberg, Stacy; Thorgeirsson, Thorgeir; Levinson, Douglas F.; Potash, James B.; Shi, Jianxin; Weissman, Myrna M.; Guipponi, Michel; Lewis, Glyn; O'Donovan, Michael; Tansey, Katherine E.; Uher, Rudolf; Coryell, William H.; Knowles, James A.; Lawson, William B.; Levinson, Douglas F.; Potash, James B.; Scheftner, William A.; Shi, Jianxin; Weissman, Myrna M.; Castro, Victor M.; Churchill, Susanne E.; Fava, Maurizio; Gainer, Vivian S.; Gallagher, Patience J.; Goryachev, Sergey; Iosifescu, Dan V.; Kohane, Isaac S.; Murphy, Shawn N.; Perlis, Roy H.; Smoller, Jordan W.; Weilburg, Jeffrey B.; Kutalik, Zoltan; Preisig, Martin; Grabe, Hans J.; Nauck, Matthias; Schulz, Andrea; Teumer, Alexander; Voelzke, Henry; Landen, Mikael; Lichtenstein, Paul; Magnusson, Patrik; Pedersen, Nancy; Viktorin, Alexander

    2013-01-01

    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 chro

  9. 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.

    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

  10. 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 (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

  11. Methods for meta-analysis of genome-wide association studies

    Science.gov (United States)

    A limitation of many genome-wide association studies (GWA) in animal breeding is that there are many loci with small effect sizes; thus, larger sample sizes (N) are required to guarantee suitable power of detection. For increasing N, results from different GWA can be combined in a meta-analysis (MA-...

  12. Meta-analysis of genome wide association studies for pork quality traits

    Science.gov (United States)

    Given the importance of pork quality in the meat processing industry, genome-wide association studies were performed for eight meat quality traits and also, a meta-analysis (MA) of GWA was implemented combining independent results from pig populations. Data from three pig datasets (USMARC, Commercia...

  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); 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 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.; Magi, R.; Dimitriou, M.; Garcia, M.E.; Ho, W.K.; Wright, M.J.; Rose, L.M.; Magnusson, P.K.; Pedersen, N.L.; Couper, D.; Oostra, B.A.; Hofman, A.; Ikram, M.A.; Tiemeier, H.W.; Uitterlinden, A.G.; Rooij, F.J. van; 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., Jr.; 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.; Doring, 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.; Tonjes, A.; Deloukas, P.; Kanoni, S.; Lorentzon, M.; Houston, D.K.; Liu, Y.; Danesh, J.; Rasheed, A.; Bloem, B.R.; Post, B.; Scheffer, H.; Warrenburg, B.P.C. van de

    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

  15. 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 (Marjo-Riitta); 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

  16. 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.J. 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 (Marjo-Riitta); 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

  17. 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 (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

  18. A mega-analysis of genome-wide association studies for major depressive disorder

    NARCIS (Netherlands)

    Sullivan, Patrick F.; Daly, Mark J.; Ripke, Stephan; Lewis, Cathryn M.; Lin, Dan-Yu; Wray, Naomi R.; Neale, Benjamin; Levinson, Douglas F.; Breen, Gerome; Byrne, Enda M.; Wray, Naomi R.; Levinson, Douglas F.; Rietschel, Marcella; Hoogendijk, Witte; Ripke, Stephan; Sullivan, Patrick F.; Hamilton, Steven P.; Levinson, Douglas F.; Lewis, Cathryn M.; Ripke, Stephan; Weissman, Myrna M.; Wray, Naomi R.; Breuer, Rene; Cichon, Sven; Degenhardt, Franziska; Frank, Josef; Gross, Magdalena; Herms, Stefan; Hoefels, Susanne; Maier, Wolfgang; Mattheisen, Manuel; Noeethen, Markus M.; Rietschel, Marcella; Schulze, Thomas G.; Steffens, Michael; Treutlein, Jens; Boomsma, Dorret I.; De Geus, Eco J.; Hoogendijk, Witte; Hottenga, Jouke Jan; Jung-Ying, Tzeng; Lin, Dan-Yu; Middeldorp, Christel M.; Nolen, Willem A.; Penninx, Brenda P.; Smit, Johannes H.; Sullivan, Patrick F.; van Grootheest, Gerard; Willemsen, Gonneke; Zitman, Frans G.; Coryell, William H.; Knowles, James A.; Lawson, William B.; Levinson, Douglas F.; Potash, James B.; Scheftner, William A.; Shi, Jianxin; Weissman, Myrna M.; Holsboer, Florian; Muglia, Pierandrea; Tozzi, Federica; Blackwood, Douglas H. R.; Boomsma, Dorret I.; De Geus, Eco J.; Hottenga, Jouke Jan; MacIntyre, Donald J.; McIntosh, Andrew; McLean, Alan; Middeldorp, Christel M.; Penninx, Brenda P.; Ripke, Stephan; Smit, Johannes H.; Sullivan, Patrick F.; van Grootheest, Gerard; Willemsen, Gonneke; Zitman, Frans G.; van den Oord, Edwin J. C. G.; Holsboer, Florian; Lucae, Susanne; Binder, Elisabeth; Mueller-Myhsok, Bertram; Ripke, Stephan; Czamara, Darina; Kohli, Martin A.; Ising, Marcus; Uhr, Manfred; Bettecken, Thomas; Barnes, Michael R.; Breen, Gerome; Craig, Ian W.; Farmer, Anne E.; Lewis, Cathryn M.; McGuffin, Peter; Muglia, Pierandrea; Byrne, Enda; Gordon, Scott D.; Heath, Andrew C.; Henders, Anjali K.; Hickie, Ian B.; Madden, Pamela A. F.; Martin, Nicholas G.; Montgomery, Grant M.; Nyholt, Dale R.; Pergadia, Michele L.; Wray, Naomi R.; Hamilton, Steven P.; McGrath, Patrick J.; Shyn, Stanley I.; Slager, Susan L.; Oskarsson, Hoegni; Sigurdsson, Engilbert; Stefansson, Hreinn; Stefansson, Kari; Steinberg, Stacy; Thorgeirsson, Thorgeir; Levinson, Douglas F.; Potash, James B.; Shi, Jianxin; Weissman, Myrna M.; Guipponi, Michel; Lewis, Glyn; O'Donovan, Michael; Tansey, Katherine E.; Uher, Rudolf; Coryell, William H.; Knowles, James A.; Lawson, William B.; Levinson, Douglas F.; Potash, James B.; Scheftner, William A.; Shi, Jianxin; Weissman, Myrna M.; Castro, Victor M.; Churchill, Susanne E.; Fava, Maurizio; Gainer, Vivian S.; Gallagher, Patience J.; Goryachev, Sergey; Iosifescu, Dan V.; Kohane, Isaac S.; Murphy, Shawn N.; Perlis, Roy H.; Smoller, Jordan W.; Weilburg, Jeffrey B.; Kutalik, Zoltan; Preisig, Martin; Grabe, Hans J.; Nauck, Matthias; Schulz, Andrea; Teumer, Alexander; Voelzke, Henry; Landen, Mikael; Lichtenstein, Paul; Magnusson, Patrik; Pedersen, Nancy; Viktorin, Alexander

    2013-01-01

    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 chro

  19. 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

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

    NARCIS (Netherlands)

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

    2016-01-01

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

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

    NARCIS (Netherlands)

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

    2016-01-01

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

  2. Genome-wide meta-analysis identifies new susceptibility loci for migraine

    DEFF Research Database (Denmark)

    Anttila, Verneri; Winsvold, Bendik S; Gormley, Padhraig

    2013-01-01

    Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) an...

  3. Genome-wide meta-analysis identifies new susceptibility loci for migraine

    NARCIS (Netherlands)

    Anttila, Verneri; Winsvold, Bendik S.; Gormley, Padhraig; Kurth, Tobias; Bettella, Francesco; McMahon, George; Kallela, Mikko; Malik, Rainer; de Vries, Boukje; Terwindt, Gisela; Medland, Sarah E.; Todt, Unda; McArdle, Wendy L.; Quaye, Lydia; Koiranen, Markku; Ikram, M. Arfan; Lehtimaki, Terho; Stam, Anine H.; Ligthart, Lannie; Wedenoja, Juho; Dunham, Ian; Neale, Benjamin M.; Palta, Priit; Hamalainen, Eija; Schuerks, Markus; Rose, Lynda M.; Buring, Julie E.; Ridker, Paul M.; Steinberg, Stacy; Stefansson, Hreinn; Jakobsson, Finnbogi; Lawlor, Debbie A.; Evans, David M.; Ring, Susan M.; Farkkila, Markus; Artto, Ville; Kaunisto, Mari A.; Freilinger, Tobias; Schoenen, Jean; Frants, Rune R.; Pelzer, Nadine; Weller, Claudia M.; Zielman, Ronald; Heath, Andrew C.; Madden, Pamela A. F.; Montgomery, Grant W.; Martin, Nicholas G.; Borck, Guntram; Goebel, Hartmut; Heinze, Axel; Heinze-Kuhn, Katja; Williams, Frances M. K.; Hartikainen, Anna-Liisa; Pouta, Anneli; van den Ende, Joyce; Uitterlinden, Andre G.; Hofman, Albert; Amin, Najaf; Hottenga, Jouke-Jan; Vink, Jacqueline M.; Heikkila, Kauko; Alexander, Michael; Muller-Myhsok, Bertram; Schreiber, Stefan; Meitinger, Thomas; Wichmann, Heinz Erich; Aromaa, Arpo; Eriksson, Johan G.; Traynor, Bryan J.; Trabzuni, Daniah; Rossin, Elizabeth; Lage, Kasper; Jacobs, Suzanne B. R.; Gibbs, J. Raphael; Birney, Ewan; Kaprio, Jaakko; Penninx, Brenda W.; Boomsma, Dorret I.; van Duijn, Cornelia; Raitakari, Olli; Jarvelin, Marjo-Riitta; Zwart, John-Anker; Cherkas, Lynn; Strachan, David P.; Kubisch, Christian; Ferrari, Michel D.; van den Maagdenberg, Arn M. J. M.; Dichgans, Martin; Wessman, Maija; Smith, George Davey; Stefansson, Kari; Daly, Mark J.; Nyholt, Dale R.; Chasman, Daniel I.; Palotie, Aarno

    Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and

  4. On the Analysis of a Repeated Measure Design in Genome-Wide Association Analysis

    Directory of Open Access Journals (Sweden)

    Young Lee

    2014-11-01

    Full Text Available Longitudinal data enables detecting the effect of aging/time, and as a repeated measures design is statistically more efficient compared to cross-sectional data if the correlations between repeated measurements are not large. In particular, when genotyping cost is more expensive than phenotyping cost, the collection of longitudinal data can be an efficient strategy for genetic association analysis. However, in spite of these advantages, genome-wide association studies (GWAS with longitudinal data have rarely been analyzed taking this into account. In this report, we calculate the required sample size to achieve 80% power at the genome-wide significance level for both longitudinal and cross-sectional data, and compare their statistical efficiency. Furthermore, we analyzed the GWAS of eight phenotypes with three observations on each individual in the Korean Association Resource (KARE. A linear mixed model allowing for the correlations between observations for each individual was applied to analyze the longitudinal data, and linear regression was used to analyze the first observation on each individual as cross-sectional data. We found 12 novel genome-wide significant disease susceptibility loci that were then confirmed in the Health Examination cohort, as well as some significant interactions between age/sex and SNPs.

  5. Genome-wide patterns of recombination, linkage disequilibrium and nucleotide diversity from pooled resequencing and single nucleotide polymorphism genotyping unlock the evolutionary history of Eucalyptus grandis.

    Science.gov (United States)

    Silva-Junior, Orzenil B; Grattapaglia, Dario

    2015-11-01

    We used high-density single nucleotide polymorphism (SNP) data and whole-genome pooled resequencing to examine the landscape of population recombination (ρ) and nucleotide diversity (ϴw ), assess the extent of linkage disequilibrium (r(2) ) and build the highest density linkage maps for Eucalyptus. At the genome-wide level, linkage disequilibrium (LD) decayed within c. 4-6 kb, slower than previously reported from candidate gene studies, but showing considerable variation from absence to complete LD up to 50 kb. A sharp decrease in the estimate of ρ was seen when going from short to genome-wide inter-SNP distances, highlighting the dependence of this parameter on the scale of observation adopted. Recombination was correlated with nucleotide diversity, gene density and distance from the centromere, with hotspots of recombination enriched for genes involved in chemical reactions and pathways of the normal metabolic processes. The high nucleotide diversity (ϴw = 0.022) of E. grandis revealed that mutation is more important than recombination in shaping its genomic diversity (ρ/ϴw = 0.645). Chromosome-wide ancestral recombination graphs allowed us to date the split of E. grandis (1.7-4.8 million yr ago) and identify a scenario for the recent demographic history of the species. Our results have considerable practical importance to Genome Wide Association Studies (GWAS), while indicating bright prospects for genomic prediction of complex phenotypes in eucalypt breeding.

  6. Multigenic control of pod shattering resistance in Chinese rapeseed germplasm revealed by genome-wide association and linkage analyses

    Directory of Open Access Journals (Sweden)

    Jia Liu

    2016-07-01

    Full Text Available Majority of rapeseed cultivars shatter seeds upon maturity especially under hot-dry and windy conditions, reducing yield and gross margin return to growers. Here, we identified quantitative trait loci (QTL for resistance to pod shatter in unstructured diverse panel of 143 rapeseed accessions, and two structured populations derived from bi-parental doubled haploid (DH and inter-mated (IF2 crosses derived from R1 (resistant to pod shattering and R2 (prone to pod shattering accessions. Genome-wide association analysis identified six significant QTL for resistance to pod shatter located on chromosomes A01, A06, A07, A09, C02 and C05. Two of the QTL, qSRI.A09 delimited with the SNP marker Bn-A09-p30171993 (A09 and qSRI.A06 delimited with the SNP marker Bn-A06-p115948 (A06 could be repeatedly detected across environments in diversity panel, DH and IF2 populations, suggesting that at least two loci on chromosomes A06 and A09 were the main contributors to pod shatter resistance in Chinese germplasm. Significant SNP markers identified in this study especially those appeared repeatedly across environments provide a cost-effective and an efficient method for introgression and pyramiding of favorable alleles for pod shatter resistance via marker-assisted selection in rapeseed improvement programs.

  7. Genetic Diversity, Population Structure, and Linkage Disequilibrium of an Association-Mapping Panel Revealed by Genome-Wide SNP Markers in Sesame

    Science.gov (United States)

    Cui, Chengqi; Mei, Hongxian; Liu, Yanyang; Zhang, Haiyang; Zheng, Yongzhan

    2017-01-01

    The characterization of genetic diversity and population structure can be used in tandem to detect reliable phenotype–genotype associations. In the present study, we genotyped a set of 366 sesame germplasm accessions by using 89,924 single-nucleotide polymorphisms (SNPs). The number of SNPs on each chromosome was consistent with the physical length of the respective chromosome, and the average marker density was approximately 2.67 kb/SNP. The genetic diversity analysis showed that the average nucleotide diversity of the panel was 1.1 × 10-3, with averages of 1.0 × 10-4, 2.7 × 10-4, and 3.6 × 10-4 obtained, respectively for three identified subgroups of the panel: Pop 1, Pop 2, and the Mixed. The genetic structure analysis revealed that these sesame germplasm accessions were structured primarily along the basis of their geographic collection, and that an extensive admixture occurred in the panel. The genome-wide linkage disequilibrium (LD) analysis showed that an average LD extended up to ∼99 kb. The genetic diversity and population structure revealed in this study should provide guidance to the future design of association studies and the systematic utilization of the genetic variation characterizing the sesame panel. PMID:28729877

  8. Genome-wide analysis of genetic susceptibility to language impairment in an isolated Chilean population

    Science.gov (United States)

    Villanueva, Pia; Newbury, Dianne F; Jara, Lilian; De Barbieri, Zulema; Mirza, Ghazala; Palomino, Hernán M; Fernández, María Angélica; Cazier, Jean-Baptiste; Monaco, Anthony P; Palomino, Hernán

    2011-01-01

    Specific language impairment (SLI) is an unexpected deficit in the acquisition of language skills and affects between 5 and 8% of pre-school children. Despite its prevalence and high heritability, our understanding of the aetiology of this disorder is only emerging. In this paper, we apply genome-wide techniques to investigate an isolated Chilean population who exhibit an increased frequency of SLI. Loss of heterozygosity (LOH) mapping and parametric and non-parametric linkage analyses indicate that complex genetic factors are likely to underlie susceptibility to SLI in this population. Across all analyses performed, the most consistently implicated locus was on chromosome 7q. This locus achieved highly significant linkage under all three non-parametric models (max NPL=6.73, P=4.0 × 10−11). In addition, it yielded a HLOD of 1.24 in the recessive parametric linkage analyses and contained a segment that was homozygous in two affected individuals. Further, investigation of this region identified a two-SNP haplotype that occurs at an increased frequency in language-impaired individuals (P=0.008). We hypothesise that the linkage regions identified here, in particular that on chromosome 7, may contain variants that underlie the high prevalence of SLI observed in this isolated population and may be of relevance to other populations affected by language impairments. PMID:21248734

  9. Genome-wide linkage in a highly consanguineous pedigree reveals two novel loci on chromosome 7 for non-syndromic familial Premature Ovarian Failure.

    Directory of Open Access Journals (Sweden)

    Sandrine Caburet

    Full Text Available BACKGROUND: The human condition known as Premature Ovarian Failure (POF is characterized by loss of ovarian function before the age of 40. A majority of POF cases are sporadic, but 10-15% are familial, suggesting a genetic origin of the disease. Although several causal mutations have been identified, the etiology of POF is still unknown for about 90% of the patients. METHODOLOGY/PRINCIPAL FINDINGS: We report a genome-wide linkage and homozygosity analysis in one large consanguineous Middle-Eastern POF-affected family presenting an autosomal recessive pattern of inheritance. We identified two regions with a LOD(max of 3.26 on chromosome 7p21.1-15.3 and 7q21.3-22.2, which are supported as candidate regions by homozygosity mapping. Sequencing of the coding exons and known regulatory sequences of three candidate genes (DLX5, DLX6 and DSS1 included within the largest region did not reveal any causal mutations. CONCLUSIONS/SIGNIFICANCE: We detect two novel POF-associated loci on human chromosome 7, opening the way to the identification of new genes involved in the control of ovarian development and function.

  10. Novel R tools for analysis of genome-wide population genetic data with emphasis on clonality

    Directory of Open Access Journals (Sweden)

    Zhian N Kamvar

    2015-06-01

    Full Text Available To gain a detailed understanding of how plant microbes evolve and adapt to hosts, pesticides, and other factors, knowledge of the population dynamics and evolutionary history of populations is crucial. Plant pathogen populations are often clonal or partially clonal which requires different analytical tools. With the advent of high throughput sequencing technologies, obtaining genome-wide population genetic data has become easier than ever before. We previously contributed the R package poppr specifically addressing issues with analysis of clonal populations. In this paper we provide several significant extensions to poppr with a focus on large, genome-wide SNP data. Specifically, we provide several new functionalities including the new function mlg.filter to define clone boundaries allowing for inspection and definition of what is a clonal lineage, minimum spanning networks with reticulation, a sliding-window analysis of the index of association, modular bootstrapping of any genetic distance, and analyses across any level of hierarchies.

  11. Polygenic analysis of genome-wide SNP data identifies common variants on allergic rhinitis

    DEFF Research Database (Denmark)

    Mohammadnejad, Afsaneh; Brasch-Andersen, Charlotte; Haagerup, Annette

    Background: Allergic Rhinitis (AR) is a complex disorder that affects many people around the world. There is a high genetic contribution to the development of the AR, as twins and family studies have estimated heritability of more than 33%. Due to the complex nature of the disease, single SNP...... analysis has limited power in identifying the genetic variations for AR. We combined genome-wide association analysis (GWAS) with polygenic risk score (PRS) in exploring the genetic basis underlying the disease. Methods: We collected clinical data on 631 Danish subjects with AR cases consisting of 434...... sibling pairs and unrelated individuals and control subjects of 197 unrelated individuals. SNP genotyping was done by Affymetrix Genome-Wide Human SNP Array 5.0. SNP imputation was performed using "IMPUTE2". Using additive effect model, GWAS was conducted in discovery sample, the genotypes...

  12. A genome-wide linkage study of bipolar disorder and co-morbid migraine: replication of migraine linkage on chromosome 4q24, and suggestion of an overlapping susceptibility region for both disorders on chromosome 20p11.

    Science.gov (United States)

    Oedegaard, K J; Greenwood, T A; Lunde, A; Fasmer, O B; Akiskal, H S; Kelsoe, J R

    2010-04-01

    Migraine and Bipolar Disorder (BPAD) are clinically heterogeneous disorders of the brain with a significant, but complex, genetic component. Epidemiological and clinical studies have demonstrated a high degree of co-morbidity between migraine and BPAD. Several genome-wide linkage studies in BPAD and migraine have shown overlapping regions of linkage on chromosomes, and two functionally similar voltage-dependent calcium channels CACNA1A and CACNA1C have been identified in familial hemiplegic migraine and recently implicated in two whole genome BPAD association studies, respectively. We hypothesized that using migraine co-morbidity to look at subsets of BPAD families in a genetic linkage analysis would prove useful in identifying genetic susceptibility regions in both of these disorders. We used BPAD with co-morbid migraine as an alternative phenotype definition in a re-analysis of the NIMH Bipolar Genetics Initiative wave 4 data set. In this analysis we selected only those families in which at least two members were diagnosed with migraine by a doctor according to patients' reports. Nonparametric linkage analysis performed on 31 families segregating both BPAD and migraine identified a linkage signal on chromosome 4q24 for migraine (but not BPAD) with a peak LOD of 2.26. This region has previously been implicated in two independent migraine linkage studies. In addition we identified a locus on chromosome 20p11 with overlapping elevated LOD scores for both migraine (LOD=1.95) and BPAD (LOD=1.67) phenotypes. This region has previously been implicated in two BPAD linkage studies, and, interestingly, it harbors a known potassium dependant sodium/calcium exchanger gene, SLC24A3, that plays a critical role in neuronal calcium homeostasis. Our findings replicate a previously identified migraine linkage locus on chromosome 4 (not co-segregating with BPAD) in a sample of BPAD families with co-morbid migraine, and suggest a susceptibility locus on chromosome 20, harboring a

  13. Genome-wide association analysis of young onset stroke identifies a locus on chromosome 10q25 near HABP2

    Science.gov (United States)

    Cheng, Yu-Ching; Stanne, Tara M.; Giese, Anne-Katrin; Ho, Weang Kee; Traylor, Matthew; Amouyel, Philippe; Holliday, Elizabeth G.; Malik, Rainer; Xu, Huichun; Kittner, Steven J.; Cole, John W.; O’Connell, Jeffrey R.; Danesh, John; Rasheed, Asif; Zhao, Wei; Engelter, Stefan; Grond-Ginsbach, Caspar; Kamatani, Yoichiro; Lathrop, Mark; Leys, Didier; Thijs, Vincent; Metso, Tiina M.; Tatlisumak, Turgut; Pezzini, Alessandro; Parati, Eugenio A.; Norrving, Bo; Bevan, Steve; Rothwell, Peter M; Sudlow, Cathie; Slowik, Agnieszka; Lindgren, Arne; Walters, Matthew R; Jannes, Jim; Shen, Jess; Crosslin, David; Doheny, Kimberly; Laurie, Cathy C.; Kanse, Sandip M.; Bis, Joshua C.; Fornage, Myriam; Mosley, Thomas H.; Hopewell, Jemma C.; Strauch, Konstantin; Müller-Nurasyid, Martina; Gieger, Christian; Waldenberger, Melanie; Peters, Annette; Meisinger, Christine; Ikram, M. Arfan; Longstreth, WT; Meschia, James F.; Seshadri, Sudha; Sharma, Pankaj; Worrall, Bradford; Jern, Christina; Levi, Christopher; Dichgans, Martin; Boncoraglio, Giorgio B.; Markus, Hugh S.; Debette, Stephanie; Rolfs, Arndt; Saleheen, Danish; Mitchell, Braxton D.

    2015-01-01

    Background and Purpose Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a two-stage meta-analysis of genome-wide association studies (GWAS), focusing on stroke cases with an age of onset HABP2. In a further analysis in an independent sample, we found that two SNPs in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. Conclusions HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke. PMID:26732560

  14. A genome-wide 20 K citrus microarray for gene expression analysis

    OpenAIRE

    Gadea Jose; Forment Javier; Santiago Julia; Marques M Carmen; Juarez Jose; Mauri Nuria; Martinez-Godoy M Angeles

    2008-01-01

    Abstract Background Understanding of genetic elements that contribute to key aspects of citrus biology will impact future improvements in this economically important crop. Global gene expression analysis demands microarray platforms with a high genome coverage. In the last years, genome-wide EST collections have been generated in citrus, opening the possibility to create new tools for functional genomics in this crop plant. Results We have designed and constructed a publicly available genome-...

  15. Diversity of eukaryotic DNA replication origins revealed by genome-wide analysis of chromatin structure.

    Directory of Open Access Journals (Sweden)

    Nicolas M Berbenetz

    2010-09-01

    Full Text Available Eukaryotic DNA replication origins differ both in their efficiency and in the characteristic time during S phase when they become active. The biological basis for these differences remains unknown, but they could be a consequence of chromatin structure. The availability of genome-wide maps of nucleosome positions has led to an explosion of information about how nucleosomes are assembled at transcription start sites, but no similar maps exist for DNA replication origins. Here we combine high-resolution genome-wide nucleosome maps with comprehensive annotations of DNA replication origins to identify patterns of nucleosome occupancy at eukaryotic replication origins. On average, replication origins contain a nucleosome depleted region centered next to the ACS element, flanked on both sides by arrays of well-positioned nucleosomes. Our analysis identified DNA sequence properties that correlate with nucleosome occupancy at replication origins genome-wide and that are correlated with the nucleosome-depleted region. Clustering analysis of all annotated replication origins revealed a surprising diversity of nucleosome occupancy patterns. We provide evidence that the origin recognition complex, which binds to the origin, acts as a barrier element to position and phase nucleosomes on both sides of the origin. Finally, analysis of chromatin reconstituted in vitro reveals that origins are inherently nucleosome depleted. Together our data provide a comprehensive, genome-wide view of chromatin structure at replication origins and suggest a model of nucleosome positioning at replication origins in which the underlying sequence occludes nucleosomes to permit binding of the origin recognition complex, which then (likely in concert with nucleosome modifiers and remodelers positions nucleosomes adjacent to the origin to promote replication origin function.

  16. 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.

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

    Science.gov (United States)

    Loth, Daan W.; Artigas, María Soler; Gharib, Sina A.; Wain, Louise V.; Franceschini, Nora; Koch, Beate; Pottinger, Tess; 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; Viňuela, 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, Åsa; 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; 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.

    2014-01-01

    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 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, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of 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 pathogenesis of restrictive lung disease. PMID:24929828

  18. Meta-analysis of genome-wide association studies of HDL cholesterol response to statins

    DEFF Research Database (Denmark)

    Postmus, Iris; Warren, Helen R; Trompet, Stella

    2016-01-01

    BACKGROUND: In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. METHODS AND RESULTS: We performed...... a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p... in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (pHDL-C response to statin treatment. CONCLUSIONS: Based on results from this study...

  19. Genome-wide Meta-analysis on the Sense of Smell Among US Older Adults.

    Science.gov (United States)

    Dong, Jing; Yang, Jingyun; Tranah, Greg; Franceschini, Nora; Parimi, Neeta; Alkorta-Aranburu, Gorka; Xu, Zongli; Alonso, Alvaro; Cummings, Steven R; Fornage, Myriam; Huang, Xuemei; Kritchevsky, Stephen; Liu, Yongmei; London, Stephanie; Niu, Liang; Wilson, Robert S; De Jager, Philip L; Yu, Lei; Singleton, Andrew B; Harris, Tamara; Mosley, Thomas H; Pinto, Jayant M; Bennett, David A; Chen, Honglei

    2015-11-01

    Olfactory dysfunction is common among older adults and affects their safety, nutrition, quality of life, and mortality. More importantly, the decreased sense of smell is an early symptom of neurodegenerative diseases such as Parkinson disease (PD) and Alzheimer disease. However, the genetic determinants for the sense of smell have been poorly investigated. We here performed the first genome-wide meta-analysis on the sense of smell among 6252 US older adults of European descent from the Atherosclerosis Risk in Communities (ARIC) study, the Health, Aging, and Body Composition (Health ABC) study, and the Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). Genome-wide association study analysis was performed first by individual cohorts and then meta-analyzed using fixed-effect models with inverse variance weights. Although no SNPs reached genome-wide statistical significance, we identified 13 loci with suggestive evidence for an association with the sense of smell (Pmeta effects on the expression of microtubule-associated protein tau (MAPT, 17q21.31) in 447 frontal-cortex samples obtained postmortem and profiled by RNA-seq (P smell in older adults. Similar results were obtained after excluding participants who reported a physician-diagnosed PD or use of PD medications. In conclusion, we provide preliminary evidence that the MAPT locus may play a role in regulating the sense of smell in older adults and therefore offer a potential genetic link between poor sense of smell and major neurodegenerative diseases.

  20. 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.

  1. Cooperative genome-wide analysis shows increased homozygosity in early onset Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Javier Simón-Sánchez

    Full Text Available Parkinson's disease (PD occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD is particularly associated with autosomal recessive (AR mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity.We carried out genome wide SNP genotyping to look for extended runs of homozygosity (ROHs in 1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an increased level of genomic homozygosity in EOPD cases compared to controls. These differences are larger for ROH of 9 Mb and above, where there is a more than three-fold increase in the proportion of cases carrying a ROH. These differences are not explained by occult recessive mutations at existing loci. Controlling for genome wide homozygosity in logistic regression analyses increased the differences between cases and controls, indicating that in EOPD cases ROHs do not simply relate to genome wide measures of inbreeding. Homozygosity at a locus on chromosome19p13.3 was identified as being more common in EOPD cases as compared to controls. Sequencing analysis of genes and predicted transcripts within this locus failed to identify a novel mutation causing EOPD in our cohort.There is an increased rate of genome wide homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a signature of inbreeding and do not necessarily harbour disease-causing genetic variants. Although there might be other regions of interest apart from chromosome 19p13.3, we lack the power to detect them with this analysis.

  2. A meta-analysis of genome-wide association studies of follicular lymphoma

    Directory of Open Access Journals (Sweden)

    Skibola Christine F

    2012-10-01

    Full Text Available Abstract Background B-cell non-Hodgkin lymphoma represents a diverse group of hematological malignancies, of which follicular lymphoma (FL is one of the most common subtypes. Family and epidemiological studies suggest an important genetic role in the etiology of FL. In recent genome-wide association studies (GWAS of FL, several genetic susceptibility loci have been identified on chromosome 6p21.33 (rs6457327 and 6p21.32 (rs10484561, rs2647012 in the human leukocyte antigen class I and class II regions. To identify new genetic variants and further elucidate the genetic basis of FL, a meta-analysis was performed of the top 1000 SNPs associated with FL risk from two GWAS in the US, Denmark and Sweden (592 cases, 1541 controls, with independent validation in 107 cases and 681 controls. Results rs9275517 and rs3117222 in the HLA class II region were validated and inversely associated with FL risk (rs9275517: OR = 0.63, 95% CI = 0.55-0.73, p = 4.03 × 10-11; rs3117222: OR = 0.66, 95% CI = 0.57-0.77, p = 1.45 × 10-7. rs9275517, which is in high linkage disequilibrium with rs2647012 (r2 = 0.9, was no longer associated with FL after conditioning on rs2647012. The rs3117222 association was independent of established FL SNPs, but not of the HLA-DPB1*0301 allele. Using publicly available gene expression profiles with matching genotype information, we found that rs3117222 also was significantly correlated with increased HLA-DPB1 expression. Conclusions By performing a meta-analysis of two GWAS of FL, we further validated the relevance of HLA-DPB1*0301 as a protective allele in the pathogenesis of FL. Moreover, the protective rs3117222 A allele correlated with increased levels of HLA-DPB1, suggesting a possible disease mechanism involving HLA-DPB1 expression regulation. Our results add further support to the major role of HLA genetic variation in the pathogenesis of FL.

  3. Genome-Wide Analysis of Seed Acid Detergent Lignin (ADL) and Hull Content in Rapeseed (Brassica napus L.)

    Science.gov (United States)

    Wei, Lijuan; Qu, Cunmin; Xu, Xinfu; Lu, Kun; Qian, Wei; Li, Jiana; Li, Maoteng; Liu, Liezhao

    2015-01-01

    A stable yellow-seeded variety is the breeding goal for obtaining the ideal rapeseed (Brassica napus L.) plant, and the amount of acid detergent lignin (ADL) in the seeds and the hull content (HC) are often used as yellow-seeded rapeseed screening indices. In this study, a genome-wide association analysis of 520 accessions was performed using the Q + K model with a total of 31,839 single-nucleotide polymorphism (SNP) sites. As a result, three significant associations on the B. napus chromosomes A05, A09, and C05 were detected for seed ADL content. The peak SNPs were within 9.27, 14.22, and 20.86 kb of the key genes BnaA.PAL4, BnaA.CAD2/BnaA.CAD3, and BnaC.CCR1, respectively. Further analyses were performed on the major locus of A05, which was also detected in the seed HC examination. A comparison of our genome-wide association study (GWAS) results and previous linkage mappings revealed a common chromosomal region on A09, which indicates that GWAS can be used as a powerful complementary strategy for dissecting complex traits in B. napus. Genomic selection (GS) utilizing the significant SNP markers based on the GWAS results exhibited increased predictive ability, indicating that the predictive ability of a given model can be substantially improved by using GWAS and GS. PMID:26673885

  4. A genome-wide linkage scan of bipolar disorder in Latino families identifies susceptibility loci at 8q24 and 14q32.

    Science.gov (United States)

    Gonzalez, Suzanne; Camarillo, Cynthia; Rodriguez, Marco; Ramirez, Mercedes; Zavala, Juan; Armas, Regina; Contreras, Salvador A; Contreras, Javier; Dassori, Albana; Almasy, Laura; Flores, Deborah; Jerez, Alvaro; Raventós, Henriette; Ontiveros, Alfonso; Nicolini, Humberto; Escamilla, Michael

    2014-09-01

    A genome-wide nonparametric linkage screen was performed to localize Bipolar Disorder (BP) susceptibility loci in a sample of 3757 individuals of Latino ancestry. The sample included 963 individuals with BP phenotype (704 relative pairs) from 686 families recruited from the US, Mexico, Costa Rica, and Guatemala. Non-parametric analyses were performed over a 5 cM grid with an average genetic coverage of 0.67 cM. Multipoint analyses were conducted across the genome using non-parametric Kong & Cox LOD scores along with Sall statistics for all relative pairs. Suggestive and significant genome-wide thresholds were calculated based on 1000 simulations. Single-marker association tests in the presence of linkage were performed assuming a multiplicative model with a population prevalence of 2%. We identified two genome-wide significant susceptibly loci for BP at 8q24 and 14q32, and a third suggestive locus at 2q13-q14. Within these three linkage regions, the top associated single marker (rs1847694, P = 2.40 × 10(-5)) is located 195 Kb upstream of DPP10 in Chromosome 2. DPP10 is prominently expressed in brain neuronal populations, where it has been shown to bind and regulate Kv4-mediated A-type potassium channels. Taken together, these results provide additional evidence that 8q24, 14q32, and 2q13-q14 are susceptibly loci for BP and these regions may be involved in the pathogenesis of BP in the Latino population. © 2014 Wiley Periodicals, Inc.

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

    Directory of Open Access Journals (Sweden)

    Clive J Hoggart

    2008-07-01

    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.

  6. A genome-wide analysis of gene-caffeine consumption interaction on basal cell carcinoma.

    Science.gov (United States)

    Li, Xin; Cornelis, Marilyn C; Liang, Liming; Song, Fengju; De Vivo, Immaculata; Giovannucci, Edward; Tang, Jean Y; Han, Jiali

    2016-12-01

    Animal models have suggested that oral or topical administration of caffeine could inhibit ultraviolet-induced carcinogenesis via the ataxia telangiectasia and rad3 (ATR)-related apoptosis. Previous epidemiological studies have demonstrated that increased caffeine consumption is associated with reduced risk of basal cell carcinoma (BCC). To identify common genetic markers that may modify this association, we tested gene-caffeine intake interaction on BCC risk in a genome-wide analysis. We included 3383 BCC cases and 8528 controls of European ancestry from the Nurses' Health Study and Health Professionals Follow-up Study. Single nucleotide polymorphism (SNP) rs142310826 near the NEIL3 gene showed a genome-wide significant interaction with caffeine consumption (P = 1.78 × 10(-8) for interaction) on BCC risk. There was no gender difference for this interaction (P = 0.64 for heterogeneity). NEIL3, a gene belonging to the base excision DNA repair pathway, encodes a DNA glycosylase that recognizes and removes lesions produced by oxidative stress. In addition, we identified several loci with P value for interaction caffeine consumption-related SNPs reported by previous genome-wide association studies and risk of BCC, both individually and jointly, but found no significant association. In sum, we identified a DNA repair gene that could be involved in caffeine-mediated skin tumor inhibition. Further studies are warranted to confirm these findings. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

    Science.gov (United States)

    Smolonska, Joanna; Koppelman, Gerard H.; Wijmenga, Cisca; Vonk, Judith M.; Zanen, Pieter; Bruinenberg, Marcel; Curjuric, Ivan; Imboden, Medea; Thun, Gian-Andri; Franke, Lude; Probst-Hensch, Nicole M.; Nürnberg, Peter; Riemersma, Roland A.; van Schayck, Onno; Loth, Daan W.; Bruselle, Guy G.; Stricker, Bruno H; Hofman, Albert; Uitterlinden, André G.; Lahousse, Lies; London, Stephanie J.; Loehr, Laura R.; Manichaikul, Ani; Barr, R. Graham; Donohue, Kathleen M.; Rich, Stephen S.; Pare, Peter; Bossé, Yohan; Hao, Ke; van den Berge, Maarten; Groen, Harry J.M.; Lammers, Jan-Willem J.; Mali, Willem; Boezen, H. Marike; Postma, Dirkje S.

    2014-01-01

    Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background (“Dutch hypothesis”). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the NFκβ pathway) and GNG5P5, respectively. SNP rs9534578 in GNG5P5 reached genome-wide significance after first stage replication (p=9.96·*10−9). The second stage replication in seven independent cohorts provided no significant replication. eQTL analysis in blood and lung on the top 20 associated SNPs identified two SNPs in COMMD10 influencing gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NFκβ, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role of two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings either suggest that there is no common genetic component in asthma and COPD or, alternatively, different environmental factors, like lifestyle and occupation in different countries and continents may have obscured the genetic common contribution. PMID:24993907

  8. Genome-wide analysis of interactions between ATP-dependent chromatin remodeling and histone modifications

    Directory of Open Access Journals (Sweden)

    Wang Jiang

    2009-07-01

    Full Text Available Abstract Background ATP-dependent chromatin remodeling and the covalent modification of histones play central roles in determining chromatin structure and function. Although several specific interactions between these two activities have been elaborated, the global landscape remains to be elucidated. Results In this paper, we have developed a computational method to generate the first genome-wide landscape of interactions between ATP-dependent chromatin remodeling and the covalent modification of histones in Saccharomyces cerevisiae. Our method succeeds in identifying known interactions and uncovers many previously unknown interactions between these two activities. Analysis of the genome-wide picture revealed that transcription-related modifications tend to interact with more chromatin remodelers. Our results also demonstrate that most chromatin remodeling-modification interactions act via interactions of remodelers with both histone-modifying enzymes and histone residues. We also found that the co-occurrence of both modification and remodeling has significantly different influences on multiple gene features (e.g. nucleosome occupancy compared with the presence of either one. Conclusion We gave the first genome-wide picture of ATP-dependent chromatin remodeling-histone modification interactions. We also revealed how these two activities work together to regulate chromatin structure and function. Our results suggest that distinct strategies for regulating chromatin activity are selectively employed by genes with different properties.

  9. 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 ...

  10. Meta-analysis of genome-wide association studies of anxiety disorders

    Science.gov (United States)

    Otowa, Takeshi; Hek, Karin; Lee, Minyoung; Byrne, Enda M.; Mirza, Saira S.; Nivard, Michel G.; Bigdeli, Timothy; Aggen, Steven H.; Adkins, Daniel; Wolen, Aaron; Fanous, Ayman; Keller, Matthew C.; Castelao, Enrique; Kutalik, Zoltan; Van der Auwera, Sandra; Homuth, Georg; Nauck, Matthias; Teumer, Alexander; Milaneschi, Yuri; Hottenga, Jouke-Jan; Direk, Nese; Hofman, Albert; Uitterlinden, Andre; Mulder, Cornelis L.; Henders, Anjali K.; Medland, Sarah E.; Gordon, Scott; Heath, Andrew C.; Madden, Pamela A.F.; Pergadia, Michelle; van der Most, Peter J.; Nolte, Ilja M.; van Oort, Floor V.A.; Hartman, Catharina A.; Oldehinkel, Albertine J.; Preisig, Martin; Grabe, Hans Jörgen; Middeldorp, Christel M.; Penninx, Brenda WJH; Boomsma, Dorret; Martin, Nicholas G.; Montgomery, Grant; Maher, Brion S.; van den Oord, Edwin J.; Wray, Naomi R.; Tiemeier, Henning; Hettema, John M.

    2015-01-01

    Anxiety disorders, namely generalized anxiety disorder, panic disorder, and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based upon clinical presentation, anxiety disorders likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based anxiety disorders, we applied two phenotypic approaches: (1) comparisons between categorical anxiety disorder cases and super-normal controls, and (2) quantitative phenotypic factor scores derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65×10−8); for factor scores, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86×10−9). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of anxiety disorders. PMID:26754954

  11. The complex genetics of gait speed: genome-wide meta-analysis approach

    Science.gov (United States)

    Lunetta, Kathryn L.; Smith, Jennifer A.; Eicher, John D.; Vered, Rotem; Deelen, Joris; Arnold, Alice M.; Buchman, Aron S.; Tanaka, Toshiko; Faul, Jessica D.; Nethander, Maria; Fornage, Myriam; Adams, Hieab H.; Matteini, Amy M.; Callisaya, Michele L.; Smith, Albert V.; Yu, Lei; De Jager, Philip L.; Evans, Denis A.; Gudnason, Vilmundur; Hofman, Albert; Pattie, Alison; Corley, Janie; Launer, Lenore J.; Knopman, Davis S.; Parimi, Neeta; Turner, Stephen T.; Bandinelli, Stefania; Beekman, Marian; Gutman, Danielle; Sharvit, Lital; Mooijaart, Simon P.; Liewald, David C.; Houwing-Duistermaat, Jeanine J.; Ohlsson, Claes; Moed, Matthijs; Verlinden, Vincent J.; Mellström, Dan; van der Geest, Jos N.; Karlsson, Magnus; Hernandez, Dena; McWhirter, Rebekah; Liu, Yongmei; Thomson, Russell; Tranah, Gregory J.; Uitterlinden, Andre G.; Weir, David R.; Zhao, Wei; Starr, John M.; Johnson, Andrew D.; Ikram, M. Arfan; Bennett, David A.; Cummings, Steven R.; Deary, Ian J.; Harris, Tamara B.; Kardia, Sharon L. R.; Mosley, Thomas H.; Srikanth, Velandai K.; Windham, Beverly G.; Newman, Ann B.; Walston, Jeremy D.; Davies, Gail; Evans, Daniel S.; Slagboom, Eline P.; Ferrucci, Luigi; Kiel, Douglas P.; Murabito, Joanne M.; Atzmon, Gil

    2017-01-01

    Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging. PMID:28077804

  12. 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

    To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field. 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 re...

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

    OpenAIRE

    Lindgren, Cecilia; Heid, Iris; Randall, Joshua; Lamina, Claudia; Steinthorsdottir, Valgerdur; Qi, Lu; Speliotes, Elizabeth; Thorleifsson, Gudmar; Willer, Cristen; Herrera, Blanca; Jackson, Anne; Lim, Noha; Scheet, Paul; Soranzo, Nicole; Amin, Najaf

    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 evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals ...

  14. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

    OpenAIRE

    Lindgren, Cecilia M; Heid, Iris M.; Randall, Joshua C.; Claudia Lamina; Valgerdur Steinthorsdottir; Lu Qi; Speliotes, Elizabeth K.; Gudmar Thorleifsson; Willer, Cristen J.; Herrera, Blanca M; Jackson, Anne U.; Noha Lim; Paul Scheet; Nicole Soranzo; Najaf Amin

    2009-01-01

    To 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 evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified t...

  15. Principal components analysis corrects for stratification in genome-wide association studies.

    Science.gov (United States)

    Price, Alkes L; Patterson, Nick J; Plenge, Robert M; Weinblatt, Michael E; Shadick, Nancy A; Reich, David

    2006-08-01

    Population stratification--allele frequency differences between cases and controls due to systematic ancestry differences-can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker's variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers.

  16. Shared genetic susceptibility to ischemic stroke and coronary artery disease: a genome-wide analysis of common variants.

    Science.gov (United States)

    Dichgans, Martin; Malik, Rainer; König, Inke R; Rosand, Jonathan; Clarke, Robert; Gretarsdottir, Solveig; Thorleifsson, Gudmar; Mitchell, Braxton D; Assimes, Themistocles L; Levi, Christopher; O'Donnell, Christopher J; Fornage, Myriam; Thorsteinsdottir, Unnur; Psaty, Bruce M; Hengstenberg, Christian; Seshadri, Sudha; Erdmann, Jeanette; Bis, Joshua C; Peters, Annette; Boncoraglio, Giorgio B; März, Winfried; Meschia, James F; Kathiresan, Sekar; Ikram, M Arfan; McPherson, Ruth; Stefansson, Kari; Sudlow, Cathie; Reilly, Muredach P; Thompson, John R; Sharma, Pankaj; Hopewell, Jemma C; Chambers, John C; Watkins, Hugh; Rothwell, Peter M; Roberts, Robert; Markus, Hugh S; Samani, Nilesh J; Farrall, Martin; Schunkert, Heribert

    2014-01-01

    Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (Pstroke (LAS) subtype. Common variants associated with CAD at Pgenetic risk of IS and particularly the LAS subtype with CAD.

  17. Analysis of genome-wide structure, diversity and fine mapping of Mendelian traits in traditional and village chickens

    Science.gov (United States)

    Wragg, D; Mwacharo, J M; Alcalde, J A; Hocking, P M; Hanotte, O

    2012-01-01

    Extensive phenotypic variation is a common feature among village chickens found throughout much of the developing world, and in traditional chicken breeds that have been artificially selected for traits such as plumage variety. We present here an assessment of traditional and village chicken populations, for fine mapping of Mendelian traits using genome-wide single-nucleotide polymorphism (SNP) genotyping while providing information on their genetic structure and diversity. Bayesian clustering analysis reveals two main genetic backgrounds in traditional breeds, Kenyan, Ethiopian and Chilean village chickens. Analysis of linkage disequilibrium (LD) reveals useful LD (r2⩾0.3) in both traditional and village chickens at pairwise marker distances of ∼10 Kb; while haplotype block analysis indicates a median block size of 11–12 Kb. Association mapping yielded refined mapping intervals for duplex comb (Gga 2:38.55–38.89 Mb) and rose comb (Gga 7:18.41–22.09 Mb) phenotypes in traditional breeds. Combined mapping information from traditional breeds and Chilean village chicken allows the oocyan phenotype to be fine mapped to two small regions (Gga 1:67.25–67.28 Mb, Gga 1:67.28–67.32 Mb) totalling ∼75 Kb. Mapping the unmapped earlobe pigmentation phenotype supports previous findings that the trait is sex-linked and polygenic. A critical assessment of the number of SNPs required to map simple traits indicate that between 90 and 110K SNPs are required for full genome-wide analysis of haplotype block structure/ancestry, and for association mapping in both traditional and village chickens. Our results demonstrate the importance and uniqueness of phenotypic diversity and genetic structure of traditional chicken breeds for fine-scale mapping of Mendelian traits in the species, with village chicken populations providing further opportunities to enhance mapping resolutions. PMID:22395157

  18. Genome-wide analysis of poly(A) site selection in Schizosaccharomyces pombe

    KAUST Repository

    Schlackow, M.

    2013-10-23

    Polyadenylation of pre-mRNAs, a critical step in eukaryotic gene expression, is mediated by cis elements collectively called the polyadenylation signal. Genome-wide analysis of such polyadenylation signals was missing in fission yeast, even though it is an important model organism. We demonstrate that the canonical AATAAA motif is the most frequent and functional polyadenylation signal in Schizosaccharomyces pombe. Using analysis of RNA-Seq data sets from cells grown under various physiological conditions, we identify 3\\' UTRs for nearly 90% of the yeast genes. Heterogeneity of cleavage sites is common, as is alternative polyadenylation within and between conditions. We validated the computationally identified sequence elements likely to promote polyadenylation by functional assays, including qRT-PCR and 3\\'RACE analysis. The biological importance of the AATAAA motif is underlined by functional analysis of the genes containing it. Furthermore, it has been shown that convergent genes require trans elements, like cohesin for efficient transcription termination. Here we show that convergent genes lacking cohesin (on chromosome 2) are generally associated with longer overlapping mRNA transcripts. Our bioinformatic and experimental genome-wide results are summarized and can be accessed and customized in a user-friendly database Pomb(A).

  19. Genome-wide analysis of alternative splicing during human heart development

    Science.gov (United States)

    Wang, He; Chen, Yanmei; Li, Xinzhong; Chen, Guojun; Zhong, Lintao; Chen, Gangbing; Liao, Yulin; Liao, Wangjun; Bin, Jianping

    2016-01-01

    Alternative splicing (AS) drives determinative changes during mouse heart development. Recent high-throughput technological advancements have facilitated genome-wide AS, while its analysis in human foetal heart transition to the adult stage has not been reported. Here, we present a high-resolution global analysis of AS transitions between human foetal and adult hearts. RNA-sequencing data showed extensive AS transitions occurred between human foetal and adult hearts, and AS events occurred more frequently in protein-coding genes than in long non-coding RNA (lncRNA). A significant difference of AS patterns was found between foetal and adult hearts. The predicted difference in AS events was further confirmed using quantitative reverse transcription-polymerase chain reaction analysis of human heart samples. Functional foetal-specific AS event analysis showed enrichment associated with cell proliferation-related pathways including cell cycle, whereas adult-specific AS events were associated with protein synthesis. Furthermore, 42.6% of foetal-specific AS events showed significant changes in gene expression levels between foetal and adult hearts. Genes exhibiting both foetal-specific AS and differential expression were highly enriched in cell cycle-associated functions. In conclusion, we provided a genome-wide profiling of AS transitions between foetal and adult hearts and proposed that AS transitions and deferential gene expression may play determinative roles in human heart development. PMID:27752099

  20. Genome-wide analysis of alternative splicing during human heart development

    Science.gov (United States)

    Wang, He; Chen, Yanmei; Li, Xinzhong; Chen, Guojun; Zhong, Lintao; Chen, Gangbing; Liao, Yulin; Liao, Wangjun; Bin, Jianping

    2016-10-01

    Alternative splicing (AS) drives determinative changes during mouse heart development. Recent high-throughput technological advancements have facilitated genome-wide AS, while its analysis in human foetal heart transition to the adult stage has not been reported. Here, we present a high-resolution global analysis of AS transitions between human foetal and adult hearts. RNA-sequencing data showed extensive AS transitions occurred between human foetal and adult hearts, and AS events occurred more frequently in protein-coding genes than in long non-coding RNA (lncRNA). A significant difference of AS patterns was found between foetal and adult hearts. The predicted difference in AS events was further confirmed using quantitative reverse transcription-polymerase chain reaction analysis of human heart samples. Functional foetal-specific AS event analysis showed enrichment associated with cell proliferation-related pathways including cell cycle, whereas adult-specific AS events were associated with protein synthesis. Furthermore, 42.6% of foetal-specific AS events showed significant changes in gene expression levels between foetal and adult hearts. Genes exhibiting both foetal-specific AS and differential expression were highly enriched in cell cycle-associated functions. In conclusion, we provided a genome-wide profiling of AS transitions between foetal and adult hearts and proposed that AS transitions and deferential gene expression may play determinative roles in human heart development.

  1. Genome-wide analysis of a Wnt1-regulated transcriptional network implicates neurodegenerative pathways.

    Science.gov (United States)

    Wexler, Eric M; Rosen, Ezra; Lu, Daning; Osborn, Gregory E; Martin, Elizabeth; Raybould, Helen; Geschwind, Daniel H

    2011-10-04

    Wnt proteins are critical to mammalian brain development and function. The canonical Wnt signaling pathway involves the stabilization and nuclear translocation of β-catenin; however, Wnt also signals through alternative, noncanonical pathways. To gain a systems-level, genome-wide view of Wnt signaling, we analyzed Wnt1-stimulated changes in gene expression by transcriptional microarray analysis in cultured human neural progenitor (hNP) cells at multiple time points over a 72-hour time course. We observed a widespread oscillatory-like pattern of changes in gene expression, involving components of both the canonical and the noncanonical Wnt signaling pathways. A higher-order, systems-level analysis that combined independent component analysis, waveform analysis, and mutual information-based network construction revealed effects on pathways related to cell death and neurodegenerative disease. Wnt effectors were tightly clustered with presenilin1 (PSEN1) and granulin (GRN), which cause dominantly inherited forms of Alzheimer's disease and frontotemporal dementia (FTD), respectively. We further explored a potential link between Wnt1 and GRN and found that Wnt1 decreased GRN expression by hNPs. Conversely, GRN knockdown increased WNT1 expression, demonstrating that Wnt and GRN reciprocally regulate each other. Finally, we provided in vivo validation of the in vitro findings by analyzing gene expression data from individuals with FTD. These unbiased and genome-wide analyses provide evidence for a connection between Wnt signaling and the transcriptional regulation of neurodegenerative disease genes.

  2. Genome-wide binding and transcriptome analysis of human farnesoid X receptor in primary human hepatocytes.

    Directory of Open Access Journals (Sweden)

    Le Zhan

    Full Text Available Farnesoid X receptor (FXR, NR1H4 is a ligand-activated transcription factor, belonging to the nuclear receptor superfamily. FXR is highly expressed in the liver and is essential in regulating bile acid homeostasis. FXR deficiency is implicated in numerous liver diseases and mice with modulation of FXR have been used as animal models to study liver physiology and pathology. We have reported genome-wide binding of FXR in mice by chromatin immunoprecipitation - deep sequencing (ChIP-seq, with results indicating that FXR may be involved in regulating diverse pathways in liver. However, limited information exists for the functions of human FXR and the suitability of using murine models to study human FXR functions.In the current study, we performed ChIP-seq in primary human hepatocytes (PHHs treated with a synthetic FXR agonist, GW4064 or DMSO control. In parallel, RNA deep sequencing (RNA-seq and RNA microarray were performed for GW4064 or control treated PHHs and wild type mouse livers, respectively.ChIP-seq showed similar profiles of genome-wide FXR binding in humans and mice in terms of motif analysis and pathway prediction. However, RNA-seq and microarray showed more different transcriptome profiles between PHHs and mouse livers upon GW4064 treatment.In summary, we have established genome-wide human FXR binding and transcriptome profiles. These results will aid in determining the human FXR functions, as well as judging to what level the mouse models could be used to study human FXR functions.

  3. Genome-wide association analysis identifies multiple loci related to resting heart rate

    Science.gov (United States)

    Eijgelsheim, Mark; Newton-Cheh, Christopher; Sotoodehnia, Nona; de Bakker, Paul I.W.; Müller, Martina; Morrison, Alanna C.; Smith, Albert V.; Isaacs, Aaron; Sanna, Serena; Dörr, Marcus; Navarro, Pau; Fuchsberger, Christian; Nolte, Ilja M.; de Geus, Eco J.C.; Estrada, Karol; Hwang, Shih-Jen; Bis, Joshua C.; Rückert, Ina-Maria; Alonso, Alvaro; Launer, Lenore J.; Hottenga, Jouke Jan; Rivadeneira, Fernando; Noseworthy, Peter A.; Rice, Kenneth M.; Perz, Siegfried; Arking, Dan E.; Spector, Tim D.; Kors, Jan A.; Aulchenko, Yurii S.; Tarasov, Kirill V.; Homuth, Georg; Wild, Sarah H.; Marroni, Fabio; Gieger, Christian; Licht, Carmilla M.; Prineas, Ronald J.; Hofman, Albert; Rotter, Jerome I.; Hicks, Andrew A.; Ernst, Florian; Najjar, Samer S.; Wright, Alan F.; Peters, Annette; Fox, Ervin R.; Oostra, Ben A.; Kroemer, Heyo K.; Couper, David; Völzke, Henry; Campbell, Harry; Meitinger, Thomas; Uda, Manuela; Witteman, Jacqueline C.M.; Psaty, Bruce M.; Wichmann, H-Erich; Harris, Tamara B.; Kääb, Stefan; Siscovick, David S.; Jamshidi, Yalda; Uitterlinden, André G.; Folsom, Aaron R.; Larson, Martin G.; Wilson, James F.; Penninx, Brenda W.; Snieder, Harold; Pramstaller, Peter P.; van Duijn, Cornelia M.; Lakatta, Edward G.; Felix, Stephan B.; Gudnason, Vilmundur; Pfeufer, Arne; Heckbert, Susan R.; Stricker, Bruno H.Ch.; Boerwinkle, Eric; O'Donnell, Christopher J.

    2010-01-01

    Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38 991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and ∼2.5 million markers. Results with P < 5 × 10−8 were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain ∼0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10−5 increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care. PMID:20639392

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

    DEFF Research Database (Denmark)

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

    2011-01-01

    -fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge...... nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U...

  5. Genome-wide analysis of homeobox gene family in legumes: identification, gene duplication and expression profiling.

    Science.gov (United States)

    Bhattacharjee, Annapurna; Ghangal, Rajesh; Garg, Rohini; Jain, Mukesh

    2015-01-01

    Homeobox genes encode transcription factors that are known to play a major role in different aspects of plant growth and development. In the present study, we identified homeobox genes belonging to 14 different classes in five legume species, including chickpea, soybean, Medicago, Lotus and pigeonpea. The characteristic differences within homeodomain sequences among various classes of homeobox gene family were quite evident. Genome-wide expression analysis using publicly available datasets (RNA-seq and microarray) indicated that homeobox genes are differentially expressed in various tissues/developmental stages and under stress conditions in different legumes. We validated the differential expression of selected chickpea homeobox genes via quantitative reverse transcription polymerase chain reaction. Genome duplication analysis in soybean indicated that segmental duplication has significantly contributed in the expansion of homeobox gene family. The Ka/Ks ratio of duplicated homeobox genes in soybean showed that several members of this family have undergone purifying selection. Moreover, expression profiling indicated that duplicated genes might have been retained due to sub-functionalization. The genome-wide identification and comprehensive gene expression profiling of homeobox gene family members in legumes will provide opportunities for functional analysis to unravel their exact role in plant growth and development.

  6. A genome-wide analysis of putative functional and exonic variation associated with extremely high intelligence.

    Science.gov (United States)

    Spain, S L; Pedroso, I; Kadeva, N; Miller, M B; Iacono, W G; McGue, M; Stergiakouli, E; Smith, G D; Putallaz, M; Lubinski, D; Meaburn, E L; Plomin, R; Simpson, M A

    2016-08-01

    Although individual differences in intelligence (general cognitive ability) are highly heritable, molecular genetic analyses to date have had limited success in identifying specific loci responsible for its heritability. This study is the first to investigate exome variation in individuals of extremely high intelligence. Under the quantitative genetic model, sampling from the high extreme of the distribution should provide increased power to detect associations. We therefore performed a case-control association analysis with 1409 individuals drawn from the top 0.0003 (IQ >170) of the population distribution of intelligence and 3253 unselected population-based controls. Our analysis focused on putative functional exonic variants assayed on the Illumina HumanExome BeadChip. We did not observe any individual protein-altering variants that are reproducibly associated with extremely high intelligence and within the entire distribution of intelligence. Moreover, no significant associations were found for multiple rare alleles within individual genes. However, analyses using genome-wide similarity between unrelated individuals (genome-wide complex trait analysis) indicate that the genotyped functional protein-altering variation yields a heritability estimate of 17.4% (s.e. 1.7%) based on a liability model. In addition, investigation of nominally significant associations revealed fewer rare alleles associated with extremely high intelligence than would be expected under the null hypothesis. This observation is consistent with the hypothesis that rare functional alleles are more frequently detrimental than beneficial to intelligence.

  7. Genome-wide DNA methylation patterns and transcription analysis in sheep muscle.

    Directory of Open Access Journals (Sweden)

    Christine Couldrey

    Full Text Available DNA methylation plays a central role in regulating many aspects of growth and development in mammals through regulating gene expression. The development of next generation sequencing technologies have paved the way for genome-wide, high resolution analysis of DNA methylation landscapes using methodology known as reduced representation bisulfite sequencing (RRBS. While RRBS has proven to be effective in understanding DNA methylation landscapes in humans, mice, and rats, to date, few studies have utilised this powerful method for investigating DNA methylation in agricultural animals. Here we describe the utilisation of RRBS to investigate DNA methylation in sheep Longissimus dorsi muscles. RRBS analysis of ∼1% of the genome from Longissimus dorsi muscles provided data of suitably high precision and accuracy for DNA methylation analysis, at all levels of resolution from genome-wide to individual nucleotides. Combining RRBS data with mRNAseq data allowed the sheep Longissimus dorsi muscle methylome to be compared with methylomes from other species. While some species differences were identified, many similarities were observed between DNA methylation patterns in sheep and other more commonly studied species. The RRBS data presented here highlights the complexity of epigenetic regulation of genes. However, the similarities observed across species are promising, in that knowledge gained from epigenetic studies in human and mice may be applied, with caution, to agricultural species. The ability to accurately measure DNA methylation in agricultural animals will contribute an additional layer of information to the genetic analyses currently being used to maximise production gains in these species.

  8. Relatedness mapping and tracts of relatedness for genome-wide data in the presence of linkage disequilibrium

    DEFF Research Database (Denmark)

    Albrechtsen, Anders; Korneliussen, Thorfinn Sand; Moltke, Ida;

    2009-01-01

    data. We use a continuous time Markov model where the hidden states are the number of alleles shared IBD between pairs of individuals at a given position. In contrast to previous methods, our method accurately accounts for linkage disequilibrium using pairwise haplotype probabilities. The method...

  9. Genome-Wide Linkage and Positional Association Analyses Identify Associations of Novel AFF3 and NTM Genes with Triglycerides: The GenSalt Study

    Science.gov (United States)

    Li, Changwei; Bazzano, Lydia A.L.; Rao, Dabeeru C.; Hixson, James E.; He, Jiang; Gu, Dongfeng; Gu, Charles C.; Shimmin, Lawrence C.; Jaquish, Cashell E.; Schwander, Karen; Liu, De-Pei; Huang, Jianfeng; Lu, Fanghong; Cao, Jie; Chong, Shen; Lu, Xiangfeng; Kelly, Tanika N.

    2016-01-01

    We conducted a genome-wide linkage scan and positional association study to identify genes and variants influencing blood lipid levels among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1906 participants from 633 Han Chinese families. Lipids were measured from overnight fasting blood samples using standard methods. Multipoint quantitative trait genome-wide linkage scans were performed on the high-density lipoprotein, low-density lipoprotein, and log-transformed triglyceride phenotypes. Using dense panels of single nucleotide polymorphisms (SNPs), single-marker and gene-based association analyses were conducted to follow-up on promising linkage signals. Additive associations between each SNP and lipid phenotypes were tested using mixed linear regression models. Gene-based analyses were performed by combining P-values from single-marker analyses within each gene using the truncated product method (TPM). Significant associations were assessed for replication among 777 Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). Bonferroni correction was used to adjust for multiple testing. In the GenSalt study, suggestive linkage signals were identified at 2p11.2–2q12.1 [maximum multipoint LOD score (MML) = 2.18 at 2q11.2] and 11q24.3–11q25 (MML = 2.29 at 11q25) for the log-transformed triglyceride phenotype. Follow-up analyses of these two regions revealed gene-based associations of charged multivesicular body protein 3 (CHMP3), ring finger protein 103 (RNF103), AF4/FMR2 family, member 3 (AFF3), and neurotrimin (NTM ) with triglycerides (P = 4 × 10−4, 1.00 × 10−5, 2.00 × 10−5, and 1.00 × 10−7, respectively). Both the AFF3 and NTM triglyceride associations were replicated among MESA study participants (P = 1.00 × 10−7 and 8.00 × 10−5, respectively). Furthermore, NTM explained the linkage signal on chromosome 11. In conclusion, we identified novel genes

  10. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

    Science.gov (United States)

    Stahl, Eli A.; Raychaudhuri, Soumya; Remmers, Elaine F.; Xie, Gang; Eyre, Stephen; Thomson, Brian P.; Li, Yonghong; Kurreeman, Fina A. S.; Zhernakova, Alexandra; Hinks, Anne; Guiducci, Candace; Chen, Robert; Alfredsson, Lars; Amos, Christopher I.; Ardlie, Kristin G.; Barton, Anne; Bowes, John; Brouwer, Elisabeth; Burtt, Noel P.; Catanese, Joseph J.; Coblyn, Jonathan; Coenen, Marieke JH; Costenbader, Karen H.; Criswell, Lindsey A.; Crusius, J. Bart A.; Cui, Jing; de Bakker, Paul I.W.; De Jager, Phillip L.; Ding, Bo; Emery, Paul; Flynn, Edward; Harrison, Pille; Hocking, Lynne J.; Huizinga, Tom W. J.; Kastner, Daniel L.; Ke, Xiayi; Lee, Annette T.; Liu, Xiangdong; Martin, Paul; Morgan, Ann W.; Padyukov, Leonid; Posthumus, Marcel D.; Radstake, Timothy RDJ; Reid, David M.; Seielstad, Mark; Seldin, Michael F.; Shadick, Nancy A.; Steer, Sophia; Tak, Paul P.; Thomson, Wendy; van der Helm-van Mil, Annette H. M.; van der Horst-Bruinsma, Irene E.; van der Schoot, C. Ellen; van Riel, Piet LCM; Weinblatt, Michael E.; Wilson, Anthony G.; Wolbink, Gert Jan; Wordsworth, Paul; Wijmenga, Cisca; Karlson, Elizabeth W.; Toes, Rene E. M.; de Vries, Niek; Begovich, Ann B.; Worthington, Jane; Siminovitch, Katherine A.; Gregersen, Peter K.; Klareskog, Lars; Plenge, Robert M.

    2014-01-01

    To identify novel genetic risk factors for rheumatoid arthritis (RA), we conducted a genome-wide association study (GWAS) meta-analysis of 5,539 autoantibody positive RA cases and 20,169 controls of European descent, followed by replication in an independent set of 6,768 RA cases and 8,806 controls. Of 34 SNPs selected for replication, 7 novel RA risk alleles were identified at genome-wide significance (P<5×10−8) in analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5, and PXK. We also refined the risk alleles at two established RA risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed RA risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P<0.05, many of which are validated autoimmune risk alleles, suggesting that most represent bona fide RA risk alleles. PMID:20453842

  11. Genome-wide analysis of DNA methylation in Arabidopsis using MeDIP-chip.

    Science.gov (United States)

    Cortijo, Sandra; Wardenaar, René; Colomé-Tatché, Maria; Johannes, Frank; Colot, Vincent

    2014-01-01

    DNA methylation is an epigenetic mark that is essential for preserving genome integrity and normal development in plants and mammals. Although this modification may serve a variety of purposes, it is best known for its role in stable transcriptional silencing of transposable elements and epigenetic regulation of some genes. In addition, it is increasingly recognized that alterations in DNA methylation patterns can sometimes be inherited across multiple generations and thus are a source of heritable phenotypic variation that is independent of any DNA sequence changes. With the advent of genomics, it is now possible to analyze DNA methylation genome-wide with high precision, which is a prerequisite for understanding fully the various functions and phenotypic impact of this modification. Indeed, several so-called epigenomic mapping methods have been developed for the analysis of DNA methylation. Among these, immunoprecipitation of methylated DNA followed by hybridization to genome tiling arrays (MeDIP-chip) arguably offers a reasonable compromise between cost, ease of implementation, and sensitivity to date. Here we describe the application of this method, from DNA extraction to data analysis, to the study of DNA methylation genome-wide in Arabidopsis.

  12. Genome-wide analysis of copy number variation in type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Britney L Grayson

    Full Text Available Type 1 diabetes (T1D tends to cluster in families, suggesting there may be a genetic component predisposing to disease. However, a recent large-scale genome-wide association study concluded that identified genetic factors, single nucleotide polymorphisms, do not account for overall familiality. Another class of genetic variation is the amplification or deletion of >1 kilobase segments of the genome, also termed copy number variations (CNVs. We performed genome-wide CNV analysis on a cohort of 20 unrelated adults with T1D and a control (Ctrl cohort of 20 subjects using the Affymetrix SNP Array 6.0 in combination with the Birdsuite copy number calling software. We identified 39 CNVs as enriched or depleted in T1D versus Ctrl. Additionally, we performed CNV analysis in a group of 10 monozygotic twin pairs discordant for T1D. Eleven of these 39 CNVs were also respectively enriched or depleted in the Twin cohort, suggesting that these variants may be involved in the development of islet autoimmunity, as the presently unaffected twin is at high risk for developing islet autoimmunity and T1D in his or her lifetime. These CNVs include a deletion on chromosome 6p21, near an HLA-DQ allele. CNVs were found that were both enriched or depleted in patients with or at high risk for developing T1D. These regions may represent genetic variants contributing to development of islet autoimmunity in T1D.

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

    Science.gov (United States)

    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 MJ; Ashton, Katie; Otton, Geoffrey; Proietto, Tony; Liu, Tao; Mints, Miriam; Tham, Emma; Consortium, CHIBCHA; Jun Li, Mulin; 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

    2016-01-01

    We conducted a meta-analysis of three endometrial cancer GWAS and two replication phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five novel 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). A second independent 8q24.21 signal (rs17232730) was found. Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2=0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103-T endometrial cancer protective allele suppressed gene expression in vitro suggesting that regulation of KLF5 expression, 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

  14. Genome-Wide Association Mapping for Intelligence in Military Working Dogs: Development of Advanced Classification Algorithm for Genome-Wide Single Nucleotide Polymorphism (SNP) Data Analysis

    Science.gov (United States)

    2011-04-01

    al. (2007) “Efficient mapping of mendelian traits in dogs through genome-wide association.” Nat Genet 39:1321-1328. 12 Distribution A...collected data to genetically map superior intelligence in the military working dog. A behavioral testing regimen was developed by canine cognitive expert Dr...TERMS Military working dog genome-wide association study genetic marker intelligence 16

  15. 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.......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....

  16. Genome-wide and fine-resolution association analysis of malaria in West Africa

    Science.gov (United States)

    Jallow, Muminatou; Teo, Yik Ying; Small, Kerrin S; Rockett, Kirk A; Deloukas, Panos; Clark, Taane G; Kivinen, Katja; Bojang, Kalifa A; Conway, David J; Pinder, Margaret; Sirugo, Giorgio; Sisay-Joof, Fatou; Usen, Stanley; Auburn, Sarah; Bumpstead, Suzannah J; Campino, Susana; Coffey, Alison; Dunham, Andrew; Fry, Andrew E; Green, Angela; Gwilliam, Rhian; Hunt, Sarah E; Inouye, Michael; Jeffreys, Anna E; Mendy, Alieu; Palotie, Aarno; Potter, Simon; Ragoussis, Jiannis; Rogers, Jane; Rowlands, Kate; Somaskantharajah, Elilan; Whittaker, Pamela; Widden, Claire; Donnelly, Peter; Howie, Bryan; Marchini, Jonathan; Morris, Andrew; SanJoaquin, Miguel; Achidi, Eric Akum; Agbenyega, Tsiri; Allen, Angela; Amodu, Olukemi; Corran, Patrick; Djimde, Abdoulaye; Dolo, Amagana; Doumbo, Ogobara K; Drakeley, Chris; Dunstan, Sarah; Evans, Jennifer; Farrar, Jeremy; Fernando, Deepika; Hien, Tran Tinh; Horstmann, Rolf D; Ibrahim, Muntaser; Karunaweera, Nadira; Kokwaro, Gilbert; Koram, Kwadwo A; Lemnge, Martha; Makani, Julie; Marsh, Kevin; Michon, Pascal; Modiano, David; Molyneux, Malcolm E; Mueller, Ivo; Parker, Michael; Peshu, Norbert; Plowe, Christopher V; Puijalon, Odile; Reeder, John; Reyburn, Hugh; Riley, Eleanor M; Sakuntabhai, Anavaj; Singhasivanon, Pratap; Sirima, Sodiomon; Tall, Adama; Taylor, Terrie E; Thera, Mahamadou; Troye-Blomberg, Marita; Williams, Thomas N; Wilson, Michael; Kwiatkowski, Dominic P

    2009-01-01

    We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10−7 to P = 4 × 10−14, with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations. PMID:19465909

  17. A genome-wide association analysis for susceptibility of pigs to enterotoxigenic Escherichia coli F41.

    Science.gov (United States)

    Ji, H Y; Yang, B; Zhang, Z Y; Ouyang, J; Yang, M; Zhang, X F; Zhang, W C; Su, Y; Zhao, K W; Xiao, S J; Yan, X M; Ren, J; Huang, L S

    2016-10-01

    Enterotoxigenic Escherichia coli (ETEC) is a type of pathogenic bacteria that cause diarrhea in piglets through colonizing pig small intestine epithelial cells by their surface fimbriae. Different fimbriae type of ETEC including F4, F18, K99 and F41 have been isolated from diarrheal pigs. In this study, we performed a genome-wide association study to map the loci associated with the susceptibility of pigs to ETEC F41 using 39454 single nucleotide polymorphisms (SNPs) in 667 F2 pigs from a White Duroc×Erhualian F2 cross. The most significant SNP (ALGA0022658, P=5.59×10-13) located at 6.95 Mb on chromosome 4. ALGA0022658 was in high linkage disequilibrium (r 2>0.5) with surrounding SNPs that span a 1.21 Mb interval. Within this 1.21 Mb region, we investigated ZFAT as a positional candidate gene. We re-sequenced cDNA of ZFAT in four pigs with different susceptibility phenotypes, and identified seven coding variants. We genotyped these seven variants in 287 unrelated pigs from 15 diverse breeds that were measured with ETEC F41 susceptibility phenotype. Five variants showed nominal significant association (P<0.05) with ETEC F41 susceptibility phenotype in International commercial pigs. This study provided refined region associated with susceptibility of pigs to ETEC F41 than that reported previously. Further works are needed to uncover the underlying causal mutation(s).

  18. Genome-wide classification and expression analysis of MYB transcription factor families in rice and Arabidopsis

    Directory of Open Access Journals (Sweden)

    Katiyar Amit

    2012-10-01

    Full Text Available Abstract Background The MYB gene family comprises one of the richest groups of transcription factors in plants. Plant MYB proteins are characterized by a highly conserved MYB DNA-binding domain. MYB proteins are classified into four major groups namely, 1R-MYB, 2R-MYB, 3R-MYB and 4R-MYB based on the number and position of MYB repeats. MYB transcription factors are involved in plant development, secondary metabolism, hormone signal transduction, disease resistance and abiotic stress tolerance. A comparative analysis of MYB family genes in rice and Arabidopsis will help reveal the evolution and function of MYB genes in plants. Results A genome-wide analysis identified at least 155 and 197 MYB genes in rice and Arabidopsis, respectively. Gene structure analysis revealed that MYB family genes possess relatively more number of introns in the middle as compared with C- and N-terminal regions of the predicted genes. Intronless MYB-genes are highly conserved both in rice and Arabidopsis. MYB genes encoding R2R3 repeat MYB proteins retained conserved gene structure with three exons and two introns, whereas genes encoding R1R2R3 repeat containing proteins consist of six exons and five introns. The splicing pattern is similar among R1R2R3 MYB genes in Arabidopsis. In contrast, variation in splicing pattern was observed among R1R2R3 MYB members of rice. Consensus motif analysis of 1kb upstream region (5′ to translation initiation codon of MYB gene ORFs led to the identification of conserved and over-represented cis-motifs in both rice and Arabidopsis. Real-time quantitative RT-PCR analysis showed that several members of MYBs are up-regulated by various abiotic stresses both in rice and Arabidopsis. Conclusion A comprehensive genome-wide analysis of chromosomal distribution, tandem repeats and phylogenetic relationship of MYB family genes in rice and Arabidopsis suggested their evolution via duplication. Genome-wide comparative analysis of MYB genes and

  19. Genome-wide analysis of the MYB transcription factor superfamily in soybean

    Directory of Open Access Journals (Sweden)

    Du Hai

    2012-07-01

    Full Text Available Abstract Background The MYB superfamily constitutes one of the most abundant groups of transcription factors described in plants. Nevertheless, their functions appear to be highly diverse and remain rather unclear. To date, no genome-wide characterization of this gene family has been conducted in a legume species. Here we report the first genome-wide analysis of the whole MYB superfamily in a legume species, soybean (Glycine max, including the gene structures, phylogeny, chromosome locations, conserved motifs, and expression patterns, as well as a comparative genomic analysis with Arabidopsis. Results A total of 244 R2R3-MYB genes were identified and further classified into 48 subfamilies based on a phylogenetic comparative analysis with their putative orthologs, showed both gene loss and duplication events. The phylogenetic analysis showed that most characterized MYB genes with similar functions are clustered in the same subfamily, together with the identification of orthologs by synteny analysis, functional conservation among subgroups of MYB genes was strongly indicated. The phylogenetic relationships of each subgroup of MYB genes were well supported by the highly conserved intron/exon structures and motifs outside the MYB domain. Synonymous nucleotide substitution (dN/dS analysis showed that the soybean MYB DNA-binding domain is under strong negative selection. The chromosome distribution pattern strongly indicated that genome-wide segmental and tandem duplication contribute to the expansion of soybean MYB genes. In addition, we found that ~ 4% of soybean R2R3-MYB genes had undergone alternative splicing events, producing a variety of transcripts from a single gene, which illustrated the extremely high complexity of transcriptome regulation. Comparative expression profile analysis of R2R3-MYB genes in soybean and Arabidopsis revealed that MYB genes play conserved and various roles in plants, which is indicative of a divergence in

  20. CONAN: copy number variation analysis software for genome-wide association studies

    Directory of Open Access Journals (Sweden)

    Wichmann Heinz-Erich

    2010-06-01

    Full Text Available Abstract Background Genome-wide association studies (GWAS based on single nucleotide polymorphisms (SNPs revolutionized our perception of the genetic regulation of complex traits and diseases. Copy number variations (CNVs promise to shed additional light on the genetic basis of monogenic as well as complex diseases and phenotypes. Indeed, the number of detected associations between CNVs and certain phenotypes are constantly increasing. However, while several software packages support the determination of CNVs from SNP chip data, the downstream statistical inference of CNV-phenotype associations is still subject to complicated and inefficient in-house solutions, thus strongly limiting the performance of GWAS based on CNVs. Results CONAN is a freely available client-server software solution which provides an intuitive graphical user interface for categorizing, analyzing and associating CNVs with phenotypes. Moreover, CONAN assists the evaluation process by visualizing detected associations via Manhattan plots in order to enable a rapid identification of genome-wide significant CNV regions. Various file formats including the information on CNVs in population samples are supported as input data. Conclusions CONAN facilitates the performance of GWAS based on CNVs and the visual analysis of calculated results. CONAN provides a rapid, valid and straightforward software solution to identify genetic variation underlying the 'missing' heritability for complex traits that remains unexplained by recent GWAS. The freely available software can be downloaded at http://genepi-conan.i-med.ac.at.

  1. Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci.

    Directory of Open Access Journals (Sweden)

    Claire L Simpson

    Full Text Available Refractive error (RE is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness and hyperopia (farsightedness, which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8, which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11 and 8q12 (minimum p value 1.82×10(-11 previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al. and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of

  2. A genome-wide linkage scan for distinct subsets of schizophrenia characterized by age at onset and neurocognitive deficits.

    Directory of Open Access Journals (Sweden)

    Yin-Ju Lien

    Full Text Available BACKGROUND: As schizophrenia is genetically and phenotypically heterogeneous, targeting genetically informative phenotypes may help identify greater linkage signals. The aim of the study is to evaluate the genetic linkage evidence for schizophrenia in subsets of families with earlier age at onset or greater neurocognitive deficits. METHODS: Patients with schizophrenia (n  =  1,207 and their first-degree relatives (n  =  1,035 from 557 families with schizophrenia were recruited from six data collection field research centers throughout Taiwan. Subjects completed a face-to-face semi-structured interview, the Continuous Performance Test (CPT, the Wisconsin Card Sorting Test, and were genotyped with 386 microsatellite markers across the genome. RESULTS: A maximum nonparametric logarithm of odds (LOD score of 4.17 at 2q22.1 was found in 295 families ranked by increasing age at onset, which had significant increases in the maximum LOD score compared with those obtained in initial linkage analyses using all available families. Based on this subset, a further subsetting by false alarm rate on the undegraded and degraded CPT obtained further increase in the nested subset-based LOD on 2q22.1, with a score of 7.36 in 228 families and 7.71 in 243 families, respectively. CONCLUSION: We found possible evidence of linkage on chromosome 2q22.1 in families of schizophrenia patients with more CPT false alarm rates nested within the families with younger age at onset. These results highlight the importance of incorporating genetically informative phenotypes in unraveling the complex genetics of schizophrenia.

  3. Protein Interaction-Based Genome-Wide Analysis of Incident Coronary Heart Disease

    DEFF Research Database (Denmark)

    Jensen, Majken Karoline; Pers, Tune Hannes; Dworzynski, Piotr

    2011-01-01

    Background-Network-based approaches may leverage genome-wide association (GWA) analysis by testing for the aggregate association across several pathway members. We aimed to examine if networks of genes that represent experimentally determined protein-protein interactions (PPIs) are enriched...... are involved in abnormal cardiovascular system physiological features based on knockout mice (4-fold enrichment; Fisher exact test, P = 0.006). Ingenuity pathway analysis revealed that canonical pathways, especially related to blood pressure regulation, were significantly enriched in the genes from the top...... complex. Conclusions-The integration of a GWA study with PPI data successfully identifies a set of candidate susceptibility genes for incident CHD that would have been missed in single-marker GWA analysis. (Circ Cardiovasc Genet. 2011; 4:549-556.)...

  4. Genome-wide analysis of the synonymous codon usage patterns in apple

    Institute of Scientific and Technical Information of China (English)

    LI Ning; SUN Mei-hong; JIANG Ze-sheng; SHU Huai-rui; ZHANG Shi-zhong

    2016-01-01

    Apple (Malus×domestica) has been proposed as an important woody plant and the major cultivated fruit trees in temperate regions. Apple whole genome sequencing has been completed, which provided an excelent opportunity for genome-wide analysis of the synonymous codon usage patterns. In this study, a multivariate bioinformatics analysis was performed to reveal the characteristics of synonymous codon usage and the main factors affecting codon bias in apple. The neutrality, correspondence, and correlation analyses were performed by CodonW and SPSS (Statistical Product and Service Solu-tions) programs, indicating that the apple genome codon usage patterns were affected by mutational pressure and selective constraint. Meanwhile, coding sequence length and the hydrophobicity of proteins could also inlfuence the codon usage patterns. In short, codon usage pattern analysis and determination of optimal codons has laid an important theoretical basis for genetic engineering, gene prediction and molecular evolution studies in apple.

  5. A method for detecting epistasis in genome-wide studies using case-control multi-locus association analysis

    OpenAIRE

    Galan Jose; Quintas Antonio; Royo Jose; Sáez María; Bermudo Fernando; González-Pérez Antonio; Gayán Javier; Morón Francisco; Ramirez-Lorca Reposo; Real Luis; Ruiz Agustín

    2008-01-01

    Abstract Background The difficulty in elucidating the genetic basis of complex diseases roots in the many factors that can affect the development of a disease. Some of these genetic effects may interact in complex ways, proving undetectable by current single-locus methodology. Results We have developed an analysis tool called Hypothesis Free Clinical Cloning (HFCC) to search for genome-wide epistasis in a case-control design. HFCC combines a relatively fast computing algorithm for genome-wide...

  6. Shared Genetic Susceptibility to Ischemic Stroke and Coronary Artery Disease A Genome-Wide Analysis of Common Variants

    OpenAIRE

    Dichgans, Martin; Malik, Rainer; König, Inke R.; Rosand, Jonathan; Clarke, Robert; Gretarsdottir, Solveig; Thorleifsson, Gudmar; Mitchell, Braxton D.; Assimes, Themistocles L.; Levi, Christopher; O′Donnell, Christopher J.; Fornage, Myriam; Thorsteinsdottir, Unnur; Psaty, Bruce M.; Hengstenberg, Christian

    2014-01-01

    To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Genome-wide association data were obtained from ...

  7. Genome-wide scan for serum ghrelin detects linkage on chromosome 1p36 in Hispanic children: results from the Viva La Familia study.

    Science.gov (United States)

    Voruganti, V Saroja; Göring, Harald H H; Diego, Vincent P; Cai, Guowen; Mehta, Nitesh R; Haack, Karin; Cole, Shelley A; Butte, Nancy F; Comuzzie, Anthony G

    2007-10-01

    This study was conducted to investigate genetic influence on serum ghrelin and its relationship with adiposity-related phenotypes in Hispanic children (n=1030) from the Viva La Familia study (VFS). Anthropometric measurements and levels of serum ghrelin were estimated and genetic analyses conducted according to standard procedures. Mean age, body mass index (BMI), and serum ghrelin were 11+/-0.13 y, 25+/-0.24 kg/m2 and 38+/-0.5 ng/mL, respectively. Significant heritabilities (p<0.001) were obtained for BMI, weight, fat mass, percent fat, waist circumference, waist-to-height ratio, and ghrelin. Bivariate analyses of ghrelin with adiposity traits showed significant negative genetic correlations (p<0.0001) with weight, BMI, fat mass, percent fat, waist circumference, and waist-to-height ratio. A genome-wide scan for ghrelin detected significant linkage on chromosome 1p36.2 between STR markers D1S2697 and D1S199 (LOD=3.2). The same region on chromosome 1 was the site of linkage for insulin (LOD=3.3), insulinlike growth factor binding protein 1 (IGFBP1) (LOD=3.4), homeostatic model assessment method (HOMA) (LOD=2.9), and C-peptide (LOD=2.0). Several family-based studies have reported linkages for obesity-related phenotypes in the region of 1p36. These results indicate the importance of this region in relation to adiposity in children from the VFS.

  8. Genome-wide analysis of potential cross-reactive endogenous allergens in rice (Oryza sativa L.

    Directory of Open Access Journals (Sweden)

    Fang Chao Zhu

    2015-01-01

    Full Text Available The proteins in the food are the source of common allergic components to certain patients. Current lists of plant endogenous allergens were based on the medical/clinical reports as well as laboratory results. Plant genome sequences made it possible to predict and characterize the genome-wide of putative endogenous allergens in rice (Oryza sativa L.. In this work, we identified and characterized 122 candidate rice allergens including the 22 allergens in present databases. Conserved domain analysis also revealed 37 domains among rice allergens including one novel domain (histidine kinase-, DNA gyrase B-, and HSP90-like ATPase, PF13589 adding to the allergen protein database. Phylogenetic analysis of the allergens revealed the diversity among the Prolamin superfamily and DnaK protein family, respectively. Additionally, some allergens proteins clustered on the rice chromosome might suggest the molecular function during the evolution.

  9. MGAS: a powerful tool for multivariate gene-based genome-wide association analysis.

    Science.gov (United States)

    Van der Sluis, Sophie; Dolan, Conor V; Li, Jiang; Song, Youqiang; Sham, Pak; Posthuma, Danielle; Li, Miao-Xin

    2015-04-01

    Standard genome-wide association studies, testing the association between one phenotype and a large number of single nucleotide polymorphisms (SNPs), are limited in two ways: (i) traits are often multivariate, and analysis of composite scores entails loss in statistical power and (ii) gene-based analyses may be preferred, e.g. to decrease the multiple testing problem. Here we present a new method, multivariate gene-based association test by extended Simes procedure (MGAS), that allows gene-based testing of multivariate phenotypes in unrelated individuals. Through extensive simulation, we show that under most trait-generating genotype-phenotype models MGAS has superior statistical power to detect associated genes compared with gene-based analyses of univariate phenotypic composite scores (i.e. GATES, multiple regression), and multivariate analysis of variance (MANOVA). Re-analysis of metabolic data revealed 32 False Discovery Rate controlled genome-wide significant genes, and 12 regions harboring multiple genes; of these 44 regions, 30 were not reported in the original analysis. MGAS allows researchers to conduct their multivariate gene-based analyses efficiently, and without the loss of power that is often associated with an incorrectly specified genotype-phenotype models. MGAS is freely available in KGG v3.0 (http://statgenpro.psychiatry.hku.hk/limx/kgg/download.php). Access to the metabolic dataset can be requested at dbGaP (https://dbgap.ncbi.nlm.nih.gov/). The R-simulation code is available from http://ctglab.nl/people/sophie_van_der_sluis. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press.

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

    NARCIS (Netherlands)

    Neale, B.M.; Medland, S.E.; Ripke, S.; Asherson, P.; Franke, B.; Lesch, K.P.; Faraone, S.V.; Nguyen, T.T.; Schafer, H.; Holmans, P.; Daly, M.; Steinhausen, H.C.; Freitag, C.; Reif, A.; Renner, T.J.; Romanos, M.; Romanos, J.; Walitza, S.; Warnke, A.; Meyer, J.; Palmason, H.; Buitelaar, J.K.; Vasquez, A.A.; Lambregts-Rommelse, N.N.J.; Gill, M.; Anney, R.J.; Langely, K.; O'Donovan, M.; Williams, N.; Owen, M.; Thapar, A.; Kent, L.; Sergeant, J.A.; Roeyers, H.; Mick, E.; Biederman, J.; Doyle, A.; Smalley, S.; Loo, S.; Hakonarson, H.; Elia, J.; Todorov, A.; Miranda, A.; Mulas, F.; Ebstein, R.P.; Rothenberger, A.; Banaschewski, T.; Oades, R.D.; Sonuga-Barke, E.; McGough, J.; Nisenbaum, L.; Middleton, F.; Hu, X.; Nelson, S.

    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 signifi

  11. Stepwise Distributed Open Innovation Contests for Software Development: Acceleration of Genome-Wide Association Analysis.

    Science.gov (United States)

    Hill, Andrew; Loh, Po-Ru; Bharadwaj, Ragu B; Pons, Pascal; Shang, Jingbo; Guinan, Eva; Lakhani, Karim; Kilty, Iain; Jelinsky, Scott A

    2017-05-01

    The association of differing genotypes with disease-related phenotypic traits offers great potential to both help identify new therapeutic targets and support stratification of patients who would gain the greatest benefit from specific drug classes. Development of low-cost genotyping and sequencing has made collecting large-scale genotyping data routine in population and therapeutic intervention studies. In addition, a range of new technologies is being used to capture numerous new and complex phenotypic descriptors. As a result, genotype and phenotype datasets have grown exponentially. Genome-wide association studies associate genotypes and phenotypes using methods such as logistic regression. As existing tools for association analysis limit the efficiency by which value can be extracted from increasing volumes of data, there is a pressing need for new software tools that can accelerate association analyses on large genotype-phenotype datasets. Using open innovation (OI) and contest-based crowdsourcing, the logistic regression analysis in a leading, community-standard genetics software package (PLINK 1.07) was substantially accelerated. OI allowed us to do this in computational, numeric, and algorithmic approaches was identified that accelerated the logistic regression in PLINK 1.07 by 18- to 45-fold. Combining contest-derived logistic regression code with coarse-grained parallelization, multithreading, and associated changes to data initialization code further developed through distributed innovation, we achieved an end-to-end speedup of 591-fold for a data set size of 6678 subjects by 645 863 variants, compared to PLINK 1.07's logistic regression. This represents a reduction in run time from 4.8 hours to 29 seconds. Accelerated logistic regression code developed in this project has been incorporated into the PLINK2 project. Using iterative competition-based OI, we have developed a new, faster implementation of logistic regression for genome-wide association

  12. Genome-wide functional analysis of human cell-cycle regulators

    Science.gov (United States)

    Mukherji, Mridul; Bell, Russell; Supekova, Lubica; Wang, Yan; Orth, Anthony P.; Batalov, Serge; Miraglia, Loren; Huesken, Dieter; Lange, Joerg; Martin, Christopher; Sahasrabudhe, Sudhir; Reinhardt, Mischa; Natt, Francois; Hall, Jonathan; Mickanin, Craig; Labow, Mark; Chanda, Sumit K.; Cho, Charles Y.; Schultz, Peter G.

    2006-01-01

    Human cells have evolved complex signaling networks to coordinate the cell cycle. A detailed understanding of the global regulation of this fundamental process requires comprehensive identification of the genes and pathways involved in the various stages of cell-cycle progression. To this end, we report a genome-wide analysis of the human cell cycle, cell size, and proliferation by targeting >95% of the protein-coding genes in the human genome using small interfering RNAs (siRNAs). Analysis of >2 million images, acquired by quantitative fluorescence microscopy, showed that depletion of 1,152 genes strongly affected cell-cycle progression. These genes clustered into eight distinct phenotypic categories based on phase of arrest, nuclear area, and nuclear morphology. Phase-specific networks were built by interrogating knowledge-based and physical interaction databases with identified genes. Genome-wide analysis of cell-cycle regulators revealed a number of kinase, phosphatase, and proteolytic proteins and also suggests that processes thought to regulate G1-S phase progression like receptor-mediated signaling, nutrient status, and translation also play important roles in the regulation of G2/M phase transition. Moreover, 15 genes that are integral to TNF/NF-κB signaling were found to regulate G2/M, a previously unanticipated role for this pathway. These analyses provide systems-level insight into both known and novel genes as well as pathways that regulate cell-cycle progression, a number of which may provide new therapeutic approaches for the treatment of cancer. PMID:17001007

  13. Effects of in ovo electroporation on endogenous gene expression: genome-wide analysis

    Directory of Open Access Journals (Sweden)

    Chambers David

    2011-04-01

    Full Text Available Abstract Background In ovo electroporation is a widely used technique to study gene function in developmental biology. Despite the widespread acceptance of this technique, no genome-wide analysis of the effects of in ovo electroporation, principally the current applied across the tissue and exogenous vector DNA introduced, on endogenous gene expression has been undertaken. Here, the effects of electric current and expression of a GFP-containing construct, via electroporation into the midbrain of Hamburger-Hamilton stage 10 chicken embryos, are analysed by microarray. Results Both current alone and in combination with exogenous DNA expression have a small but reproducible effect on endogenous gene expression, changing the expression of the genes represented on the array by less than 0.1% (current and less than 0.5% (current + DNA, respectively. The subset of genes regulated by electric current and exogenous DNA span a disparate set of cellular functions. However, no genes involved in the regional identity were affected. In sharp contrast to this, electroporation of a known transcription factor, Dmrt5, caused a much greater change in gene expression. Conclusions These findings represent the first systematic genome-wide analysis of the effects of in ovo electroporation on gene expression during embryonic development. The analysis reveals that this process has minimal impact on the genetic basis of cell fate specification. Thus, the study demonstrates the validity of the in ovo electroporation technique to study gene function and expression during development. Furthermore, the data presented here can be used as a resource to refine the set of transcriptional responders in future in ovo electroporation studies of specific gene function.

  14. A genome-wide 20 K citrus microarray for gene expression analysis.

    Science.gov (United States)

    Martinez-Godoy, M Angeles; Mauri, Nuria; Juarez, Jose; Marques, M Carmen; Santiago, Julia; Forment, Javier; Gadea, Jose

    2008-07-03

    Understanding of genetic elements that contribute to key aspects of citrus biology will impact future improvements in this economically important crop. Global gene expression analysis demands microarray platforms with a high genome coverage. In the last years, genome-wide EST collections have been generated in citrus, opening the possibility to create new tools for functional genomics in this crop plant. We have designed and constructed a publicly available genome-wide cDNA microarray that include 21,081 putative unigenes of citrus. As a functional companion to the microarray, a web-browsable database 1 was created and populated with information about the unigenes represented in the microarray, including cDNA libraries, isolated clones, raw and processed nucleotide and protein sequences, and results of all the structural and functional annotation of the unigenes, like general description, BLAST hits, putative Arabidopsis orthologs, microsatellites, putative SNPs, GO classification and PFAM domains. We have performed a Gene Ontology comparison with the full set of Arabidopsis proteins to estimate the genome coverage of the microarray. We have also performed microarray hybridizations to check its usability. This new cDNA microarray replaces the first 7K microarray generated two years ago and allows gene expression analysis at a more global scale. We have followed a rational design to minimize cross-hybridization while maintaining its utility for different citrus species. Furthermore, we also provide access to a website with full structural and functional annotation of the unigenes represented in the microarray, along with the ability to use this site to directly perform gene expression analysis using standard tools at different publicly available servers. Furthermore, we show how this microarray offers a good representation of the citrus genome and present the usefulness of this genomic tool for global studies in citrus by using it to catalogue genes expressed in

  15. A genome-wide 20 K citrus microarray for gene expression analysis

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    Gadea Jose

    2008-07-01

    Full Text Available Abstract Background Understanding of genetic elements that contribute to key aspects of citrus biology will impact future improvements in this economically important crop. Global gene expression analysis demands microarray platforms with a high genome coverage. In the last years, genome-wide EST collections have been generated in citrus, opening the possibility to create new tools for functional genomics in this crop plant. Results We have designed and constructed a publicly available genome-wide cDNA microarray that include 21,081 putative unigenes of citrus. As a functional companion to the microarray, a web-browsable database 1 was created and populated with information about the unigenes represented in the microarray, including cDNA libraries, isolated clones, raw and processed nucleotide and protein sequences, and results of all the structural and functional annotation of the unigenes, like general description, BLAST hits, putative Arabidopsis orthologs, microsatellites, putative SNPs, GO classification and PFAM domains. We have performed a Gene Ontology comparison with the full set of Arabidopsis proteins to estimate the genome coverage of the microarray. We have also performed microarray hybridizations to check its usability. Conclusion This new cDNA microarray replaces the first 7K microarray generated two years ago and allows gene expression analysis at a more global scale. We have followed a rational design to minimize cross-hybridization while maintaining its utility for different citrus species. Furthermore, we also provide access to a website with full structural and functional annotation of the unigenes represented in the microarray, along with the ability to use this site to directly perform gene expression analysis using standard tools at different publicly available servers. Furthermore, we show how this microarray offers a good representation of the citrus genome and present the usefulness of this genomic tool for global

  16. Genome-wide interaction-based association analysis identified multiple new susceptibility Loci for common diseases.

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    Yang Liu

    2011-03-01

    Full Text Available Genome-wide interaction-based association (GWIBA analysis has the potential to identify novel susceptibility loci. These interaction effects could be missed with the prevailing approaches in genome-wide association studies (GWAS. However, no convincing loci have been discovered exclusively from GWIBA methods, and the intensive computation involved is a major barrier for application. Here, we developed a fast, multi-thread/parallel program named "pair-wise interaction-based association mapping" (PIAM for exhaustive two-locus searches. With this program, we performed a complete GWIBA analysis on seven diseases with stringent control for false positives, and we validated the results for three of these diseases. We identified one pair-wise interaction between a previously identified locus, C1orf106, and one new locus, TEC, that was specific for Crohn's disease, with a Bonferroni corrected P < 0.05 (P = 0.039. This interaction was replicated with a pair of proxy linked loci (P = 0.013 on an independent dataset. Five other interactions had corrected P < 0.5. We identified the allelic effect of a locus close to SLC7A13 for coronary artery disease. This was replicated with a linked locus on an independent dataset (P = 1.09 × 10⁻⁷. Through a local validation analysis that evaluated association signals, rather than locus-based associations, we found that several other regions showed association/interaction signals with nominal P < 0.05. In conclusion, this study demonstrated that the GWIBA approach was successful for identifying novel loci, and the results provide new insights into the genetic architecture of common diseases. In addition, our PIAM program was capable of handling very large GWAS datasets that are likely to be produced in the future.

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

    DEFF Research Database (Denmark)

    Mechelli, Rosella; Umeton, Renato; Policano, Claudia

    2013-01-01

    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...... 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...... 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....

  18. Moving towards system genetics through multiple trait analysis in genome-wide association studies

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    Daniel eShriner

    2012-01-01

    Full Text Available Association studies are a staple of genotype-phenotype mapping studies, whether they are based on single markers, haplotypes, candidate genes, genome-wide genotypes, or whole genome sequences. Although genetic epidemiological studies typically contain data collected on multiple traits which themselves are often correlated, most analyses have been performed on single traits. Here, I review several methods that have been developed to perform multiple trait analysis. These methods range from traditional multivariate models for systems of equations to recently developed graphical approaches based on network theory. The application of network theory to genetics is termed systems genetics and has the potential to address long-standing questions in genetics about complex processes such as coordinate regulation, homeostasis, and pleiotropy.

  19. Genome-Wide Analysis and Molecular Characterization of Heat Shock Transcription Factor Family in Glycine max

    Institute of Scientific and Technical Information of China (English)

    Eunsook Chung; Kyoung-Mi Kim; Jai-Heon Lee

    2013-01-01

    Heat shock transcription factors (Hsfs) play an essential role on the increased tolerance against heat stress by regulating the expression of heat-responsive genes.In this study,a genome-wide analysis was performed to identify all of the soybean (Glycine max) GmHsfgenes based on the latest soybean genome sequence.Chromosomal location,protein domain,motif organization,and phylogenetic relationships of 26 non-redundant GmHsf genes were analyzed compared with AtHsfs (Arabidopsis thaliana Hsfs).According to their structural features,the predicted members were divided into the previously defined classes A-C,as described for AtHsfs.Transcript levels and subcellular localization of five GmHsfs responsive to abiotic stresses were analyzed by real-time RT-PCR.These results provide a fundamental clue for understanding the complexity of the soybean GmHsfgene family and cloning the functional genes in future studies.

  20. Genome-Wide Analysis Reveals Novel Regulators of Growth in Drosophila melanogaster.

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    Sibylle Chantal Vonesch

    2016-01-01

    Full Text Available Organismal size depends on the interplay between genetic and environmental factors. Genome-wide association (GWA analyses in humans have implied many genes in the control of height but suffer from the inability to control the environment. Genetic analyses in Drosophila have identified conserved signaling pathways controlling size; however, how these pathways control phenotypic diversity is unclear. We performed GWA of size traits using the Drosophila Genetic Reference Panel of inbred, sequenced lines. We find that the top associated variants differ between traits and sexes; do not map to canonical growth pathway genes, but can be linked to these by epistasis analysis; and are enriched for genes and putative enhancers. Performing GWA on well-studied developmental traits under controlled conditions expands our understanding of developmental processes underlying phenotypic diversity.

  1. Genome-Wide Analysis Reveals Novel Regulators of Growth in Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Sibylle Chantal Vonesch

    2016-01-01

    Full Text Available Organismal size depends on the interplay between genetic and environmental factors. Genome-wide association (GWA analyses in humans have implied many genes in the control of height but suffer from the inability to control the environment. Genetic analyses in Drosophila have identified conserved signaling pathways controlling size; however, how these pathways control phenotypic diversity is unclear. We performed GWA of size traits using the Drosophila Genetic Reference Panel of inbred, sequenced lines. We find that the top associated variants differ between traits and sexes; do not map to canonical growth pathway genes, but can be linked to these by epistasis analysis; and are enriched for genes and putative enhancers. Performing GWA on well-studied developmental traits under controlled conditions expands our understanding of developmental processes underlying phenotypic diversity.

  2. Multi-platform genome-wide analysis of melanoma progression to brain metastasis

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    Diego M. Marzese

    2014-12-01

    Full Text Available Melanoma has a high tendency to metastasize to brain tissue. The understanding about the molecular alterations of early-stage melanoma progression to brain metastasis (MBM is very limited. Identifying MBM-specific genomic and epigenomic alterations is a key initial step in understanding its aggressive nature and identifying specific novel druggable targets. Here, we describe a multi-platform dataset generated with different stages of melanoma progression to MBM. This data includes genome-wide DNA methylation (Illumina HM450K BeadChip, gene expression (Affymetrix HuEx 1.0 ST array, single nucleotide polymorphisms (SNPs and copy number variation (CNV; Affymetrix SNP 6.0 array analyses of melanocyte cells (MNCs, primary melanoma tumors (PRMs, lymph node metastases (LNMs and MBMs. The analysis of this data has been reported in our recently published study (Marzese et al., 2014.

  3. Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis.

    Science.gov (United States)

    Peters, Ulrike; Jiao, Shuo; Schumacher, Fredrick R; Hutter, Carolyn M; Aragaki, Aaron K; Baron, John A; Berndt, Sonja I; Bézieau, Stéphane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J; Campbell, Peter T; Carlson, Christopher S; Casey, Graham; Chan, Andrew T; Chang-Claude, Jenny; Chanock, Stephen J; Chen, Lin S; Coetzee, Gerhard A; Coetzee, Simon G; Conti, David V; Curtis, Keith R; Duggan, David; Edwards, Todd; Fuchs, Charles S; Gallinger, Steven; Giovannucci, Edward L; Gogarten, Stephanie M; Gruber, Stephen B; Haile, Robert W; Harrison, Tabitha A; Hayes, Richard B; Henderson, Brian E; Hoffmeister, Michael; Hopper, John L; Hudson, Thomas J; Hunter, David J; Jackson, Rebecca D; Jee, Sun Ha; Jenkins, Mark A; Jia, Wei-Hua; Kolonel, Laurence N; Kooperberg, Charles; Küry, Sébastien; Lacroix, Andrea Z; Laurie, Cathy C; Laurie, Cecelia A; Le Marchand, Loic; Lemire, Mathieu; Levine, David; Lindor, Noralane M; Liu, Yan; Ma, Jing; Makar, Karen W; Matsuo, Keitaro; Newcomb, Polly A; Potter, John D; Prentice, Ross L; Qu, Conghui; Rohan, Thomas; Rosse, Stephanie A; Schoen, Robert E; Seminara, Daniela; Shrubsole, Martha; Shu, Xiao-Ou; Slattery, Martha L; Taverna, Darin; Thibodeau, Stephen N; Ulrich, Cornelia M; White, Emily; Xiang, Yongbing; Zanke, Brent W; Zeng, Yi-Xin; Zhang, Ben; Zheng, Wei; Hsu, Li

    2013-04-01

    Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)). In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further

  4. Development and Integration of Genome-Wide Polymorphic Microsatellite Markers onto a Reference Linkage Map for Constructing a High-Density Genetic Map of Chickpea.

    Science.gov (United States)

    Khajuria, Yash Paul; Saxena, Maneesha S; Gaur, Rashmi; Chattopadhyay, Debasis; Jain, Mukesh; Parida, Swarup K; Bhatia, Sabhyata

    2015-01-01

    The identification of informative in silico polymorphic genomic and genic microsatellite markers by comparing the genome and transcriptome sequences of crop genotypes is a rapid, cost-effective and non-laborious approach for large-scale marker validation and genotyping applications, including construction of high-density genetic maps. We designed 1494 markers, including 1016 genomic and 478 transcript-derived microsatellite markers showing in-silico fragment length polymorphism between two parental genotypes (Cicer arietinum ICC4958 and C. reticulatum PI489777) of an inter-specific reference mapping population. High amplification efficiency (87%), experimental validation success rate (81%) and polymorphic potential (55%) of these microsatellite markers suggest their effective use in various applications of chickpea genetics and breeding. Intra-specific polymorphic potential (48%) detected by microsatellite markers in 22 desi and kabuli chickpea genotypes was lower than inter-specific polymorphic potential (59%). An advanced, high-density, integrated and inter-specific chickpea genetic map (ICC4958 x PI489777) having 1697 map positions spanning 1061.16 cM with an average inter-marker distance of 0.625 cM was constructed by assigning 634 novel informative transcript-derived and genomic microsatellite markers on eight linkage groups (LGs) of our prior documented, 1063 marker-based genetic map. The constructed genome map identified 88, including four major (7-23 cM) longest high-resolution genomic regions on LGs 3, 5 and 8, where the maximum number of novel genomic and genic microsatellite markers were specifically clustered within 1 cM genetic distance. It was for the first time in chickpea that in silico FLP analysis at genome-wide level was carried out and such a large number of microsatellite markers were identified, experimentally validated and further used in genetic mapping. To best of our knowledge, in the presently constructed genetic map, we mapped highest

  5. Development and Integration of Genome-Wide Polymorphic Microsatellite Markers onto a Reference Linkage Map for Constructing a High-Density Genetic Map of Chickpea.

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    Yash Paul Khajuria

    Full Text Available The identification of informative in silico polymorphic genomic and genic microsatellite markers by comparing the genome and transcriptome sequences of crop genotypes is a rapid, cost-effective and non-laborious approach for large-scale marker validation and genotyping applications, including construction of high-density genetic maps. We designed 1494 markers, including 1016 genomic and 478 transcript-derived microsatellite markers showing in-silico fragment length polymorphism between two parental genotypes (Cicer arietinum ICC4958 and C. reticulatum PI489777 of an inter-specific reference mapping population. High amplification efficiency (87%, experimental validation success rate (81% and polymorphic potential (55% of these microsatellite markers suggest their effective use in various applications of chickpea genetics and breeding. Intra-specific polymorphic potential (48% detected by microsatellite markers in 22 desi and kabuli chickpea genotypes was lower than inter-specific polymorphic potential (59%. An advanced, high-density, integrated and inter-specific chickpea genetic map (ICC4958 x PI489777 having 1697 map positions spanning 1061.16 cM with an average inter-marker distance of 0.625 cM was constructed by assigning 634 novel informative transcript-derived and genomic microsatellite markers on eight linkage groups (LGs of our prior documented, 1063 marker-based genetic map. The constructed genome map identified 88, including four major (7-23 cM longest high-resolution genomic regions on LGs 3, 5 and 8, where the maximum number of novel genomic and genic microsatellite markers were specifically clustered within 1 cM genetic distance. It was for the first time in chickpea that in silico FLP analysis at genome-wide level was carried out and such a large number of microsatellite markers were identified, experimentally validated and further used in genetic mapping. To best of our knowledge, in the presently constructed genetic map, we mapped

  6. Development and Integration of Genome-Wide Polymorphic Microsatellite Markers onto a Reference Linkage Map for Constructing a High-Density Genetic Map of Chickpea

    Science.gov (United States)

    Gaur, Rashmi; Chattopadhyay, Debasis; Jain, Mukesh; Parida, Swarup K.; Bhatia, Sabhyata

    2015-01-01

    The identification of informative in silico polymorphic genomic and genic microsatellite markers by comparing the genome and transcriptome sequences of crop genotypes is a rapid, cost-effective and non-laborious approach for large-scale marker validation and genotyping applications, including construction of high-density genetic maps. We designed 1494 markers, including 1016 genomic and 478 transcript-derived microsatellite markers showing in-silico fragment length polymorphism between two parental genotypes (Cicer arietinum ICC4958 and C. reticulatum PI489777) of an inter-specific reference mapping population. High amplification efficiency (87%), experimental validation success rate (81%) and polymorphic potential (55%) of these microsatellite markers suggest their effective use in various applications of chickpea genetics and breeding. Intra-specific polymorphic potential (48%) detected by microsatellite markers in 22 desi and kabuli chickpea genotypes was lower than inter-specific polymorphic potential (59%). An advanced, high-density, integrated and inter-specific chickpea genetic map (ICC4958 x PI489777) having 1697 map positions spanning 1061.16 cM with an average inter-marker distance of 0.625 cM was constructed by assigning 634 novel informative transcript-derived and genomic microsatellite markers on eight linkage groups (LGs) of our prior documented, 1063 marker-based genetic map. The constructed genome map identified 88, including four major (7–23 cM) longest high-resolution genomic regions on LGs 3, 5 and 8, where the maximum number of novel genomic and genic microsatellite markers were specifically clustered within 1 cM genetic distance. It was for the first time in chickpea that in silico FLP analysis at genome-wide level was carried out and such a large number of microsatellite markers were identified, experimentally validated and further used in genetic mapping. To best of our knowledge, in the presently constructed genetic map, we mapped highest

  7. Goldsurfer2 (Gs2: A comprehensive tool for the analysis and visualization of genome wide association studies

    Directory of Open Access Journals (Sweden)

    Barnes Michael R

    2008-03-01

    Full Text Available Abstract Background Genome wide association (GWA studies are now being widely undertaken aiming to find the link between genetic variations and common diseases. Ideally, a well-powered GWA study will involve the measurement of hundreds of thousands of single nucleotide polymorphisms (SNPs in thousands of individuals. The sheer volume of data generated by these experiments creates very high analytical demands. There are a number of important steps during the analysis of such data, many of which may present severe bottlenecks. The data need to be imported and reviewed to perform initial quality control (QC before proceeding to association testing. Evaluation of results may involve further statistical analysis, such as permutation testing, or further QC of associated markers, for example, reviewing raw genotyping intensities. Finally significant associations need to be prioritised using functional and biological interpretation methods, browsing available biological annotation, pathway information and patterns of linkage disequilibrium (LD. Results We have developed an interactive and user-friendly graphical application to be used in all steps in GWA projects from initial data QC and analysis to biological evaluation and validation of results. The program is implemented in Java and can be used on all platforms. Conclusion Very large data sets (e.g. 500 k markers and 5000 samples can be quality assessed, rapidly analysed and integrated with genomic sequence information. Candidate SNPs can be selected and functionally evaluated.

  8. Genome-wide linkage scan for loci of musical aptitude in Finnish families: evidence for a major locus at 4q22.

    Science.gov (United States)

    Pulli, K; Karma, K; Norio, R; Sistonen, P; Göring, H H H; Järvelä, I

    2008-07-01

    Music perception and performance are comprehensive human cognitive functions and thus provide an excellent model system for studying human behaviour and brain function. However, the molecules involved in mediating music perception and performance are so far uncharacterised. To unravel the biological background of music perception, using molecular and statistical genetic approaches. 15 Finnish multigenerational families (with a total of 234 family members) were recruited via a nationwide search. The phenotype of all family members was determined using three tests used in defining musical aptitude: a test for auditory structuring ability (Karma Music test; KMT) commonly used in Finland, and the Seashore pitch and time discrimination subtests (SP and ST respectively) used internationally. We calculated heritabilities and performed a genome-wide variance components-based linkage scan using genotype data for 1113 microsatellite markers. The heritability estimates were 42% for KMT, 57% for SP, 21% for ST and 48% for the combined music test scores. Significant evidence of linkage was obtained on chromosome 4q22 (LOD 3.33) and suggestive evidence of linkage at 8q13-21 (LOD 2.29) with the combined music test scores, using variance component linkage analyses. The major contribution of the 4q22 locus was obtained for the KMT (LOD 2.91). Interestingly, a positive LOD score of 1.69 was shown at 18q, a region previously linked to dyslexia (DYX6) using combined music test scores. Our results show that there is a genetic contribution to musical aptitude that is likely to be regulated by several predisposing genes or variants.

  9. A genome-wide analysis of small regulatory RNAs in the human pathogen group A Streptococcus.

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    Nataly Perez

    Full Text Available The coordinated regulation of gene expression is essential for pathogens to infect and cause disease. A recently appreciated mechanism of regulation is that afforded by small regulatory RNA (sRNA molecules. Here, we set out to assess the prevalence of sRNAs in the human bacterial pathogen group A Streptococcus (GAS. Genome-wide identification of candidate GAS sRNAs was performed through a tiling Affymetrix microarray approach and identified 40 candidate sRNAs within the M1T1 GAS strain MGAS2221. Together with a previous bioinformatic approach this brings the number of novel candidate sRNAs in GAS to 75, a number that approximates the number of GAS transcription factors. Transcripts were confirmed by Northern blot analysis for 16 of 32 candidate sRNAs tested, and the abundance of several of these sRNAs were shown to be temporally regulated. Six sRNAs were selected for further study and the promoter, transcriptional start site, and Rho-independent terminator identified for each. Significant variation was observed between the six sRNAs with respect to their stability during growth, and with respect to their inter- and/or intra-serotype-specific levels of abundance. To start to assess the contribution of sRNAs to gene regulation in M1T1 GAS we deleted the previously described sRNA PEL from four clinical isolates. Data from genome-wide expression microarray, quantitative RT-PCR, and Western blot analyses are consistent with PEL having no regulatory function in M1T1 GAS. The finding that candidate sRNA molecules are prevalent throughout the GAS genome provides significant impetus to the study of this fundamental gene-regulatory mechanism in an important human pathogen.

  10. Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases.

    Directory of Open Access Journals (Sweden)

    Vincent Plagnol

    2011-08-01

    Full Text Available The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC human leukocyte antigen (HLA region. The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP data in type 1 diabetes (T1D patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506, insulinoma-associated antigen 2 (IA-2A, n = 2,498, antibodies to the autoimmune thyroid (Graves' disease (AITD autoantigen thyroid peroxidase (TPOA, n = 8,300, and antibodies against gastric parietal cells (PCA, n = 4,328 that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10(-10: 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A.

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

    Science.gov (United States)

    Ali Hassan, Nur Zarina; Mokhtar, Norfilza Mohd; Kok Sin, Teow; Mohamed Rose, Isa; Sagap, Ismail; Harun, Roslan; Jamal, Rahman

    2014-01-01

    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.

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

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    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.

  13. Genome-wide copy number analysis uncovers a new HSCR gene: NRG3.

    Directory of Open Access Journals (Sweden)

    Clara Sze-Man Tang

    Full Text Available Hirschsprung disease (HSCR is a congenital disorder characterized by aganglionosis of the distal intestine. To assess the contribution of copy number variants (CNVs to HSCR, we analysed the data generated from our previous genome-wide association study on HSCR patients, whereby we identified NRG1 as a new HSCR susceptibility locus. Analysis of 129 Chinese patients and 331 ethnically matched controls showed that HSCR patients have a greater burden of rare CNVs (p = 1.50 × 10(-5, particularly for those encompassing genes (p = 5.00 × 10(-6. Our study identified 246 rare-genic CNVs exclusive to patients. Among those, we detected a NRG3 deletion (p = 1.64 × 10(-3. Subsequent follow-up (96 additional patients and 220 controls on NRG3 revealed 9 deletions (combined p = 3.36 × 10(-5 and 2 de novo duplications among patients and two deletions among controls. Importantly, NRG3 is a paralog of NRG1. Stratification of patients by presence/absence of HSCR-associated syndromes showed that while syndromic-HSCR patients carried significantly longer CNVs than the non-syndromic or controls (p = 1.50 × 10(-5, non-syndromic patients were enriched in CNV number when compared to controls (p = 4.00 × 10(-6 or the syndromic counterpart. Our results suggest a role for NRG3 in HSCR etiology and provide insights into the relative contribution of structural variants in both syndromic and non-syndromic HSCR. This would be the first genome-wide catalog of copy number variants identified in HSCR.

  14. Genome-wide linkage mapping of QTL for black point reaction in bread wheat (Triticum aestivum L.).

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    Liu, Jindong; He, Zhonghu; Wu, Ling; Bai, Bin; Wen, Weie; Xie, Chaojie; Xia, Xianchun

    2016-11-01

    Nine QTL for black point resistance in wheat were identified using a RIL population derived from a Linmai 2/Zhong 892 cross and 90K SNP assay. Black point, discoloration of the embryo end of the grain, downgrades wheat grain quality leading to significant economic losses to the wheat industry. The availability of molecular markers will accelerate improvement of black point resistance in wheat breeding. The aims of this study were to identify quantitative trait loci (QTL) for black point resistance and tightly linked molecular markers, and to search for candidate genes using a high-density genetic linkage map of wheat. A recombinant inbred line (RIL) population derived from the cross Linmai 2/Zhong 892 was evaluated for black point reaction during the 2011-2012, 2012-2013 and 2013-2014 cropping seasons, providing data for seven environments. A high-density linkage map was constructed by genotyping the RILs with the wheat 90K single nucleotide polymorphism (SNP) chip. Composite interval mapping detected nine QTL on chromosomes 2AL, 2BL, 3AL, 3BL, 5AS, 6A, 7AL (2) and 7BS, designated as QBp.caas-2AL, QBp.caas-2BL, QBp.caas-3AL, QBp.caas-3BL, QBp.caas-5AS, QBp.caas-6A, QBp.caas-7AL.1, QBp.caas-7AL.2 and QBp.caas-7BS, respectively. All resistance alleles, except for QBp.caas-7AL.1 from Linmai 2, were contributed by Zhong 892. QBp.caas-3BL, QBp.caas-5AS, QBp.caas-7AL.1, QBp.caas-7AL.2 and QBp.caas-7BS probably represent new loci for black point resistance. Sequences of tightly linked SNPs were used to survey wheat and related cereal genomes identifying three candidate genes for black point resistance. The tightly linked SNP markers can be used in marker-assisted breeding in combination with the kompetitive allele specific PCR technique to improve black point resistance.

  15. Accounting for selection and correlation in the analysis of two-stage genome-wide association studies.

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    Robertson, David S; Prevost, A Toby; Bowden, Jack

    2016-10-01

    The problem of selection bias has long been recognized in the analysis of two-stage trials, where promising candidates are selected in stage 1 for confirmatory analysis in stage 2. To efficiently correct for bias, uniformly minimum variance conditionally unbiased estimators (UMVCUEs) have been proposed for a wide variety of trial settings, but where the population parameter estimates are assumed to be independent. We relax this assumption and derive the UMVCUE in the multivariate normal setting with an arbitrary known covariance structure. One area of application is the estimation of odds ratios (ORs) when combining a genome-wide scan with a replication study. Our framework explicitly accounts for correlated single nucleotide polymorphisms, as might occur due to linkage disequilibrium. We illustrate our approach on the measurement of the association between 11 genetic variants and the risk of Crohn's disease, as reported in Parkes and others (2007. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Gen. 39: (7), 830-832.), and show that the estimated ORs can vary substantially if both selection and correlation are taken into account.

  16. Genome-wide identification and phylogenetic analysis of the ERF gene family in cucumbers

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    Lifang Hu

    2011-01-01

    Full Text Available Members of the ERF transcription-factor family participate in a number of biological processes, viz., responses to hormones, adaptation to biotic and abiotic stress, metabolism regulation, beneficial symbiotic interactions, cell differentiation and developmental processes. So far, no tissue-expression profile of any cucumber ERF protein has been reported in detail. Recent completion of the cucumber full-genome sequence has come to facilitate, not only genome-wide analysis of ERF family members in cucumbers themselves, but also a comparative analysis with those in Arabidopsis and rice. In this study, 103 hypothetical ERF family genes in the cucumber genome were identified, phylogenetic analysis indicating their classification into 10 groups, designated I to X. Motif analysis further indicated that most of the conserved motifs outside the AP2/ERF domain, are selectively distributed among the specific clades in the phylogenetic tree. From chromosomal localization and genome distribution analysis, it appears that tandem-duplication may have contributed to CsERF gene expansion. Intron/exon structure analysis indicated that a few CsERFs still conserved the former intron-position patterns existent in the common ancestor of monocots and eudicots. Expression analysis revealed the widespread distribution of the cucumber ERF gene family within plant tissues, thereby implying the probability of their performing various roles therein. Furthermore, members of some groups presented mutually similar expression patterns that might be related to their phylogenetic groups.

  17. Genome-Wide Analysis of the Aquaporin Gene Family in Chickpea (Cicer arietinum L.).

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    Deokar, Amit A; Tar'an, Bunyamin

    2016-01-01

    Aquaporins (AQPs) are essential membrane proteins that play critical role in the transport of water and many other solutes across cell membranes. In this study, a comprehensive genome-wide analysis identified 40 AQP genes in chickpea (Cicer arietinum L.). A complete overview of the chickpea AQP (CaAQP) gene family is presented, including their chromosomal locations, gene structure, phylogeny, gene duplication, conserved functional motifs, gene expression, and conserved promoter motifs. To understand AQP's evolution, a comparative analysis of chickpea AQPs with AQP orthologs from soybean, Medicago, common bean, and Arabidopsis was performed. The chickpea AQP genes were found on all of the chickpea chromosomes, except chromosome 7, with a maximum of six genes on chromosome 6, and a minimum of one gene on chromosome 5. Gene duplication analysis indicated that the expansion of chickpea AQP gene family might have been due to segmental and tandem duplications. CaAQPs were grouped into four subfamilies including 15 NOD26-like intrinsic proteins (NIPs), 13 tonoplast intrinsic proteins (TIPs), eight plasma membrane intrinsic proteins (PIPs), and four small basic intrinsic proteins (SIPs) based on sequence similarities and phylogenetic position. Gene structure analysis revealed a highly conserved exon-intron pattern within CaAQP subfamilies supporting the CaAQP family classification. Functional prediction based on conserved Ar/R selectivity filters, Froger's residues, and specificity-determining positions suggested wide differences in substrate specificity among the subfamilies of CaAQPs. Expression analysis of the AQP genes indicated that some of the genes are tissue-specific, whereas few other AQP genes showed differential expression in response to biotic and abiotic stresses. Promoter profiling of CaAQP genes for conserved cis-acting regulatory elements revealed enrichment of cis-elements involved in circadian control, light response, defense and stress responsiveness

  18. A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder.

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    Wang, Ke-Sheng; Liu, Xue-Feng; Aragam, Nagesh

    2010-12-01

    Schizophrenia and bipolar disorder both have strong inherited components. Recent studies have indicated that schizophrenia and bipolar disorder may share more than half of their genetic determinants. In this study, we performed a meta-analysis (combined analysis) for genome-wide association data of the Affymetrix Genome-Wide Human SNP array 6.0 to detect genetic variants influencing both schizophrenia and bipolar disorder using European-American samples (653 bipolar cases and 1034 controls, 1172 schizophrenia cases and 1379 controls). The best associated SNP rs11789399 was located at 9q33.1 (p=2.38 × 10(-6), 5.74 × 10(-4), and 5.56 × 10(-9), for schizophrenia, bipolar disorder and meta-analysis of schizophrenia and bipolar disorder, respectively), where one flanking gene, ASTN2 (220kb away) has been associated with attention deficit/hyperactivity disorder and schizophrenia. The next best SNP was rs12201676 located at 6q15 (p=2.67 × 10(-4), 2.12 × 10(-5), 3.88 × 10(-8) for schizophrenia, bipolar disorder and meta-analysis, respectively), near two flanking genes, GABRR1 and GABRR2 (15 and 17kb away, respectively). The third interesting SNP rs802568 was at 7q35 within CNTNAP2 (p=8.92 × 10(-4), 1.38 × 10(-5), and 1.62 × 10(-7) for schizophrenia, bipolar disorder and meta-analysis, respectively). Through meta-analysis, we found two additional associated genes NALCN (the top SNP is rs2044117, p=4.57 × 10(-7)) and NAP5 (the top SNP is rs10496702, p=7.15 × 10(-7)). Haplotype analyses of above five loci further supported the associations with schizophrenia and bipolar disorder. These results provide evidence of common genetic variants influencing schizophrenia and bipolar disorder. These findings will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in schizophrenia and bipolar disorder.

  19. Genome-wide identification, classification and analysis of heat shock transcription factor family in maize

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    Zhu Su-Wen

    2011-01-01

    Full Text Available Abstract Background Heat shock response in eukaryotes is transcriptionally regulated by conserved heat shock transcription factors (Hsfs. Hsf genes are represented by a large multigene family in plants and investigation of the Hsf gene family will serve to elucidate the mechanisms by which plants respond to stress. In recent years, reports of genome-wide structural and evolutionary analysis of the entire Hsf gene family have been generated in two model plant systems, Arabidopsis and rice. Maize, an important cereal crop, has represented a model plant for genetics and evolutionary research. Although some Hsf genes have been characterized in maize, analysis of the entire Hsf gene family were not completed following Maize (B73 Genome Sequencing Project. Results A genome-wide analysis was carried out in the present study to identify all Hsfs maize genes. Due to the availability of complete maize genome sequences, 25 nonredundant Hsf genes, named ZmHsfs were identified. Chromosomal location, protein domain and motif organization of ZmHsfs were analyzed in maize genome. The phylogenetic relationships, gene duplications and expression profiles of ZmHsf genes were also presented in this study. Twenty-five ZmHsfs were classified into three major classes (class A, B, and C according to their structural characteristics and phylogenetic comparisons, and class A was further subdivided into 10 subclasses. Moreover, phylogenetic analysis indicated that the orthologs from the three species (maize, Arabidopsis and rice were distributed in all three classes, it also revealed diverse Hsf gene family expression patterns in classes and subclasses. Chromosomal/segmental duplications played a key role in Hsf gene family expansion in maize by investigation of gene duplication events. Furthermore, the transcripts of 25 ZmHsf genes were detected in the leaves by heat shock using quantitative real-time PCR. The result demonstrated that ZmHsf genes exhibit different

  20. Genome-wide and expression analysis of protein phosphatase 2C in rice and Arabidopsis

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    Jakab Stephen

    2008-11-01

    Full Text Available Abstract Background The protein phosphatase 2Cs (PP2Cs from various organisms have been implicated to act as negative modulators of protein kinase pathways involved in diverse environmental stress responses and developmental processes. A genome-wide overview of the PP2C gene family in plants is not yet available. Results A comprehensive computational analysis identified 80 and 78 PP2C genes in Arabidopsis thaliana (AtPP2Cs and Oryza sativa (OsPP2Cs, respectively, which denotes the PP2C gene family as one of the largest families identified in plants. Phylogenic analysis divided PP2Cs in Arabidopsis and rice into 13 and 11 subfamilies, respectively, which are supported by the analyses of gene structures and protein motifs. Comparative analysis between the PP2C genes in Arabidopsis and rice identified common and lineage-specific subfamilies and potential 'gene birth-and-death' events. Gene duplication analysis reveals that whole genome and chromosomal segment duplications mainly contributed to the expansion of both OsPP2Cs and AtPP2Cs, but tandem or local duplication occurred less frequently in Arabidopsis than rice. Some protein motifs are widespread among the PP2C proteins, whereas some other motifs are specific to only one or two subfamilies. Expression pattern analysis suggests that 1 most PP2C genes play functional roles in multiple tissues in both species, 2 the induced expression of most genes in subfamily A by diverse stimuli indicates their primary role in stress tolerance, especially ABA response, and 3 the expression pattern of subfamily D members suggests that they may constitute positive regulators in ABA-mediated signaling pathways. The analyses of putative upstream regulatory elements by two approaches further support the functions of subfamily A in ABA signaling, and provide insights into the shared and different transcriptional regulation machineries in dicots and monocots. Conclusion This comparative genome-wide overview of the PP

  1. Genome wide analysis of stress responsive WRKY transcription factors in Arabidopsis thaliana

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    Shaiq Sultan

    2016-04-01

    Full Text Available WRKY transcription factors are a class of DNA-binding proteins that bind with a specific sequence C/TTGACT/C known as W-Box found in promoters of genes which are regulated by these WRKYs. From previous studies, 43 different stress responsive WRKY transcription factors in Arabidopsis thaliana, identified and then categorized in three groups viz., abiotic, biotic and both of these stresses. A comprehensive genome wide analysis including chromosomal localization, gene structure analysis, multiple sequence alignment, phylogenetic analysis and promoter analysis of these WRKY genes was carried out in this study to determine the functional homology in Arabidopsis. This analysis led to the classification of these WRKY family members into 3 major groups and subgroups and showed evolutionary relationship among these groups on the base of their functional WRKY domain, chromosomal localization and intron/exon structure. The proposed groups of these stress responsive WRKY genes and annotation based on their position on chromosomes can also be explored to determine their functional homology in other plant species in relation to different stresses. The result of the present study provides indispensable genomic information for the stress responsive WRKY transcription factors in Arabidopsis and will pave the way to explain the precise role of various AtWRKYs in plant growth and development under stressed conditions.

  2. Genome-wide association analysis of imputed rare variants: application to seven common complex diseases.

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    Mägi, Reedik; Asimit, Jennifer L; Day-Williams, Aaron G; Zeggini, Eleftheria; Morris, Andrew P

    2012-12-01

    Genome-wide association studies have been successful in identifying loci contributing effects to a range of complex human traits. The majority of reproducible associations within these loci are with common variants, each of modest effect, which together explain only a small proportion of heritability. It has been suggested that much of the unexplained genetic component of complex traits can thus be attributed to rare variation. However, genome-wide association study genotyping chips have been designed primarily to capture common variation, and thus are underpowered to detect the effects of rare variants. Nevertheless, we demonstrate here, by simulation, that imputation from an existing scaffold of genome-wide genotype data up to high-density reference panels has the potential to identify rare variant associations with complex traits, without the need for costly re-sequencing experiments. By application of this approach to genome-wide association studies of seven common complex diseases, imputed up to publicly available reference panels, we identify genome-wide significant evidence of rare variant association in PRDM10 with coronary artery disease and multiple genes in the major histocompatibility complex (MHC) with type 1 diabetes. The results of our analyses highlight that genome-wide association studies have the potential to offer an exciting opportunity for gene discovery through association with rare variants, conceivably leading to substantial advancements in our understanding of the genetic architecture underlying complex human traits.

  3. Pathway analysis of genome-wide association datasets of personality traits.

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    Kim, H-N; Kim, B-H; Cho, J; Ryu, S; Shin, H; Sung, J; Shin, C; Cho, N H; Sung, Y A; Choi, B-O; Kim, H-L

    2015-04-01

    Although several genome-wide association (GWA) studies of human personality have been recently published, genetic variants that are highly associated with certain personality traits remain unknown, due to difficulty reproducing results. To further investigate these genetic variants, we assessed biological pathways using GWA datasets. Pathway analysis using GWA data was performed on 1089 Korean women whose personality traits were measured with the Revised NEO Personality Inventory for the 5-factor model of personality. A total of 1042 pathways containing 8297 genes were included in our study. Of these, 14 pathways were highly enriched with association signals that were validated in 1490 independent samples. These pathways include association of: Neuroticism with axon guidance [L1 cell adhesion molecule (L1CAM) interactions]; Extraversion with neuronal system and voltage-gated potassium channels; Agreeableness with L1CAM interaction, neurotransmitter receptor binding and downstream transmission in postsynaptic cells; and Conscientiousness with the interferon-gamma and platelet-derived growth factor receptor beta polypeptide pathways. Several genes that contribute to top-ranked pathways in this study were previously identified in GWA studies or by pathway analysis in schizophrenia or other neuropsychiatric disorders. Here we report the first pathway analysis of all five personality traits. Importantly, our analysis identified novel pathways that contribute to understanding the etiology of personality traits.

  4. A variational Bayes algorithm for fast and accurate multiple locus genome-wide association analysis

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    Mezey Jason G

    2010-01-01

    Full Text Available Abstract Background The success achieved by genome-wide association (GWA studies in the identification of candidate loci for complex diseases has been accompanied by an inability to explain the bulk of heritability. Here, we describe the algorithm V-Bay, a variational Bayes algorithm for multiple locus GWA analysis, which is designed to identify weaker associations that may contribute to this missing heritability. Results V-Bay provides a novel solution to the computational scaling constraints of most multiple locus methods and can complete a simultaneous analysis of a million genetic markers in a few hours, when using a desktop. Using a range of simulated genetic and GWA experimental scenarios, we demonstrate that V-Bay is highly accurate, and reliably identifies associations that are too weak to be discovered by single-marker testing approaches. V-Bay can also outperform a multiple locus analysis method based on the lasso, which has similar scaling properties for large numbers of genetic markers. For demonstration purposes, we also use V-Bay to confirm associations with gene expression in cell lines derived from the Phase II individuals of HapMap. Conclusions V-Bay is a versatile, fast, and accurate multiple locus GWA analysis tool for the practitioner interested in identifying weaker associations without high false positive rates.

  5. Genome-Wide Analysis of the RNA Helicase Gene Family in Gossypium raimondii

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    Jie Chen

    2014-03-01

    Full Text Available The RNA helicases, which help to unwind stable RNA duplexes, and have important roles in RNA metabolism, belong to a class of motor proteins that play important roles in plant development and responses to stress. Although this family of genes has been the subject of systematic investigation in Arabidopsis, rice, and tomato, it has not yet been characterized in cotton. In this study, we identified 161 putative RNA helicase genes in the genome of the diploid cotton species Gossypium raimondii. We classified these genes into three subfamilies, based on the presence of either a DEAD-box (51 genes, DEAH-box (52 genes, or DExD/H-box (58 genes in their coding regions. Chromosome location analysis showed that the genes that encode RNA helicases are distributed across all 13 chromosomes of G. raimondii. Syntenic analysis revealed that 62 of the 161 G. raimondii helicase genes (38.5% are within the identified syntenic blocks. Sixty-six (40.99% helicase genes from G. raimondii have one or several putative orthologs in tomato. Additionally, GrDEADs have more conserved gene structures and more simple domains than GrDEAHs and GrDExD/Hs. Transcriptome sequencing data demonstrated that many of these helicases, especially GrDEADs, are highly expressed at the fiber initiation stage and in mature leaves. To our knowledge, this is the first report of a genome-wide analysis of the RNA helicase gene family in cotton.

  6. A genome-wide longitudinal transcriptome analysis of the aging model Podospora anserina.

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    Oliver Philipp

    Full Text Available Aging of biological systems is controlled by various processes which have a potential impact on gene expression. Here we report a genome-wide transcriptome analysis of the fungal aging model Podospora anserina. Total RNA of three individuals of defined age were pooled and analyzed by SuperSAGE (serial analysis of gene expression. A bioinformatics analysis identified different molecular pathways to be affected during aging. While the abundance of transcripts linked to ribosomes and to the proteasome quality control system were found to decrease during aging, those associated with autophagy increase, suggesting that autophagy may act as a compensatory quality control pathway. Transcript profiles associated with the energy metabolism including mitochondrial functions were identified to fluctuate during aging. Comparison of wild-type transcripts, which are continuously down-regulated during aging, with those down-regulated in the long-lived, copper-uptake mutant grisea, validated the relevance of age-related changes in cellular copper metabolism. Overall, we (i present a unique age-related data set of a longitudinal study of the experimental aging model P. anserina which represents a reference resource for future investigations in a variety of organisms, (ii suggest autophagy to be a key quality control pathway that becomes active once other pathways fail, and (iii present testable predictions for subsequent experimental investigations.

  7. Genome-wide Analysis of Plant-specific Dof Transcription Factor Family in Tomato

    Institute of Scientific and Technical Information of China (English)

    Xiaofeng Cai; Yuyang Zhang; Chanjuan Zhang; Tingyan Zhang; Tixu Hu; Jie Ye; Junhong Zhang

    2013-01-01

    The Dof (DNA binding with One Finger) family encoding single zinc finger proteins has been known as a family of plant-specific transcription factors.These transcription factors are involved in a variety of functions of importance for different biological processes in plants.In the current study,we identified 34 Dof family genes in tomato (Solanum lycopersicum L.),distributed on 11 chromosomes.A complete overview of SIDof genes in tomato is presented,including the gene structures,chromosome locations,phylogeny,protein motifs and evolution pattern.Phylogenetic analysis of 34 SlDof proteins resulted in four classes constituting six clusters.In addition,a comparative analysis between these genes in tomato,Arabidopsis (Arabidopsis thaliana L.) and rice (Oryza sativa L.) was also performed.The tomato Dof family expansion has been dated to recent duplication events,and segmental duplication is predominant for the SlDof genes.Furthermore,the SlDof genes displayed differential expression either in their transcript abundance or in their expression patterns under normal growth conditions.This is the first step towards genome-wide analyses of the Dof genes in tomato.Our study provides a very useful reference for cloning and functional analysis of the members of this gene family in tomato and other species.

  8. Pathway analysis for genome-wide association study of lung cancer in Han Chinese population.

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    Ruyang Zhang

    Full Text Available Genome-wide association studies (GWAS have identified a number of genetic variants associated with lung cancer risk. However, these loci explain only a small fraction of lung cancer hereditability and other variants with weak effect may be lost in the GWAS approach due to the stringent significance level after multiple comparison correction. In this study, in order to identify important pathways involving the lung carcinogenesis, we performed a two-stage pathway analysis in GWAS of lung cancer in Han Chinese using gene set enrichment analysis (GSEA method. Predefined pathways by BioCarta and KEGG databases were systematically evaluated on Nanjing study (Discovery stage: 1,473 cases and 1,962 controls and the suggestive pathways were further to be validated in Beijing study (Replication stage: 858 cases and 1,115 controls. We found that four pathways (achPathway, metPathway, At1rPathway and rac1Pathway were consistently significant in both studies and the P values for combined dataset were 0.012, 0.010, 0.022 and 0.005 respectively. These results were stable after sensitivity analysis based on gene definition and gene overlaps between pathways. These findings may provide new insights into the etiology of lung cancer.

  9. Genome-wide system analysis reveals stable yet flexible network dynamics in yeast.

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    Gustafsson, M; Hörnquist, M; Björkegren, J; Tegnér, J

    2009-07-01

    Recently, important insights into static network topology for biological systems have been obtained, but still global dynamical network properties determining stability and system responsiveness have not been accessible for analysis. Herein, we explore a genome-wide gene-to-gene regulatory network based on expression data from the cell cycle in Saccharomyces cerevisae (budding yeast). We recover static properties like hubs (genes having several out-going connections), network motifs and modules, which have previously been derived from multiple data sources such as whole-genome expression measurements, literature mining, protein-protein and transcription factor binding data. Further, our analysis uncovers some novel dynamical design principles; hubs are both repressed and repressors, and the intra-modular dynamics are either strongly activating or repressing whereas inter-modular couplings are weak. Finally, taking advantage of the inferred strength and direction of all interactions, we perform a global dynamical systems analysis of the network. Our inferred dynamics of hubs, motifs and modules produce a more stable network than what is expected given randomised versions. The main contribution of the repressed hubs is to increase system stability, while higher order dynamic effects (e.g. module dynamics) mainly increase system flexibility. Altogether, the presence of hubs, motifs and modules induce few flexible modes, to which the network is extra sensitive to an external signal. We believe that our approach, and the inferred biological mode of strong flexibility and stability, will also apply to other cellular networks and adaptive systems.

  10. Genome-wide meta-analysis of systolic blood pressure in children with sickle cell disease.

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    Pallav Bhatnagar

    Full Text Available In pediatric sickle cell disease (SCD patients, it has been reported that higher systolic blood pressure (SBP is associated with increased risk of a silent cerebral infarction (SCI. SCI is a major cause of neurologic morbidity in children with SCD, and blood pressure is a potential modulator of clinical manifestations of SCD; however, the risk factors underlying these complications are not well characterized. The aim of this study was to identify genetic variants that influence SBP in an African American population in the setting of SCD, and explore the use of SBP as an endo-phenotype for SCI. We conducted a genome-wide meta-analysis for SBP using two SCD cohorts, as well as a candidate screen based on published SBP loci. A total of 1,617 patients were analyzed, and while no SNP reached genome-wide significance (P-value<5.0 x 10(-8, a number of suggestive candidate loci were identified. The most significant SNP, rs7952106 (P-value=8.57 x 10(-7, was in the DRD2 locus on chromosome 11. In a gene-based association analysis, MIR4301 (micro-RNA4301, which resides in an intron of DRD2, was the most significant gene (P-value=5.2 x 10(-5. Examining 27 of the previously reported SBP associated SNPs, 4 SNPs were nominally significant. A genetic risk score was constructed to assess the aggregated genetic effect of the published SBP variants, demonstrating a significant association (P=0.05. In addition, we also assessed whether these variants are associated with SCI, validating the use of SBP as an endo-phenotype for SCI. Three SNPs were nominally associated, and only rs2357790 (5' CACNB2 was significant for both SBP and SCI. None of these SNPs retained significance after Bonferroni correction. Taken together, our results suggest the importance of DRD2 genetic variation in the modulation of SBP, and extend the aggregated importance of previously reported SNPs in the modulation of SBP in an African American cohort, more specifically in children with SCD.

  11. Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci

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    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

    2016-01-01

    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

  12. Genome-wide identification of specific oligonucleotides using artificial neural network and computational genomic analysis

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    Chen Jiun-Ching

    2007-05-01

    Full Text Available Abstract Background Genome-wide identification of specific oligonucleotides (oligos is a computationally-intensive task and is a requirement for designing microarray probes, primers, and siRNAs. An artificial neural network (ANN is a machine learning technique that can effectively process complex and high noise data. Here, ANNs are applied to process the unique subsequence distribution for prediction of specific oligos. Results We present a novel and efficient algorithm, named the integration of ANN and BLAST (IAB algorithm, to identify specific oligos. We establish the unique marker database for human and rat gene index databases using the hash table algorithm. We then create the input vectors, via the unique marker database, to train and test the ANN. The trained ANN predicted the specific oligos with high efficiency, and these oligos were subsequently verified by BLAST. To improve the prediction performance, the ANN over-fitting issue was avoided by early stopping with the best observed error and a k-fold validation was also applied. The performance of the IAB algorithm was about 5.2, 7.1, and 6.7 times faster than the BLAST search without ANN for experimental results of 70-mer, 50-mer, and 25-mer specific oligos, respectively. In addition, the results of polymerase chain reactions showed that the primers predicted by the IAB algorithm could specifically amplify the corresponding genes. The IAB algorithm has been integrated into a previously published comprehensive web server to support microarray analysis and genome-wide iterative enrichment analysis, through which users can identify a group of desired genes and then discover the specific oligos of these genes. Conclusion The IAB algorithm has been developed to construct SpecificDB, a web server that provides a specific and valid oligo database of the probe, siRNA, and primer design for the human genome. We also demonstrate the ability of the IAB algorithm to predict specific oligos through

  13. 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

  14. Genome-wide divergence and linkage disequilibrium analyses for Capsicum baccatum revealed by genome-anchored single nucleotide polymorphisms

    Science.gov (United States)

    Principal component analysis (PCA) with 36,621 polymorphic genome-anchored single nucleotide polymorphisms (SNPs) identified collectively for Capsicum annuum and Capsicum baccatum was used to show the distribution of these 2 important incompatible cultivated pepper species. Estimated mean nucleotide...

  15. Genome-wide methylation analysis of tubulocystic and papillary renal cell carcinomas.

    Science.gov (United States)

    Korabecna, M; Geryk, J; Hora, M; Steiner, P; Seda, O; Tesar, V

    2016-01-01

    Tubulocystic renal cell carcinoma (TRCC) represents a rare tumor with incidence lower than 1 % of all renal carcinomas. This study was undertaken to contribute to characterization of molecular signatures associated with TRCC and to compare them with the features of papillary renal cell carcinoma (PRCC) at the level of genome wide methylation analysis.We performed methylated DNA immunoprecipitation (MeDIP) coupled with microarray analysis (Roche NimbleGen). Using the CHARM package, we compared the levels of gene methylation between paired samples of tumors and control renal tissues of each examined individual. We found significant global demethylation in all tumor samples in comparison with adjacent kidney tissues of normal histological appearance but no significant differences in gene methylation between the both compared tumor entities. Therefore we focused on characterization of differentially methylated regions between both tumors and control tissues. We found 42 differentially methylated genes.Hypermethylated genes for protocadherins (PCDHG) and genes coding for products associated with functions of plasma membrane were evaluated as significantly overrepresented among hypermethylated genes detected in both types of renal cell carcinomas.In our pilot study, we provide the first evidence that identical features in the process of carcinogenesis leading to TRCC and/or to PRCC may be found at the gene methylation level.

  16. Genome-wide analysis of the homeobox C6 transcriptional network in prostate cancer.

    Science.gov (United States)

    McCabe, Colleen D; Spyropoulos, Demetri D; Martin, David; Moreno, Carlos S

    2008-03-15

    Homeobox transcription factors are developmentally regulated genes that play crucial roles in tissue patterning. Homeobox C6 (HOXC6) is overexpressed in prostate cancers and correlated with cancer progression, but the downstream targets of HOXC6 are largely unknown. We have performed genome-wide localization analysis to identify promoters bound by HOXC6 in prostate cancer cells. This analysis identified 468 reproducibly bound promoters whose associated genes are involved in functions such as cell proliferation and apoptosis. We have complemented these data with expression profiling of prostates from mice with homozygous disruption of the Hoxc6 gene to identify 31 direct regulatory target genes of HOXC6. We show that HOXC6 directly regulates expression of bone morphogenic protein 7, fibroblast growth factor receptor 2, insulin-like growth factor binding protein 3, and platelet-derived growth factor receptor alpha (PDGFRA) in prostate cells and indirectly influences the Notch and Wnt signaling pathways in vivo. We further show that inhibition of PDGFRA reduces proliferation of prostate cancer cells, and that overexpression of HOXC6 can overcome the effects of PDGFRA inhibition. HOXC6 regulates genes with both oncogenic and tumor suppressor activities as well as several genes such as CD44 that are important for prostate branching morphogenesis and metastasis to the bone microenvironment.

  17. Genome-wide identification and expression analysis of TCP transcription factors in Gossypium raimondii.

    Science.gov (United States)

    Ma, Jun; Wang, Qinglian; Sun, Runrun; Xie, Fuliang; Jones, Don C; Zhang, Baohong

    2014-10-16

    Plant-specific TEOSINTE-BRANCHED1/CYCLOIDEA/PCF (TCP) transcription factors play versatile functions in multiple aspects of plant growth and development. However, no systematical study has been performed in cotton. In this study, we performed for the first time the genome-wide identification and expression analysis of the TCP transcription factor family in Gossypium raimondii. A total of 38 non-redundant cotton TCP encoding genes were identified. The TCP transcription factors were divided into eleven subgroups based on phylogenetic analysis. Most TCP genes within the same subfamily demonstrated similar exon and intron organization and the motif structures were highly conserved among the subfamilies. Additionally, the chromosomal distribution pattern revealed that TCP genes were unevenly distributed across 11 out of the 13 chromosomes; segmental duplication is a predominant duplication event for TCP genes and the major contributor to the expansion of TCP gene family in G. raimondii. Moreover, the expression profiles of TCP genes shed light on their functional divergence.

  18. Genome-wide transcriptome analysis of fluoroquinolone resistance in clinical isolates of Escherichia coli.

    Science.gov (United States)

    Yamane, Takashi; Enokida, Hideki; Hayami, Hiroshi; Kawahara, Motoshi; Nakagawa, Masayuki

    2012-04-01

    Coincident with their worldwide use, resistance to fluoroquinolones in Escherichia coli has increased. To identify the gene expression profiles underlying fluoroquinolone resistance, we carried out genome-wide transcriptome analysis of fluoroquinolone-sensitive E. coli. Four fluoroquinolone-sensitive E. coli and five fluoroquinolone-resistant E. coli clinical isolates were subjected to complementary deoxyribonucleic acid microarray analysis. Some upregulated genes' expression was verified by real-time polymerase chain reaction using 104 E. coli clinical isolates, and minimum inhibitory concentration tests were carried out by using their transformants. A total of 40 genes were significantly upregulated in fluoroquinolone-resistant E. coli isolates (P fluoroquinolone-resistant E. coli. One of the phage shock protein operons, pspC, was significantly upregulated in 50 fluoroquinolone-resistant E. coli isolates (P fluoroquinolone-resistant E. coli. Deoxyribonucleic acid adenine methyltransferase (dam), which represses type I fimbriae genes, was significantly upregulated in the clinical fluoroquinolone-resistant E. coli isolates (P = 0.007). We established pspC- and dam-expressing E. coli transformants from fluoroquinolone-sensitive E. coli, and the minimum inhibitory concentration tests showed that the transformants acquired fluoroquinolone resistance, suggesting that upregulation of these genes contributes to acquiring fluoroquinolone resistance. Upregulation of psp operones and dam underlying pilus operons downregulation might be associated with fluoroquinolone resistance in E. coli. © 2011 The Japanese Urological Association.

  19. Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia

    Science.gov (United States)

    Legge, Sophie E; Hamshere, Marian L; Ripke, Stephan; Pardinas, Antonio F; Goldstein, Jacqueline I; Rees, Elliott; Richards, Alexander L; Leonenko, Ganna; Jorskog, L Fredrik; Chambert, Kimberly D; Collier, David A; Genovese, Giulio; Giegling, Ina; Holmans, Peter; Jonasdottir, Adalbjorg; Kirov, George; McCarroll, Steven A; MacCabe, James H; Mantripragada, Kiran; Moran, Jennifer L; Neale, Benjamin M; Stefansson, Hreinn; Rujescu, Dan; Daly, Mark J; Sullivan, Patrick F; Owen, Michael J; O’Donovan, Michael C; Walters, James T R

    2016-01-01

    The antipsychotic clozapine is uniquely effective in the management of schizophrenia, but its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown although genetic factors play an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed HLA alleles, exome array, and copy number variation analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (OR=4.32, P=1.79×10-8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P = 0.015, positive predictive value = 35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect. PMID:27400856

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

    Science.gov (United States)

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

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility. PMID:26956414

  1. Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility.

    Science.gov (United States)

    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

    2015-04-23

    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 identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations.

  2. 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.

  3. 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

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

    NARCIS (Netherlands)

    E. Evangelou (Evangelos); J.M. Kerkhof (Hanneke); U. Styrkarsdottir (Unnur); E.E. Ntzani (Evangelia); S.D. Bos (Steffan); T. Esko (Tõnu); D.S. Evans (Daniel); S. Metrustry (Sarah); K. Panoutsopoulou (Kalliope); Y.F.M. Ramos (Yolande); G. Thorleifsson (Gudmar); K.K. Tsilidis (Konstantinos); N.K. Arden (Nigel); N. Aslam (Nadim); N. Bellamy (Nicholas); F. Birrell (Fraser); F.J. Blanco; A.J. Carr (Andrew Jonathan); K. Chapman (Kay); A.G. Day-Williams (Aaron); P. Deloukas (Panagiotis); M. Doherty (Michael); G. Engström; H.T. Helgadottir (Hafdis); A. Hofman (Albert); T. Ingvarsson (Torvaldur); H. Jonsson (Helgi); A. Keis (Aime); J.C. Keurentjes (J. Christiaan); M. Kloppenburg (Margreet); P.A. Lind (Penelope); A. McCaskie (Andrew); N.G. Martin; A.L. Milani (Alfredo); G.W. Montgomery; R.G.H.H. Nelissen (Rob); M.C. Nevitt (Michael); P. Nilsson (Peter); W.E.R. Ollier (William); N. Parimi (Neeta); A. Rai (Ashok); S.H. Ralston; M.R. Reed (Mike); J.A. Riancho (José); F. Rivadeneira Ramirez (Fernando); C. Rodriguez-Fontenla (Cristina); L. Southam (Lorraine); U. Thorsteinsdottir (Unnur); A. Tsezou (Aspasia); G.A. Wallis (Gillian); J.M. Wilkinson (Mark); A. Gonzalez (Antonio); N.E. Lane; L.S. Lohmander (Stefan); J. Loughlin (John); A. Metspalu (Andres); A.G. Uitterlinden (André); I. Jonsdottir (Ingileif); J-A. Zwart (John-Anker); P.E. Slagboom (Eline); E. Zeggini (Eleftheria); I. Meulenbelt (Ingrid); J.P.A. Ioannidis (John); T.D. Spector (Timothy); J.B.J. van Meurs (Joyce); A.M. Valdes (Ana Maria)

    2013-01-01

    textabstractObjectives: 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

  5. Elucidation of the role of Grr1p in glucose sensing by Saccharomyces cerevisiae through genome-wide transcription analysis

    DEFF Research Database (Denmark)

    Westergaard, Steen Lund; Bro, Christoffer; Olsson, Lisbeth

    2004-01-01

    The role of Grr1p in glucose sensing in Saccharomyces cerevisiae was elucidated through genome-wide transcription analysis. From triplicate analysis of a strain with deletion of the GRR1-gene from the genome and an isogenic reference strain, 68 genes were identified to have significantly altered...

  6. Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

    NARCIS (Netherlands)

    Cho, Yoon Shin; Chen, Chien-Hsiun; Hu, Cheng; Long, Jirong; Ong, Rick Twee Hee; Sim, Xueling; Takeuchi, Fumihiko; Wu, Ying; Go, Min Jin; Yamauchi, Toshimasa; Chang, Yi-Cheng; Kwak, Soo Heon; Ma, Ronald C. W.; Yamamoto, Ken; Adair, Linda S.; Aung, Tin; Cai, Qiuyin; Chang, Li-Ching; Chen, Yuan-Tsong; Gao, Yutang; Hu, Frank B.; Kim, Hyung-Lae; Kim, Sangsoo; Kim, Young Jin; Lee, Jeannette Jen-Mai; Lee, Nanette R.; Li, Yun; Liu, Jian Jun; Lu, Wei; Nakamura, Jiro; Nakashima, Eitaro; Ng, Daniel Peng-Keat; Tay, Wan Ting; Tsai, Fuu-Jen; Wong, Tien Yin; Yokota, Mitsuhiro; Zheng, Wei; Zhang, Rong; Wang, Congrong; So, Wing Yee; Ohnaka, Keizo; Ikegami, Hiroshi; Hara, Kazuo; Cho, Young Min; Cho, Nam H.; Chang, Tien-Jyun; Bao, Yuqian; Hedman, Asa K.; Morris, Andrew P.; McCarthy, Mark I.; Takayanagi, Ryoichi; Park, Kyong Soo; Jia, Weiping; Chuang, Lee-Ming; Chan, Juliana C. N.; Maeda, Shiro; Kadowaki, Takashi; Lee, Jong-Young; Wu, Jer-Yuarn; Teo, Yik Ying; Tai, E. Shyong; Shu, Xiao Ou; Mohlke, Karen L.; Kato, Norihiro; Han, Bok-Ghee; Seielstad, Mark

    2012-01-01

    We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5

  7. Genome-wide analysis of single nucleotide polymorphisms uncovers population structure in Northern Europe.

    Directory of Open Access Journals (Sweden)

    Elina Salmela

    Full Text Available BACKGROUND: Genome-wide data provide a powerful tool for inferring patterns of genetic variation and structure of human populations. PRINCIPAL FINDINGS: In this study, we analysed almost 250,000 SNPs from a total of 945 samples from Eastern and Western Finland, Sweden, Northern Germany and Great Britain complemented with HapMap data. Small but statistically significant differences were observed between the European populations (F(ST = 0.0040, p<10(-4, also between Eastern and Western Finland (F(ST = 0.0032, p<10(-3. The latter indicated the existence of a relatively strong autosomal substructure within the country, similar to that observed earlier with smaller numbers of markers. The Germans and British were less differentiated than the Swedes, Western Finns and especially the Eastern Finns who also showed other signs of genetic drift. This is likely caused by the later founding of the northern populations, together with subsequent founder and bottleneck effects, and a smaller population size. Furthermore, our data suggest a small eastern contribution among the Finns, consistent with the historical and linguistic background of the population. SIGNIFICANCE: Our results warn against a priori assumptions of homogeneity among Finns and other seemingly isolated populations. Thus, in association studies in such populations, additional caution for population structure may be necessary. Our results illustrate that population history is often important for patterns of genetic variation, and that the analysis of hundreds of thousands of SNPs provides high resolution also for population genetics.

  8. A molecular scheme for Yersinia enterocolitica patho-serotyping derived from genome-wide analysis.

    Science.gov (United States)

    Garzetti, Debora; Susen, Rosa; Fruth, Angelika; Tietze, Erhard; Heesemann, Jürgen; Rakin, Alexander

    2014-05-01

    Yersinia enterocolitica is a food-borne, gastro-intestinal pathogen with world-wide distribution. Only 11 serotypes have been isolated from patients, with O:3, O:9, O:8 and O:5,27 being the serotypes most commonly associated with human yersiniosis. Serotype is an important characteristic of Y. enterocolitica strains, allowing differentiation for epidemiology, diagnosis and phylogeny studies. Conventional serotyping, performed by slide agglutination, is a tedious and laborious procedure whose interpretation tends to be subjective, leading to poor reproducibility. Here we present a PCR-based typing scheme for molecular identification and patho-serotyping of Y. enterocolitica. Genome-wide comparison of Y. enterocolitica sequences allowed analysis of the O-antigen gene clusters of different serotypes, uncovering their formerly unknown genomic locations, and selection of targets for serotype-specific amplification. Two multiplex PCRs and one additional PCR were designed and tested on various reference strains and isolates from different origins. Our genotypic assay proved to be highly specific for identification of Y. enterocolitica species, discrimination between virulent and non-virulent strains, distinguishing the main human-related serotypes, and typing of conventionally untypeable strains. This genotyping scheme could be applied in microbiology laboratories as an alternative or complementary method to the traditional phenotypic assays, providing data for epidemiological studies.

  9. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

    Science.gov (United States)

    Law, Philip J.; Berndt, Sonja I.; Speedy, Helen E.; Camp, Nicola J.; Sava, Georgina P.; Skibola, Christine F.; Holroyd, Amy; Joseph, Vijai; Sunter, Nicola J.; Nieters, Alexandra; Bea, Silvia; Monnereau, Alain; Martin-Garcia, David; Goldin, Lynn R.; Clot, Guillem; Teras, Lauren R.; Quintela, Inés; Birmann, Brenda M.; Jayne, Sandrine; Cozen, Wendy; Majid, Aneela; Smedby, Karin E.; Lan, Qing; Dearden, Claire; Brooks-Wilson, Angela R.; Hall, Andrew G.; Purdue, Mark P.; Mainou-Fowler, Tryfonia; Vajdic, Claire M.; Jackson, Graham H.; Cocco, Pierluigi; Marr, Helen; Zhang, Yawei; Zheng, Tongzhang; Giles, Graham G.; Lawrence, Charles; Call, Timothy G.; Liebow, Mark; Melbye, Mads; Glimelius, Bengt; Mansouri, Larry; Glenn, Martha; Curtin, Karen; Diver, W Ryan; Link, Brian K.; Conde, Lucia; Bracci, Paige M.; Holly, Elizabeth A.; Jackson, Rebecca D.; Tinker, Lesley F.; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Maynadie, Marc; McKay, James; Albanes, Demetrius; Weinstein, Stephanie; Wang, Zhaoming; Caporaso, Neil E.; Morton, Lindsay M.; Severson, Richard K.; Riboli, Elio; Vineis, Paolo; Vermeulen, Roel C. H.; Southey, Melissa C.; Milne, Roger L.; Clavel, Jacqueline; Topka, Sabine; Spinelli, John J.; Kraft, Peter; Ennas, Maria Grazia; Summerfield, Geoffrey; Ferri, Giovanni M.; Harris, Robert J.; Miligi, Lucia; Pettitt, Andrew R.; North, Kari E.; Allsup, David J.; Fraumeni, Joseph F.; Bailey, James R.; Offit, Kenneth; Pratt, Guy; Hjalgrim, Henrik; Pepper, Chris; Chanock, Stephen J.; Fegan, Chris; Rosenquist, Richard; de Sanjose, Silvia; Carracedo, Angel; Dyer, Martin J. S.; Catovsky, Daniel; Campo, Elias; Cerhan, James R.; Allan, James M.; Rothman, Nathanial; Houlston, Richard; Slager, Susan

    2017-01-01

    Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10−13), 1q42.13 (rs41271473, P=1.06 × 10−10), 4q24 (rs71597109, P=1.37 × 10−10), 4q35.1 (rs57214277, P=3.69 × 10−8), 6p21.31 (rs3800461, P=1.97 × 10−8), 11q23.2 (rs61904987, P=2.64 × 10−11), 18q21.1 (rs1036935, P=3.27 × 10−8), 19p13.3 (rs7254272, P=4.67 × 10−8) and 22q13.33 (rs140522, P=2.70 × 10−9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response. PMID:28165464

  10. Genome-wide analysis in Brazilian Xavante Indians reveals low degree of admixture.

    Science.gov (United States)

    Kuhn, Patricia C; Horimoto, Andréa R V Russo; Sanches, José Maurício; Vieira Filho, João Paulo B; Franco, Luciana; Fabbro, Amaury Dal; Franco, Laercio Joel; Pereira, Alexandre C; Moises, Regina S

    2012-01-01

    Characterization of population genetic variation and structure can be used as tools for research in human genetics and population isolates are of great interest. The aim of the present study was to characterize the genetic structure of Xavante Indians and compare it with other populations. The Xavante, an indigenous population living in Brazilian Central Plateau, is one of the largest native groups in Brazil. A subset of 53 unrelated subjects was selected from the initial sample of 300 Xavante Indians. Using 86,197 markers, Xavante were compared with all populations of HapMap Phase III and HGDP-CEPH projects and with a Southeast Brazilian population sample to establish its population structure. Principal Components Analysis showed that the Xavante Indians are concentrated in the Amerindian axis near other populations of known Amerindian ancestry such as Karitiana, Pima, Surui and Maya and a low degree of genetic admixture was observed. This is consistent with the historical records of bottlenecks experience and cultural isolation. By calculating pair-wise F(st) statistics we characterized the genetic differentiation between Xavante Indians and representative populations of the HapMap and from HGDP-CEPH project. We found that the genetic differentiation between Xavante Indians and populations of Ameridian, Asian, European, and African ancestry increased progressively. Our results indicate that the Xavante is a population that remained genetically isolated over the past decades and can offer advantages for genome-wide mapping studies of inherited disorders.

  11. Genome-wide analysis of complex wheat gliadins, the dominant carriers of celiac disease epitopes.

    Science.gov (United States)

    Wang, Da-Wei; Li, Da; Wang, Junjun; Zhao, Yue; Wang, Zhaojun; Yue, Guidong; Liu, Xin; Qin, Huanju; Zhang, Kunpu; Dong, Lingli; Wang, Daowen

    2017-03-16

    Gliadins, specified by six compound chromosomal loci (Gli-A1/B1/D1 and Gli-A2/B2/D2) in hexaploid bread wheat, are the dominant carriers of celiac disease (CD) epitopes. Because of their complexity, genome-wide characterization of gliadins is a strong challenge. Here, we approached this challenge by combining transcriptomic, proteomic and bioinformatic investigations. Through third-generation RNA sequencing, full-length transcripts were identified for 52 gliadin genes in the bread wheat cultivar Xiaoyan 81. Of them, 42 were active and predicted to encode 25 α-, 11 γ-, one δ- and five ω-gliadins. Comparative proteomic analysis between Xiaoyan 81 and six newly-developed mutants each lacking one Gli locus indicated the accumulation of 38 gliadins in the mature grains. A novel group of α-gliadins (the CSTT group) was recognized to contain very few or no CD epitopes. The δ-gliadins identified here or previously did not carry CD epitopes. Finally, the mutant lacking Gli-D2 showed significant reductions in the most celiac-toxic α-gliadins and derivative CD epitopes. The insights and resources generated here should aid further studies on gliadin functions in CD and the breeding of healthier wheat.

  12. Gowinda: unbiased analysis of gene set enrichment for genome-wide association studies.

    Science.gov (United States)

    Kofler, Robert; Schlötterer, Christian

    2012-08-01

    An analysis of gene set [e.g. Gene Ontology (GO)] enrichment assumes that all genes are sampled independently from each other with the same probability. These assumptions are violated in genome-wide association (GWA) studies since (i) longer genes typically have more single-nucleotide polymorphisms resulting in a higher probability of being sampled and (ii) overlapping genes are sampled in clusters. Herein, we introduce Gowinda, a software specifically designed to test for enrichment of gene sets in GWA studies. We show that GO tests on GWA data could result in a substantial number of false-positive GO terms. Permutation tests implemented in Gowinda eliminate these biases, but maintain sufficient power to detect enrichment of GO terms. Since sufficient resolution for large datasets requires millions of permutations, we use multi-threading to keep computation times reasonable. Gowinda is implemented in Java (v1.6) and freely available on http://code.google.com/p/gowinda/ christian.schloetterer@vetmeduni.ac.at Manual: http://code.google.com/p/gowinda/wiki/Manual. Test data and tutorial: http://code.google.com/p/gowinda/wiki/Tutorial. http://code.google.com/p/gowinda/wiki/VALIDATION.

  13. Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution

    Science.gov (United States)

    Qi, Lu; Speliotes, Elizabeth K.; Thorleifsson, Gudmar; Willer, Cristen J.; Herrera, Blanca M.; Jackson, Anne U.; Lim, Noha; Scheet, Paul; Soranzo, Nicole; Amin, Najaf; Aulchenko, Yurii S.; Chambers, John C.; Drong, Alexander; Luan, Jian'an; Lyon, Helen N.; Rivadeneira, Fernando; Sanna, Serena; Timpson, Nicholas J.; Zillikens, M. Carola; Zhao, Jing Hua; Almgren, Peter; Bandinelli, Stefania; Bennett, Amanda J.; Bergman, Richard N.; Bonnycastle, Lori L.; Bumpstead, Suzannah J.; Chanock, Stephen J.; Cherkas, Lynn; Chines, Peter; Coin, Lachlan; Cooper, Cyrus; Crawford, Gabriel; Doering, Angela; Dominiczak, Anna; Doney, Alex S. F.; Ebrahim, Shah; Elliott, Paul; Erdos, Michael R.; Estrada, Karol; Ferrucci, Luigi; Fischer, Guido; Forouhi, Nita G.; Gieger, Christian; Grallert, Harald; Groves, Christopher J.; Grundy, Scott; Guiducci, Candace; Hadley, David; Hamsten, Anders; Havulinna, Aki S.; Hofman, Albert; Holle, Rolf; Holloway, John W.; Illig, Thomas; Isomaa, Bo; Jacobs, Leonie C.; Jameson, Karen; Jousilahti, Pekka; Karpe, Fredrik; Kuusisto, Johanna; Laitinen, Jaana; Lathrop, G. Mark; Lawlor, Debbie A.; Mangino, Massimo; McArdle, Wendy L.; Meitinger, Thomas; Morken, Mario A.; Morris, Andrew P.; Munroe, Patricia; Narisu, Narisu; Nordström, Anna; Nordström, Peter; Oostra, Ben A.; Palmer, Colin N. A.; Payne, Felicity; Peden, John F.; Prokopenko, Inga; Renström, Frida; Ruokonen, Aimo; Salomaa, Veikko; Sandhu, Manjinder S.; Scott, Laura J.; Scuteri, Angelo; Silander, Kaisa; Song, Kijoung; Yuan, Xin; Stringham, Heather M.; Swift, Amy J.; Tuomi, Tiinamaija; Uda, Manuela; Vollenweider, Peter; Waeber, Gerard; Wallace, Chris; Walters, G. Bragi; Weedon, Michael N.; Witteman, Jacqueline C. M.; Zhang, Cuilin; Zhang, Weihua; Caulfield, Mark J.; Collins, Francis S.; Davey Smith, George; Day, Ian N. M.; Franks, Paul W.; Hattersley, Andrew T.; Hu, Frank B.; Jarvelin, Marjo-Riitta; Kong, Augustine; Kooner, Jaspal S.; Laakso, Markku; Lakatta, Edward; Mooser, Vincent; Morris, Andrew D.; Peltonen, Leena; Samani, Nilesh J.; Spector, Timothy D.; Strachan, David P.; Tanaka, Toshiko; Tuomilehto, Jaakko; Uitterlinden, André G.; van Duijn, Cornelia M.; Wareham, Nicholas J.; Watkins for the PROCARDIS consortia, Hugh; Waterworth, Dawn M.; Boehnke, Michael; Deloukas, Panos; Groop, Leif; Hunter, David J.; Thorsteinsdottir, Unnur; Schlessinger, David; Wichmann, H.-Erich; Frayling, Timothy M.; Abecasis, Gonçalo R.; Hirschhorn, Joel N.; Loos, Ruth J. F.; Stefansson, Kari; Mohlke, Karen L.; Barroso, Inês; McCarthy for the GIANT consortium, Mark I.

    2009-01-01

    To 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 evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10−11) and MSRA (WC, P = 8.9×10−9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10−8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity. PMID:19557161

  14. Genome-wide analysis in Brazilian Xavante Indians reveals low degree of admixture.

    Directory of Open Access Journals (Sweden)

    Patricia C Kuhn

    Full Text Available Characterization of population genetic variation and structure can be used as tools for research in human genetics and population isolates are of great interest. The aim of the present study was to characterize the genetic structure of Xavante Indians and compare it with other populations. The Xavante, an indigenous population living in Brazilian Central Plateau, is one of the largest native groups in Brazil. A subset of 53 unrelated subjects was selected from the initial sample of 300 Xavante Indians. Using 86,197 markers, Xavante were compared with all populations of HapMap Phase III and HGDP-CEPH projects and with a Southeast Brazilian population sample to establish its population structure. Principal Components Analysis showed that the Xavante Indians are concentrated in the Amerindian axis near other populations of known Amerindian ancestry such as Karitiana, Pima, Surui and Maya and a low degree of genetic admixture was observed. This is consistent with the historical records of bottlenecks experience and cultural isolation. By calculating pair-wise F(st statistics we characterized the genetic differentiation between Xavante Indians and representative populations of the HapMap and from HGDP-CEPH project. We found that the genetic differentiation between Xavante Indians and populations of Ameridian, Asian, European, and African ancestry increased progressively. Our results indicate that the Xavante is a population that remained genetically isolated over the past decades and can offer advantages for genome-wide mapping studies of inherited disorders.

  15. Genome-wide analysis of homeobox genes from Mesobuthus martensii reveals Hox gene duplication in scorpions.

    Science.gov (United States)

    Di, Zhiyong; Yu, Yao; Wu, Yingliang; Hao, Pei; He, Yawen; Zhao, Huabin; Li, Yixue; Zhao, Guoping; Li, Xuan; Li, Wenxin; Cao, Zhijian

    2015-06-01

    Homeobox genes belong to a large gene group, which encodes the famous DNA-binding homeodomain that plays a key role in development and cellular differentiation during embryogenesis in animals. Here, one hundred forty-nine homeobox genes were identified from the Asian scorpion, Mesobuthus martensii (Chelicerata: Arachnida: Scorpiones: Buthidae) based on our newly assembled genome sequence with approximately 248 × coverage. The identified homeobox genes were categorized into eight classes including 82 families: 67 ANTP class genes, 33 PRD genes, 11 LIM genes, five POU genes, six SINE genes, 14 TALE genes, five CUT genes, two ZF genes and six unclassified genes. Transcriptome data confirmed that more than half of the genes were expressed in adults. The homeobox gene diversity of the eight classes is similar to the previously analyzed Mandibulata arthropods. Interestingly, it is hypothesized that the scorpion M. martensii may have two Hox clusters. The first complete genome-wide analysis of homeobox genes in Chelicerata not only reveals the repertoire of scorpion, arachnid and chelicerate homeobox genes, but also shows some insights into the evolution of arthropod homeobox genes.

  16. Meta-analysis of genome-wide association studies of HDL cholesterol response to statins.

    Science.gov (United States)

    Postmus, Iris; Warren, Helen R; Trompet, Stella; Arsenault, Benoit J; Avery, Christy L; Bis, Joshua C; Chasman, Daniel I; de Keyser, Catherine E; Deshmukh, Harshal A; Evans, Daniel S; Feng, QiPing; Li, Xiaohui; Smit, Roelof A J; Smith, Albert V; Sun, Fangui; Taylor, Kent D; Arnold, Alice M; Barnes, Michael R; Barratt, Bryan J; Betteridge, John; Boekholdt, S Matthijs; Boerwinkle, Eric; Buckley, Brendan M; Chen, Y-D Ida; de Craen, Anton J M; Cummings, Steven R; Denny, Joshua C; Dubé, Marie Pierre; Durrington, Paul N; Eiriksdottir, Gudny; Ford, Ian; Guo, Xiuqing; Harris, Tamara B; Heckbert, Susan R; Hofman, Albert; Hovingh, G Kees; Kastelein, John J P; Launer, Leonore J; Liu, Ching-Ti; Liu, Yongmei; Lumley, Thomas; McKeigue, Paul M; Munroe, Patricia B; Neil, Andrew; Nickerson, Deborah A; Nyberg, Fredrik; O'Brien, Eoin; O'Donnell, Christopher J; Post, Wendy; Poulter, Neil; Vasan, Ramachandran S; Rice, Kenneth; Rich, Stephen S; Rivadeneira, Fernando; Sattar, Naveed; Sever, Peter; Shaw-Hawkins, Sue; Shields, Denis C; Slagboom, P Eline; Smith, Nicholas L; Smith, Joshua D; Sotoodehnia, Nona; Stanton, Alice; Stott, David J; Stricker, Bruno H; Stürmer, Til; Uitterlinden, André G; Wei, Wei-Qi; Westendorp, Rudi G J; Whitsel, Eric A; Wiggins, Kerri L; Wilke, Russell A; Ballantyne, Christie M; Colhoun, Helen M; Cupples, L Adrienne; Franco, Oscar H; Gudnason, Vilmundur; Hitman, Graham; Palmer, Colin N A; Psaty, Bruce M; Ridker, Paul M; Stafford, Jeanette M; Stein, Charles M; Tardif, Jean-Claude; Caulfield, Mark J; Jukema, J Wouter; Rotter, Jerome I; Krauss, Ronald M

    2016-12-01

    In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Inter-individual variation in HDL-C response to statins may be partially explained by genetic variation. We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with pHDL-C response to statin treatment. Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  17. Genome-Wide Analysis Revealed the Complex Regulatory Network of Brassinosteroid Effects in Photomorphogenesis

    Institute of Scientific and Technical Information of China (English)

    Li Song; Xiao-Yi Zhou; Li Li; Liang-Jiao Xue; Xi Yang; Hong-Wei Xue

    2009-01-01

    Light and brassinosteroids (BRs) have been proved to be crucial in regulating plant growth and development;however,the mechanism of how they synergistically function is still largely unknown.To explore the underlying mechanisms in photomorphogenesis,genome-wide analyses were carried out through examining the gene expressions of the dark-grown WT or BR biosynthesis-defective mutant det2 seedlings in the presence of light stimuli or exogenous Brassinolide (BL).Results showed that BR deficiency stimulates,while BL treatment suppresses,the expressions of lightresponsive genes and photomorphogenesis,confirming the negative effects of BR in photomorphogenesis.This is consistent with the specific effects of BR on the expression of genes involved in cell wall modification,cellular metabolism and energy utilization during dark-light transition.Further analysis revealed that hormone biosynthesis and signaling-related genes,especially those of auxin,were altered under BL treatment or light stimuli,indicating that BR may modulate photomorphogenesis through synergetic regulation with other hormones.Additionally,suppressed ubiquitin-cycle pathway during light-dark transition hinted the presence of a complicated network among light,hormone,and protein degradation.The study provides the direct evidence of BR effects in photomorphogenesis and identified the genes involved in BR and light signaling pathway,which will help to elucidate the molecular mechanism of plant photomorphogenesis.

  18. Genome-wide expression analysis in Down syndrome: insight into immunodeficiency.

    Directory of Open Access Journals (Sweden)

    Chong Li

    Full Text Available Down syndrome (DS is caused by triplication of Human chromosome 21 (Hsa21 and associated with an array of deleterious phenotypes, including mental retardation, heart defects and immunodeficiency. Genome-wide expression patterns of uncultured peripheral blood cells are useful to understanding of DS-associated immune dysfunction. We used a Human Exon microarray to characterize gene expression in uncultured peripheral blood cells derived from DS individuals and age-matched controls from two age groups: neonate (N and child (C. A total of 174 transcript clusters (gene-level with eight located on Hsa21 in N group and 383 transcript clusters including 56 on Hsa21 in C group were significantly dysregulated in DS individuals. Microarray data were validated by quantitative polymerase chain reaction. Functional analysis revealed that the dysregulated genes in DS were significantly enriched in two and six KEGG pathways in N and C group, respectively. These pathways included leukocyte trans-endothelial migration, B cell receptor signaling pathway and primary immunodeficiency, etc., which causally implicated dysfunctional immunity in DS. Our results provided a comprehensive picture of gene expression patterns in DS at the two developmental stages and pointed towards candidate genes and molecular pathways potentially associated with the immune dysfunction in DS.

  19. Genome-wide analysis of glutathione reductase (GR) genes from rice and Arabidopsis.

    Science.gov (United States)

    Trivedi, Dipesh Kumar; Gill, Sarvajeet Singh; Yadav, Sandep; Tuteja, Narendra

    2013-02-01

    Plant cells and tissues remain always on risk under abiotic and biotic stresses due to increased production of reactive oxygen species (ROS). Plants protect themselves against ROS induced oxidative damage by the upregulation of antioxidant machinery. Out of many components of antioxidant machinery, glutathione reductase (GR, EC 1.6.4.2) and glutathione (GSH, γ-Glu-Cys-Gly) play important role in the protection of cell against oxidative damage. In stress condition, the GR helps in maintaining the reduced glutathione pool for strengthening the antioxidative processes in plants. Present study investigates genome wide analysis of GR from rice and Arabidopsis. We were able to identify 3 rice GR genes (LOC_Os02 g56850, LOC_Os03 g06740, LOC_Os10 g28000) and 2 Arabidopsis GR genes (AT3G54660, AT3G24170) from their respective genomes on the basis of their annotation as well as the presence of pyridine nucleotide-disulphide oxidoreductases class-I active site. The evolutionary relationship of the GR genes from rice and Arabidopsis genomes was analyzed using the multiple sequence alignment and phylogenetic tree. This revealed evolutionary conserved pyridine nucleotide-disulphide oxidoreductases class-I active site among the GR protein in rice and Arabidopsis. This study should make an important contribution to our better understanding of the GR under normal and stress condition in plants.

  20. Genome-wide analysis of complex wheat gliadins, the dominant carriers of celiac disease epitopes

    Science.gov (United States)

    Wang, Da-Wei; Li, Da; Wang, Junjun; Zhao, Yue; Wang, Zhaojun; Yue, Guidong; Liu, Xin; Qin, Huanju; Zhang, Kunpu; Dong, Lingli; Wang, Daowen

    2017-01-01

    Gliadins, specified by six compound chromosomal loci (Gli-A1/B1/D1 and Gli-A2/B2/D2) in hexaploid bread wheat, are the dominant carriers of celiac disease (CD) epitopes. Because of their complexity, genome-wide characterization of gliadins is a strong challenge. Here, we approached this challenge by combining transcriptomic, proteomic and bioinformatic investigations. Through third-generation RNA sequencing, full-length transcripts were identified for 52 gliadin genes in the bread wheat cultivar Xiaoyan 81. Of them, 42 were active and predicted to encode 25 α-, 11 γ-, one δ- and five ω-gliadins. Comparative proteomic analysis between Xiaoyan 81 and six newly-developed mutants each lacking one Gli locus indicated the accumulation of 38 gliadins in the mature grains. A novel group of α-gliadins (the CSTT group) was recognized to contain very few or no CD epitopes. The δ-gliadins identified here or previously did not carry CD epitopes. Finally, the mutant lacking Gli-D2 showed significant reductions in the most celiac-toxic α-gliadins and derivative CD epitopes. The insights and resources generated here should aid further studies on gliadin functions in CD and the breeding of healthier wheat. PMID:28300172

  1. 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 psoriasis susceptibility.

  2. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

    Directory of Open Access Journals (Sweden)

    Cecilia M Lindgren

    2009-06-01

    Full Text Available To 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 evidence of association with measures of central adiposity (WC and/or WHR was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11 and MSRA (WC, P = 8.9x10(-9. A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8. The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.

  3. Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction

    Directory of Open Access Journals (Sweden)

    Johnson Catherine

    2011-10-01

    Full Text Available Abstract Background Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction. Results Here, we performed a meta-analysis of addiction candidate gene association studies and GWAS to investigate possible functional mechanisms associated with addiction susceptibility. From meta-data retrieved from 212 publications on candidate gene association studies and 5 GWAS reports, we linked a total of 843 haplotypes to addiction susceptibility. We mapped the SNPs in these haplotypes to functional and regulatory elements in the genome and estimated the magnitude of the contributions of different molecular mechanisms to their effects on addiction susceptibility. In addition to SNPs in coding regions, these data suggest that haplotypes in gene regulatory regions may also contribute to addiction susceptibility. When we compared the lists of genes identified by association studies and those identified by molecular biological studies of drug-regulated genes, we observed significantly higher participation in the same gene interaction networks than expected by chance, despite little overlap between the two gene lists. Conclusions These results appear to offer new insights into the genetic factors underlying drug addiction.

  4. Shared genetic susceptibility to ischemic stroke and coronary artery disease – a genome-wide analysis of common variants

    Science.gov (United States)

    Dichgans, Martin; Malik, Rainer; König, Inke R.; Rosand, Jonathan; Clarke, Robert; Gretarsdottir, Solveig; Thorleifsson, Gudmar; Mitchell, Braxton D.; Assimes, Themistocles L.; Levi, Christopher; O′Donnell, Christopher J.; Fornage, Myriam; Thorsteinsdottir, Unnur; Psaty, Bruce M.; Hengstenberg, Christian; Seshadri, Sudha; Erdmann, Jeanette; Bis, Joshua C.; Peters, Annette; Boncoraglio, Giorgio B.; März, Winfried; Meschia, James F.; Kathiresan, Sekar; Ikram, M. Arfan; McPherson, Ruth; Stefansson, Kari; Sudlow, Cathie; Reilly, Muredach P.; Thompson, John R.; Sharma, Pankaj; Hopewell, Jemma C.; Chambers, John C.; Watkins, Hugh; Rothwell, Peter M.; Roberts, Robert; Markus, Hugh S.; Samani, Nilesh J.; Farrall, Martin; Schunkert, Heribert

    2014-01-01

    Summary Background and Purpose Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each have a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases. Methods Genome-wide association data were obtained from the METASTROKE, CARDIoGRAM, and C4D consortia. We first analyzed common variants reaching a nominal threshold of significance (pstroke (LAS) subtype. Results Common variants associated with CAD at pgenetic risk of ischemic stroke and particularly the large artery stroke subtype with coronary artery disease. PMID:24262325

  5. Genome-wide analysis of mutations in mutant lineages selected following fast-neutron irradiation mutagenesis of Arabidopsis thaliana

    KAUST Repository

    Belfield, E.J.

    2012-04-12

    Ionizing radiation has long been known to induce heritable mutagenic change in DNA sequence. However, the genome-wide effect of radiation is not well understood. Here we report the molecular properties and frequency of mutations in phenotypically selected mutant lines isolated following exposure of the genetic model flowering plant Arabidopsis thaliana to fast neutrons (FNs). Previous studies suggested that FNs predominantly induce deletions longer than a kilobase in A. thaliana. However, we found a higher frequency of single base substitution than deletion mutations. While the overall frequency and molecular spectrum of fast-neutron (FN)-induced single base substitutions differed substantially from those of "background" mutations arising spontaneously in laboratory-grown plants, G:C>A:T transitions were favored in both. We found that FN-induced G:C>A:T transitions were concentrated at pyrimidine dinucleotide sites, suggesting that FNs promote the formation of mutational covalent linkages between adjacent pyrimidine residues. In addition, we found that FNs induced more single base than large deletions, and that these single base deletions were possibly caused by replication slippage. Our observations provide an initial picture of the genome-wide molecular profile of mutations induced in A. thaliana by FN irradiation and are particularly informative of the nature and extent of genome-wide mutation in lines selected on the basis of mutant phenotypes from FN-mutagenized A. thaliana populations.

  6. Genome-wide transcriptome and expression profile analysis of Phalaenopsis during explant browning.

    Directory of Open Access Journals (Sweden)

    Chuanjun Xu

    Full Text Available Explant browning presents a major problem for in vitro culture, and can lead to the death of the explant and failure of regeneration. Considerable work has examined the physiological mechanisms underlying Phalaenopsis leaf explant browning, but the molecular mechanisms of browning remain elusive. In this study, we used whole genome RNA sequencing to examine Phalaenopsis leaf explant browning at genome-wide level.We first used Illumina high-throughput technology to sequence the transcriptome of Phalaenopsis and then performed de novo transcriptome assembly. We assembled 79,434,350 clean reads into 31,708 isogenes and generated 26,565 annotated unigenes. We assigned Gene Ontology (GO terms, Kyoto Encyclopedia of Genes and Genomes (KEGG annotations, and potential Pfam domains to each transcript. Using the transcriptome data as a reference, we next analyzed the differential gene expression of explants cultured for 0, 3, and 6 d, respectively. We then identified differentially expressed genes (DEGs before and after Phalaenopsis explant browning. We also performed GO, KEGG functional enrichment and Pfam analysis of all DEGs. Finally, we selected 11 genes for quantitative real-time PCR (qPCR analysis to confirm the expression profile analysis.Here, we report the first comprehensive analysis of transcriptome and expression profiles during Phalaenopsis explant browning. Our results suggest that Phalaenopsis explant browning may be due in part to gene expression changes that affect the secondary metabolism, such as: phenylpropanoid pathway and flavonoid biosynthesis. Genes involved in photosynthesis and ATPase activity have been found to be changed at transcription level; these changes may perturb energy metabolism and thus lead to the decay of plant cells and tissues. This study provides comprehensive gene expression data for Phalaenopsis browning. Our data constitute an important resource for further functional studies to prevent explant browning.

  7. Genome-wide transcriptome and expression profile analysis of Phalaenopsis during explant browning.

    Science.gov (United States)

    Xu, Chuanjun; Zeng, Biyu; Huang, Junmei; Huang, Wen; Liu, Yumei

    2015-01-01

    Explant browning presents a major problem for in vitro culture, and can lead to the death of the explant and failure of regeneration. Considerable work has examined the physiological mechanisms underlying Phalaenopsis leaf explant browning, but the molecular mechanisms of browning remain elusive. In this study, we used whole genome RNA sequencing to examine Phalaenopsis leaf explant browning at genome-wide level. We first used Illumina high-throughput technology to sequence the transcriptome of Phalaenopsis and then performed de novo transcriptome assembly. We assembled 79,434,350 clean reads into 31,708 isogenes and generated 26,565 annotated unigenes. We assigned Gene Ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations, and potential Pfam domains to each transcript. Using the transcriptome data as a reference, we next analyzed the differential gene expression of explants cultured for 0, 3, and 6 d, respectively. We then identified differentially expressed genes (DEGs) before and after Phalaenopsis explant browning. We also performed GO, KEGG functional enrichment and Pfam analysis of all DEGs. Finally, we selected 11 genes for quantitative real-time PCR (qPCR) analysis to confirm the expression profile analysis. Here, we report the first comprehensive analysis of transcriptome and expression profiles during Phalaenopsis explant browning. Our results suggest that Phalaenopsis explant browning may be due in part to gene expression changes that affect the secondary metabolism, such as: phenylpropanoid pathway and flavonoid biosynthesis. Genes involved in photosynthesis and ATPase activity have been found to be changed at transcription level; these changes may perturb energy metabolism and thus lead to the decay of plant cells and tissues. This study provides comprehensive gene expression data for Phalaenopsis browning. Our data constitute an important resource for further functional studies to prevent explant browning.

  8. Insights into pancreatic cancer etiology from pathway analysis of genome-wide association study data.

    Directory of Open Access Journals (Sweden)

    Peng Wei

    Full Text Available Pancreatic cancer is the fourth leading cause of cancer death in the U.S. and the etiology of this highly lethal disease has not been well defined. To identify genetic susceptibility factors for pancreatic cancer, we conducted pathway analysis of genome-wide association study (GWAS data in 3,141 pancreatic cancer patients and 3,367 controls with European ancestry.Using the gene set ridge regression in association studies (GRASS method, we analyzed 197 pathways identified from the Kyoto Encyclopedia of Genes and Genomes database. We used the logistic kernel machine (LKM test to identify major contributing genes to each pathway. We conducted functional enrichment analysis of the most significant genes (P<0.01 using the Database for Annotation, Visualization, and Integrated Discovery (DAVID.Two pathways were significantly associated with risk of pancreatic cancer after adjusting for multiple comparisons (P<0.00025 and in replication testing: neuroactive ligand-receptor interaction, (Ps<0.00002, and the olfactory transduction pathway (P = 0.0001. LKM test identified four genes that were significantly associated with risk of pancreatic cancer after Bonferroni correction (P<1×10(-5: ABO, HNF1A, OR13C4, and SHH. Functional enrichment analysis using DAVID consistently found the G protein-coupled receptor signaling pathway (including both neuroactive ligand-receptor interaction and olfactory transduction pathways to be the most significant pathway for pancreatic cancer risk in this study population.These novel findings provide new perspectives on genetic susceptibility to and molecular mechanisms of pancreatic cancer.

  9. From human monocytes to genome-wide binding sites--a protocol for small amounts of blood: monocyte isolation/ChIP-protocol/library amplification/genome wide computational data analysis.

    Directory of Open Access Journals (Sweden)

    Sebastian Weiterer

    Full Text Available Chromatin immunoprecipitation in combination with a genome-wide analysis via high-throughput sequencing is the state of the art method to gain genome-wide representation of histone modification or transcription factor binding profiles. However, chromatin immunoprecipitation analysis in the context of human experimental samples is limited, especially in the case of blood cells. The typically extremely low yields of precipitated DNA are usually not compatible with library amplification for next generation sequencing. We developed a highly reproducible protocol to present a guideline from the first step of isolating monocytes from a blood sample to analyse the distribution of histone modifications in a genome-wide manner.The protocol describes the whole work flow from isolating monocytes from human blood samples followed by a high-sensitivity and small-scale chromatin immunoprecipitation assay with guidance for generating libraries compatible with next generation sequencing from small amounts of immunoprecipitated DNA.

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

    NARCIS (Netherlands)

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

    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 similar to 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising

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

    NARCIS (Netherlands)

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

    2015-01-01

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

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

    NARCIS (Netherlands)

    Speliotes, E.K.; Yerges-Armstrong, L.M.; Wu, J.; Hernaez, R.; Kim, L.J.; Palmer, C.D.; Gudnason, V.; Eiriksdottir, G.; Garcia, M.E.; Launer, L.J.; Nalls, M.A.; Clark, J.M.; Mitchell, B.D.; Shuldiner, A.R.; Butler, J.L.; Tomas, M.; Hoffmann, U.; Hwang, S.J.; Massaro, J.M.; O'Donnell, C.J.; Sahani, D.V.; Salomaa, V.; Schadt, E.E.; Schwartz, S.M.; Siscovick, D.S.; Voight, B.F.; Carr, J.J.; Feitosa, M.F.; Harris, T.B.; Fox, C.S.; Smith, A.V.; Kao, W.H.; Hirschhorn, J.N.; Borecki, I.B.; Heijer, M. den

    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

  13. 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...

  14. 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...

  15. Meta-analysis of genome-wide association for migraine in six population-based European cohorts

    NARCIS (Netherlands)

    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 H. M.; Janssens, A. Cecile J. W.; Aulchenko, Yurii S.; Oostra, Ben A.; de Geus, Eco J. C.; Smit, Johannes H.; Zitman, Frans G.; Uitterlinden, Andre G.; Hofman, Albert; Willemsen, Gonneke; Nyholt, Dale R.; Montgomery, Grant W.; Terwindt, Gisela M.; Gudnason, Vilmundur; Penninx, Brenda W. J. H.; Breteler, Monique; Ferrari, Michel D.; Launer, Lenore J.; van Duijn, Cornelia M.; van den Maagdenberg, Arn M. J. M.; Boomsma, Dorret I.

    2011-01-01

    Migraine is a common neurological 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 migra

  16. 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.A. Boerwinkle (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

  17. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

    NARCIS (Netherlands)

    P.G. Hysi (Pirro); C-Y. Cheng (Ching-Yu); H. Springelkamp (Henriët); S. MacGregor (Stuart); J.N.C. Bailey (Jessica N. Cooke); R. Wojciechowski (Robert); V. Vitart (Veronique); A. Nag (Abhishek); A.W. Hewit (Alex); R. Höhn (René); C. Venturini (Cristina); A. Mirshahi (Alireza); W.D. Ramdas (Wishal); G. Thorleifsson (Gudmar); E.N. Vithana (Eranga); C.C. Khor; A.B. Stefansson (Arni B.); J. Liao (Jie); J.L. Haines (Jonathan); N. Amin (Najaf); Y. Wang (Ying); P.S. Wild (Philipp S.); A.B. Ozel (Ayse B.); J. Li; B.W. Fleck (Brian W.); T. Zeller (Tanja); S.E. Staffieri (Sandra E.); Y.Y. Teo (Yik Ying); G. Cuellar-Partida (Gabriel); X. Luo (Xiaoyan); R.R. Allingham (R Rand); J.E. Richards (Julia); A. Senft (Andrea); L.C. Karssen (Lennart); Y. Zheng (Yingfeng); C. Bellenguez (Céline); L. Xu (Liang); A.I. Iglesias González (Adriana); J.F. Wilson (James F); J.H. Kang (Jae H.); E.M. van Leeuwen (Elisa); V. Jonsson (Vesteinn); U. Thorsteinsdottir (Unnur); D.D.G. Despriet (Dominique); S. Ennis (Sarah); S.E. Moroi (Sayoko); N.G. Martin (Nicholas); N.M. Jansonius (Nomdo); S. Yazar (Seyhan); E.S. Tai (Shyong); P. Amouyel (Philippe); J. Kirwan (James); L.M.E. van Koolwijk (Leonieke); M.A. Hauser (Michael); F. Jonasson (Fridbert); P.J. Leo (Paul); S.J. Loomis (Stephanie J.); R. Fogarty (Rhys); F. Rivadeneira Ramirez (Fernando); L.S. Kearns (Lisa S.); K.J. Lackner (Karl); P.T.V.M. de Jong (Paulus); C.L. Simpson (Claire); C.E. Pennell (Craig); B.A. Oostra (Ben); A.G. Uitterlinden (André); S-M. Saw (Seang-Mei); A.J. Lotery (Andrew); J.E. Bailey-Wilson (Joan E.); A. Hofman (Albert); J.R. Vingerling (Hans); C. Maubaret (Cécilia); A.F.H. Pfeiffer (Andreas); R.C.W. Wolfs (Roger); H.G. Lemij (Hans); T.L. Young (Terri); L.R. Pasquale (Louis); C. Delcourt (Cécile); T.D. Spector (Timothy); C.C.W. Klaver (Caroline); K.S. Small (Kerrin); K.P. Burdon (Kathryn); J-A. Zwart (John-Anker); T.Y. Wong (Tien); A.C. Viswanathan (Ananth); D.A. Mackey (David); J.E. Craig (Jamie); J.L. Wiggs (Janey); C.M. van Duijn (Cock); C.J. Hammond (Christopher); T. Aung (Tin)

    2014-01-01

    textabstractElevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International

  18. 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.

    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

  19. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

    NARCIS (Netherlands)

    Hysi, Pirro G; Cheng, Ching-Yu; Springelkamp, Henriët; Macgregor, Stuart; Bailey, Jessica N Cooke; Wojciechowski, Robert; Vitart, Veronique; Nag, Abhishek; Hewitt, Alex W; Höhn, René; Venturini, Cristina; Mirshahi, Alireza; Ramdas, Wishal D; Thorleifsson, Gudmar; Vithana, Eranga; Khor, Chiea-Chuen; Stefansson, Arni B; Liao, Jiemin; Haines, Jonathan L; Amin, Najaf; Wang, Ya Xing; Wild, Philipp S; Ozel, Ayse B; Li, Jun Z; Fleck, Brian W; Zeller, Tanja; Staffieri, Sandra E; Teo, Yik-Ying; Cuellar-Partida, Gabriel; Luo, Xiaoyan; Allingham, R Rand; Richards, Julia E; Senft, Andrea; Karssen, Lennart C; Zheng, Yingfeng; Bellenguez, Céline; Xu, Liang; Iglesias, Adriana I; Wilson, James F; Kang, Jae H; van Leeuwen, Elisabeth M; Jonsson, Vesteinn; Thorsteinsdottir, Unnur; Despriet, Dominiek D G; Ennis, Sarah; Moroi, Sayoko E; Martin, Nicholas G; Jansonius, Nomdo M; Yazar, Seyhan; Tai, E-Shyong; Amouyel, Philippe; Kirwan, James; van Koolwijk, Leonieke M E; Hauser, Michael A; Jonasson, Fridbert; Leo, Paul; Loomis, Stephanie J; Fogarty, Rhys; Rivadeneira, Fernando; Kearns, Lisa; Lackner, Karl J; de Jong, Paulus T V M; Simpson, Claire L; Pennell, Craig E; Oostra, Ben A; Uitterlinden, André G; Saw, Seang-Mei; Lotery, Andrew J; Bailey-Wilson, Joan E; Hofman, Albert; Vingerling, Johannes R; Maubaret, Cécilia; Pfeiffer, Norbert; Wolfs, Roger C W; Lemij, Hans G; Young, Terri L; Pasquale, Louis R; Delcourt, Cécile; Spector, Timothy D; Klaver, Caroline C W; Small, Kerrin S; Burdon, Kathryn P; Stefansson, Kari; Wong, Tien-Yin; Viswanathan, Ananth; Mackey, David A; Craig, Jamie E; Wiggs, Janey L; van Duijn, Cornelia M; Hammond, Christopher J; Aung, Tin

    2014-01-01

    Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma

  20. 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); S.F. Janssen (Sarah); 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); A.I. Iglesias González (Adriana); 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); 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)

    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

  1. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

    NARCIS (Netherlands)

    Springelkamp, Henriët; Höhn, René; 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, Grant W; 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, André 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

  2. 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

  3. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

    NARCIS (Netherlands)

    Franke, Andre; McGovern, Dermot P. B.; Barrett, Jeffrey C.; Wang, Kai; Radford-Smith, Graham L.; Ahmad, Tariq; Lees, Charlie W.; Balschun, Tobias; Lee, James; Roberts, Rebecca; Anderson, Carl A.; Bis, Joshua C.; Bumpstead, Suzanne; Ellinghaus, David; Festen, Eleonora M.; Georges, Michel; Green, Todd; Haritunians, Talin; Jostins, Luke; Latiano, Anna; Mathew, Christopher G.; Montgomery, Grant W.; Prescott, Natalie J.; Raychaudhuri, Soumya; Rotter, Jerome I.; Schumm, Philip; Sharma, Yashoda; Simms, Lisa A.; Taylor, Kent D.; Whiteman, David; Wijmenga, Cisca; Baldassano, Robert N.; Barclay, Murray; Bayless, Theodore M.; Brand, Stephan; Buening, Carsten; Cohen, Albert; Colombel, Jean-Frederick; Cottone, Mario; Stronati, Laura; Denson, Ted; De Vos, Martine; D'Inca, Renata; Dubinsky, Marla; Edwards, Cathryn; Florin, Tim; Franchimont, Denis; Gearry, Richard; Glas, Juergen; Van Gossum, Andre; Guthery, Stephen L.; Halfvarson, Jonas; Verspaget, Hein W.; Hugot, Jean-Pierre; Karban, Amir; Laukens, Debby; Lawrance, Ian; Lemann, Marc; Levine, Arie; Libioulle, Cecile; Louis, Edouard; Mowat, Craig; Newman, William; Panes, Julian; Phillips, Anne; Proctor, Deborah D.; Regueiro, Miguel; Russell, Richard; Rutgeerts, Paul; Sanderson, Jeremy; Sans, Miquel; Seibold, Frank; Steinhart, A. Hillary; Stokkers, Pieter C. F.; Torkvist, Leif; Kullak-Ublick, Gerd; Wilson, David; Walters, Thomas; Targan, Stephan R.; Brant, Steven R.; Rioux, John D.; D'Amato, Mauro; Weersma, Rinse K.; Kugathasan, Subra; Griffiths, Anne M.; Mansfield, John C.; Vermeire, Severine; Duerr, Richard H.; Silverberg, Mark S.; Satsangi, Jack; Schreiber, Stefan; Cho, Judy H.; Annese, Vito; Hakonarson, Hakon; Daly, Mark J.; Parkes, Miles

    2010-01-01

    We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibilit

  4. 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

    Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 popul...

  5. A meta-analysis of four genome-wide association studies of survival to age 90 years or older

    DEFF Research Database (Denmark)

    Newman, Anne B; Walter, Stefan; Lunetta, Kathryn L

    2010-01-01

    BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity. METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart S...

  6. Meta-analysis of genome-wide association studies identifies novel loci that influence cupping and the glaucomatous process

    NARCIS (Netherlands)

    Springelkamp, Henriët; Höhn, René; 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, Grant W; 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, André 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

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

    NARCIS (Netherlands)

    Paternoster, Lavinia; Standl, Marie; Chen, Chih-Mei; Ramasamy, Adaikalavan; Bonnelykke, Klaus; Duijts, Liesbeth; Ferreira, Manuel A.; Alves, Alexessander Couto; Thyssen, Jacob P.; Albrecht, Eva; Baurecht, Hansjoerg; Feenstra, Bjarke; Sleiman, Patrick M. A.; Hysi, Pirro; Warrington, Nicole M.; Curjuric, Ivan; Myhre, Ronny; Curtin, John A.; Groen-Blokhuis, Maria M.; Kerkhof, Marjan; Saaf, Annika; Franke, Andre; Ellinghaus, David; Foelster-Holst, Regina; Dermitzakis, Emmanouil; Montgomery, Stephen B.; Prokisch, Holger; Heim, Katharina; Hartikainen, Anna-Liisa; Pouta, Anneli; Pekkanen, Juha; Blakemore, Alexandra I. F.; Buxton, Jessica L.; Kaakinen, Marika; Duffy, David L.; Madden, Pamela A.; Heath, Andrew C.; Montgomery, Grant W.; Thompson, Philip J.; Matheson, Melanie C.; Le Souef, Peter; St Pourcain, Beate; Smith, George Davey; Henderson, John; Kemp, John P.; Timpson, Nicholas J.; Deloukas, Panos; Ring, Susan M.; Wichmann, H-Erich; Mueller-Nurasyid, Martina; Novak, Natalija; Klopp, Norman; Rodriguez, Elke; McArdle, Wendy; Linneberg, Allan; Menne, Torkil; Nohr, Ellen A.; Hofman, Albert; Uitterlinden, Andre G.; van Duijin, Cornelia M.; Rivadeneira, Fernando; de Jongste, Johan C.; van der Valk, Ralf J. P.; Wjst, Matthias; Jogi, Rain; Geller, Frank; Boyd, Heather A.; Murray, Jeffrey C.; Kim, Cecilia; Mentch, Frank; March, Michael; Mangino, Massimo; Spector, Tim D.; Bataille, Veronique; Pennell, Craig E.; Holt, Patrick G.; Sly, Peter; Tiesler, Carla M. T.; Thiering, Elisabeth; Illig, Thomas; Imboden, Medea; Nystad, Wenche; Simpson, Angela; Hottenga, Jouke-Jan; Postma, Dirkje; Koppelman, Gerard H.; Smit, Henriette A.; Soderhall, Cilla; Chawes, Bo; Kreiner-Moller, Eskil; Bisgaard, Hans; Melen, Erik; Boomsma, Dorret I.; Custovic, Adnan; Jacobsson, Bo; Probst-Hensch, Nicole M.; Palmer, Lyle J.; Glass, Daniel; Hakonarson, Hakon; Melbye, Mads; Jarvis, Deborah L.; Jaddoe, Vincent W. V.; Gieger, Christian; Strachan, David P.; Martin, Nicholas G.; Jarvelin, Marjo-Riitta; Heinrich, Joachim; Evans, David M.; Weidinger, Stephan

    Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16

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

    NARCIS (Netherlands)

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

    2015-01-01

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

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

    NARCIS (Netherlands)

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

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

  10. Meta-analysis of genome-wide association for migraine in six population-based European cohorts

    NARCIS (Netherlands)

    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 H. M.; Janssens, A. Cecile J. W.; Aulchenko, Yurii S.; Oostra, Ben A.; de Geus, Eco J. C.; Smit, Johannes H.; Zitman, Frans G.; Uitterlinden, Andre G.; Hofman, Albert; Willemsen, Gonneke; Nyholt, Dale R.; Montgomery, Grant W.; Terwindt, Gisela M.; Gudnason, Vilmundur; Penninx, Brenda W. J. H.; Breteler, Monique; Ferrari, Michel D.; Launer, Lenore J.; van Duijn, Cornelia M.; van den Maagdenberg, Arn M. J. M.; Boomsma, Dorret I.

    2011-01-01

    Migraine is a common neurological 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 migra

  11. Genome-wide polysomal analysis of a yeast strain with mutated ribosomal protein S9

    Directory of Open Access Journals (Sweden)

    Arava Yoav

    2007-08-01

    Full Text Available Abstract Background The yeast ribosomal protein S9 (S9 is located at the entrance tunnel of the mRNA into the ribosome. It is known to play a role in accurate decoding and its bacterial homolog (S4 has recently been shown to be involved in opening RNA duplexes. Here we examined the effects of changing the C terminus of S9, which is rich in acidic amino acids and extends out of the ribosome surface. Results We performed a genome-wide analysis to reveal effects at the transcription and translation levels of all yeast genes. While negligible relative changes were observed in steady-state mRNA levels, a significant number of mRNAs appeared to have altered ribosomal density. Notably, 40% of the genes having reliable signals changed their ribosomal association by more than one ribosome. Yet, no general correlations with physical or functional features of the mRNA were observed. Ribosome Density Mapping (RDM along four of the mRNAs with increased association revealed an increase in ribosomal density towards the end of the coding region for at least two of them. Read-through analysis did not reveal any increase in read-through of a premature stop codon by the mutant strain. Conclusion The ribosomal protein rpS9 appears to be involved in the translation of many mRNAs, since altering its C terminus led to a significant change in ribosomal association of many mRNAs. We did not find strong correlations between these changes and several physical features of the mRNA, yet future studies with advanced tools may allow such correlations to be determined. Importantly, our results indicate an accumulation of ribosomes towards the end of the coding regions of some mRNAs. This suggests an involvement of S9 in ribosomal dissociation during translation termination.

  12. Genome-Wide Identification, Characterization and Expression Analysis of the TCP Gene Family in Prunus mume.

    Science.gov (United States)

    Zhou, Yuzhen; Xu, Zongda; Zhao, Kai; Yang, Weiru; Cheng, Tangren; Wang, Jia; Zhang, Qixiang

    2016-01-01

    TCP proteins, belonging to a plant-specific transcription factors family, are known to have great functions in plant development, especially flower and leaf development. However, there is little information about this gene family in Prunus mume, which is widely cultivated in China as an ornamental and fruit tree. Here a genome-wide analysis of TCP genes was performed to explore their evolution in P. mume. Nineteen PmTCPs were identified and three of them contained putative miR319 target sites. Phylogenetic and comprehensive bioinformatics analyses of these genes revealed that different types of TCP genes had undergone different evolutionary processes and the genes in the same clade had similar chromosomal location, gene structure, and conserved domains. Expression analysis of these PmTCPs indicated that there were diverse expression patterns among different clades. Most TCP genes were predominantly expressed in flower, leaf, and stem, and showed high expression levels in the different stages of flower bud differentiation, especially in petal formation stage and gametophyte development. Genes in TCP-P subfamily had main roles in both flower development and gametophyte development. The CIN genes in double petal cultivars might have key roles in the formation of petal, while they were correlated with gametophyte development in the single petal cultivar. The CYC/TB1 type genes were highly detected in the formation of petal and pistil. The less-complex flower types of P. mume might result from the fact that there were only two CYC type genes present in P. mume and a lack of CYC2 genes to control the identity of flower types. These results lay the foundation for further study on the functions of TCP genes during flower development.

  13. Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis.

    Directory of Open Access Journals (Sweden)

    Matthew T Dyson

    2014-03-01

    Full Text Available Endometriosis is a gynecological disease defined by the extrauterine growth of endometrial-like cells that cause chronic pain and infertility. The disease is limited to primates that exhibit spontaneous decidualization, and diseased cells are characterized by significant defects in the steroid-dependent genetic pathways that typify this process. Altered DNA methylation may underlie these defects, but few regions with differential methylation have been implicated in the disease. We mapped genome-wide differences in DNA methylation between healthy human endometrial and endometriotic stromal cells and correlated this with gene expression using an interaction analysis strategy. We identified 42,248 differentially methylated CpGs in endometriosis compared to healthy cells. These extensive differences were not unidirectional, but were focused intragenically and at sites distal to classic CpG islands where methylation status was typically negatively correlated with gene expression. Significant differences in methylation were mapped to 403 genes, which included a disproportionally large number of transcription factors. Furthermore, many of these genes are implicated in the pathology of endometriosis and decidualization. Our results tremendously improve the scope and resolution of differential methylation affecting the HOX gene clusters, nuclear receptor genes, and intriguingly the GATA family of transcription factors. Functional analysis of the GATA family revealed that GATA2 regulates key genes necessary for the hormone-driven differentiation of healthy stromal cells, but is hypermethylated and repressed in endometriotic cells. GATA6, which is hypomethylated and abundant in endometriotic cells, potently blocked hormone sensitivity, repressed GATA2, and induced markers of endometriosis when expressed in healthy endometrial cells. The unique epigenetic fingerprint in endometriosis suggests DNA methylation is an integral component of the disease, and

  14. Genome-Wide Analysis of miRNA targets in Brachypodium and Biomass Energy Crops

    Energy Technology Data Exchange (ETDEWEB)

    Green, Pamela J. [Univ. of Delaware, Newark, DE (United States)

    2015-08-11

    MicroRNAs (miRNAs) contribute to the control of numerous biological processes through the regulation of specific target mRNAs. Although the identities of these targets are essential to elucidate miRNA function, the targets are much more difficult to identify than the small RNAs themselves. Before this work, we pioneered the genome-wide identification of the targets of Arabidopsis miRNAs using an approach called PARE (German et al., Nature Biotech. 2008; Nature Protocols, 2009). Under this project, we applied PARE to Brachypodium distachyon (Brachypodium), a model plant in the Poaceae family, which includes the major food grain and bioenergy crops. Through in-depth global analysis and examination of specific examples, this research greatly expanded our knowledge of miRNAs and target RNAs of Brachypodium. New regulation in response to environmental stress or tissue type was found, and many new miRNAs were discovered. More than 260 targets of new and known miRNAs with PARE sequences at the precise sites of miRNA-guided cleavage were identified and characterized. Combining PARE data with the small RNA data also identified the miRNAs responsible for initiating approximately 500 phased loci, including one of the novel miRNAs. PARE analysis also revealed that differentially expressed miRNAs in the same family guide specific target RNA cleavage in a correspondingly tissue-preferential manner. The project included generation of small RNA and PARE resources for bioenergy crops, to facilitate ongoing discovery of conserved miRNA-target RNA regulation. By associating specific miRNA-target RNA pairs with known physiological functions, the research provides insights about gene regulation in different tissues and in response to environmental stress. This, and release of new PARE and small RNA data sets should contribute basic knowledge to enhance breeding and may suggest new strategies for improvement of biomass energy crops.

  15. Genome-wide analysis of antiviral signature genes in porcine macrophages at different activation statuses.

    Directory of Open Access Journals (Sweden)

    Yongming Sang

    Full Text Available Macrophages (MФs can be polarized to various activation statuses, including classical (M1, alternative (M2, and antiviral states. To study the antiviral activation status of porcine MФs during porcine reproductive and respiratory syndrome virus (PRRSV infection, we used RNA Sequencing (RNA-Seq for transcriptomic analysis of differentially expressed genes (DEGs. Sequencing assessment and quality evaluation showed that our RNA-Seq data met the criteria for genome-wide transcriptomic analysis. Comparisons of any two activation statuses revealed more than 20,000 DEGs that were normalized to filter out 153-5,303 significant DEGs [false discovery rate (FDR ≤0.001, fold change ≥2] in each comparison. The highest 5,303 significant DEGs were found between lipopolysaccharide- (LPS and interferon (IFNγ-stimulated M1 cells, whereas only 153 significant DEGs were detected between interleukin (IL-10-polarized M2 cells and control mock-activated cells. To identify signature genes for antiviral regulation pertaining to each activation status, we identified a set of DEGs that showed significant up-regulation in only one activation state. In addition, pathway analyses defined the top 20-50 significantly regulated pathways at each activation status, and we further analyzed DEGs pertinent to pathways mediated by AMP kinase (AMPK and epigenetic mechanisms. For the first time in porcine macrophages, our transcriptomic analyses not only compared family-wide differential expression of most known immune genes at different activation statuses, but also revealed transcription evidence of multiple gene families. These findings show that using RNA-Seq transcriptomic analyses in virus-infected and status-synchronized macrophages effectively profiled signature genes and gene response pathways for antiviral regulation, which may provide a framework for optimizing antiviral immunity and immune homeostasis.

  16. Genome-Wide Association Analysis of the Anthocyanin and Carotenoid Contents of Rose Petals

    Science.gov (United States)

    Schulz, Dietmar F.; Schott, Rena T.; Voorrips, Roeland E.; Smulders, Marinus J. M.; Linde, Marcus; Debener, Thomas

    2016-01-01

    Petal color is one of the key characteristics determining the attractiveness and therefore the commercial value of an ornamental crop. Here, we present the first genome-wide association study for the important ornamental crop rose, focusing on the anthocyanin and carotenoid contents in petals of 96 diverse tetraploid garden rose genotypes. Cultivated roses display a vast phenotypic and genetic diversity and are therefore ideal targets for association genetics. For marker analysis, we used a recently designed Axiom SNP chip comprising 68,000 SNPs with additionally 281 SSRs, 400 AFLPs and 246 markers from candidate genes. An analysis of the structure of the rose population revealed three subpopulations with most of the genetic variation between individual genotypes rather than between clusters and with a high average proportion of heterozygous loci. The mapping of markers significantly associated with anthocyanin and carotenoid content to the related Fragaria and Prunus genomes revealed clusters of associated markers indicating five genomic regions associated with the total anthocyanin content and two large clusters associated with the carotenoid content. Among the marker clusters associated with the phenotypes, we found several candidate genes with known functions in either the anthocyanin or the carotenoid biosynthesis pathways. Among others, we identified a glutathione-S-transferase, 4CL, an auxin response factor and F3'H as candidate genes affecting anthocyanin concentration, and CCD4 and Zeaxanthine epoxidase as candidates affecting the concentration of carotenoids. These markers are starting points for future validation experiments in independent populations as well as for functional genomic studies to identify the causal factors for the observed color phenotypes. Furthermore, validated markers may be interesting tools for marker-assisted selection in commercial breeding programmes in that they provide the tools to identify superior parental combinations that

  17. Genome-wide microarray analysis of tomato roots showed defined responses to iron deficiency

    Directory of Open Access Journals (Sweden)

    Zamboni Anita

    2012-03-01

    Full Text Available Abstract Background Plants react to iron deficiency stress adopting different kind of adaptive responses. Tomato, a Strategy I plant, improves iron uptake through acidification of rhizosphere, reduction of Fe3+ to Fe2+ and transport of Fe2+ into the cells. Large-scale transcriptional analyses of roots under iron deficiency are only available for a very limited number of plant species with particular emphasis for Arabidopsis thaliana. Regarding tomato, an interesting model species for Strategy I plants and an economically important crop, physiological responses to Fe-deficiency have been thoroughly described and molecular analyses have provided evidence for genes involved in iron uptake mechanisms and their regulation. However, no detailed transcriptome analysis has been described so far. Results A genome-wide transcriptional analysis, performed with a chip that allows to monitor the expression of more than 25,000 tomato transcripts, identified 97 differentially expressed transcripts by comparing roots of Fe-deficient and Fe-sufficient tomato plants. These transcripts are related to the physiological responses of tomato roots to the nutrient stress resulting in an improved iron uptake, including regulatory aspects, translocation, root morphological modification and adaptation in primary metabolic pathways, such as glycolysis and TCA cycle. Other genes play a role in flavonoid biosynthesis and hormonal metabolism. Conclusions The transcriptional characterization confirmed the presence of the previously described mechanisms to adapt to iron starvation in tomato, but also allowed to identify other genes potentially playing a role in this process, thus opening new research perspectives to improve the knowledge on the tomato root response to the nutrient deficiency.

  18. Transport genes and chemotaxis in Laribacter hongkongensis: a genome-wide analysis

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    Lau Susanna KP

    2011-08-01

    Full Text Available Abstract Background Laribacter hongkongensis is a Gram-negative, sea gull-shaped rod associated with community-acquired gastroenteritis. The bacterium has been found in diverse freshwater environments including fish, frogs and drinking water reservoirs. Using the complete genome sequence data of L. hongkongensis, we performed a comprehensive analysis of putative transport-related genes and genes related to chemotaxis, motility and quorum sensing, which may help the bacterium adapt to the changing environments and combat harmful substances. Results A genome-wide analysis using Transport Classification Database TCDB, similarity and keyword searches revealed the presence of a large diversity of transporters (n = 457 and genes related to chemotaxis (n = 52 and flagellar biosynthesis (n = 40 in the L. hongkongensis genome. The transporters included those from all seven major transporter categories, which may allow the uptake of essential nutrients or ions, and extrusion of metabolic end products and hazardous substances. L. hongkongensis is unique among closely related members of Neisseriaceae family in possessing higher number of proteins related to transport of ammonium, urea and dicarboxylate, which may reflect the importance of nitrogen and dicarboxylate metabolism in this assacharolytic bacterium. Structural modeling of two C4-dicarboxylate transporters showed that they possessed similar structures to the determined structures of other DctP-TRAP transporters, with one having an unusual disulfide bond. Diverse mechanisms for iron transport, including hemin transporters for iron acquisition from host proteins, were also identified. In addition to the chemotaxis and flagella-related genes, the L. hongkongensis genome also contained two copies of qseB/qseC homologues of the AI-3 quorum sensing system. Conclusions The large number of diverse transporters and genes involved in chemotaxis, motility and quorum sensing suggested that the bacterium may

  19. Genome-Wide Identification, Characterization and Expression Analysis of the TCP Gene Family in Prunus mume

    Science.gov (United States)

    Zhou, Yuzhen; Xu, Zongda; Zhao, Kai; Yang, Weiru; Cheng, Tangren; Wang, Jia; Zhang, Qixiang

    2016-01-01

    TCP proteins, belonging to a plant-specific transcription factors family, are known to have great functions in plant development, especially flower and leaf development. However, there is little information about this gene family in Prunus mume, which is widely cultivated in China as an ornamental and fruit tree. Here a genome-wide analysis of TCP genes was performed to explore their evolution in P. mume. Nineteen PmTCPs were identified and three of them contained putative miR319 target sites. Phylogenetic and comprehensive bioinformatics analyses of these genes revealed that different types of TCP genes had undergone different evolutionary processes and the genes in the same clade had similar chromosomal location, gene structure, and conserved domains. Expression analysis of these PmTCPs indicated that there were diverse expression patterns among different clades. Most TCP genes were predominantly expressed in flower, leaf, and stem, and showed high expression levels in the different stages of flower bud differentiation, especially in petal formation stage and gametophyte development. Genes in TCP-P subfamily had main roles in both flower development and gametophyte development. The CIN genes in double petal cultivars might have key roles in the formation of petal, while they were correlated with gametophyte development in the single petal cultivar. The CYC/TB1 type genes were highly detected in the formation of petal and pistil. The less-complex flower types of P. mume might result from the fact that there were only two CYC type genes present in P. mume and a lack of CYC2 genes to control the identity of flower types. These results lay the foundation for further study on the functions of TCP genes during flower development. PMID:27630648

  20. A combined analysis of genome-wide expression profiling of bipolar disorder in human prefrontal cortex.

    Science.gov (United States)

    Wang, Jinglu; Qu, Susu; Wang, Weixiao; Guo, Liyuan; Zhang, Kunlin; Chang, Suhua; Wang, Jing

    2016-11-01

    Numbers of gene expression profiling studies of bipolar disorder have been published. Besides different array chips and tissues, variety of the data processes in different cohorts aggravated the inconsistency of results of these genome-wide gene expression profiling studies. By searching the gene expression databases, we obtained six data sets for prefrontal cortex (PFC) of bipolar disorder with raw data and combinable platforms. We used standardized pre-processing and quality control procedures to analyze each data set separately and then combined them into a large gene expression matrix with 101 bipolar disorder subjects and 106 controls. A standard linear mixed-effects model was used to calculate the differentially expressed genes (DEGs). Multiple levels of sensitivity analyses and cross validation with genetic data were conducted. Functional and network analyses were carried out on basis of the DEGs. In the result, we identified 198 unique differentially expressed genes in the PFC of bipolar disorder and control. Among them, 115 DEGs were robust to at least three leave-one-out tests or different pre-processing methods; 51 DEGs were validated with genetic association signals. Pathway enrichment analysis showed these DEGs were related with regulation of neurological system, cell death and apoptosis, and several basic binding processes. Protein-protein interaction network further identified one key hub gene. We have contributed the most comprehensive integrated analysis of bipolar disorder expression profiling studies in PFC to date. The DEGs, especially those with multiple validations, may denote a common signature of bipolar disorder and contribute to the pathogenesis of disease.

  1. Genome-wide analysis of blood pressure variability and ischemic stroke.

    Science.gov (United States)

    Yadav, Sunaina; Cotlarciuc, Ioana; Munroe, Patricia B; Khan, Muhammad S; Nalls, Michael A; Bevan, Steve; Cheng, Yu-Ching; Chen, Wei-Min; Malik, Rainer; McCarthy, Nina S; Holliday, Elizabeth G; Speed, Douglas; Hasan, Nazeeha; Pucek, Mateusz; Rinne, Paul E; Sever, Peter; Stanton, Alice; Shields, Denis C; Maguire, Jane M; McEvoy, Mark; Scott, Rodney J; Ferrucci, Luigi; Macleod, Mary J; Attia, John; Markus, Hugh S; Sale, Michele M; Worrall, Bradford B; Mitchell, Braxton D; Dichgans, Martin; Sudlow, Cathy; Meschia, James F; Rothwell, Peter M; Caulfield, Mark; Sharma, Pankaj

    2013-10-01

    Visit-to-visit variability in blood pressure (vBP) is associated with ischemic stroke. We sought to determine whether such variability has genetic causes and whether genetic variants associated with BP variability are also associated with ischemic stroke. A Genome Wide Association Study (GWAS) for loci influencing BP variability was undertaken in 3802 individuals from the Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) study, in which long-term visit-to-visit and within-visit BP measures were available. Because BP variability is strongly associated with ischemic stroke, we genotyped the sentinel single nucleotide polymorphism in an independent ischemic stroke population comprising 8624 cases and 12 722 controls and in 3900 additional (Scandinavian) participants from the ASCOT study to replicate our findings. The ASCOT discovery GWAS identified a cluster of 17 correlated single nucleotide polymorphisms within the NLGN1 gene (3q26.31) associated with BP variability. The strongest association was with rs976683 (P=1.4×10(-8)). Conditional analysis of rs976683 provided no evidence of additional independent associations at the locus. Analysis of rs976683 in patients with ischemic stroke found no association for overall stroke (odds ratio, 1.02; 95% CI, 0.97-1.07; P=0.52) or its subtypes: cardioembolic (odds ratio, 1.07; 95% CI, 0.97-1.16; P=0.17), large vessel disease (odds ratio, 0.98; 95% CI, 0.89-1.07; P=0.60), and small vessel disease (odds ratio, 1.07; 95% CI, 0.97-1.17; P=0.19). No evidence for association was found between rs976683 and BP variability in the additional (Scandinavian) ASCOT participants (P=0.18). We identified a cluster of single nucleotide polymorphisms at the NLGN1 locus showing significant association with BP variability. Follow-up analyses did not support an association with risk of ischemic stroke and its subtypes.

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

    NARCIS (Netherlands)

    Bonnelykke, Klaus; Matheson, Melanie C.; Pers, Tune H.; 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-Moller, 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

    2013-01-01

    Allergen-specific immunoglobulin E (present in allergic sensitization) has 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 t

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  4. 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 ...

  5. Genome wide association analysis for residual feed intake in Danish Duroc boars

    DEFF Research Database (Denmark)

    Do, Duy Ngoc; Ostersen, Tage; Strathe, Anders Bjerring;

    2013-01-01

    gain (30-100 kg). RFI2 was the same as RFI1 except that it was also regressed on backfat (BF). A total of 868 boars had phenotypic and genotype (i.e. Illumina Porcine SNP60 BeadChip) records. A total of 33945 SNPs were available for genome wide association studies (GWAS) after quality control...

  6. Identification of six Loci associated with pelvic organ prolapse using genome-wide association analysis.

    NARCIS (Netherlands)

    Allen-Brady, K.; Cannon-Albright, L.; Farnham, J.M.; Teerlink, C.; Vierhout, M.E.; Kempen, L.C.L.T. van; Kluivers, K.B.; Norton, P.A.

    2011-01-01

    OBJECTIVE: : There is evidence that both environmental and genetic factors contribute to pelvic organ prolapse. We conducted a genome-wide association study to investigate whether common genetic variants modify the risk of pelvic organ prolapse. METHODS: : We recruited women who had been evaluated

  7. Using Genome-Wide Pathway Analysis to Unravel the Etiology of Complex Diseases

    NARCIS (Netherlands)

    Elbers, Clara C.; van Eijk, Kristel R.; Franke, Lude; Mulder, Flip; van der Schouw, Yvonne T.; Wijmenga, Cisca; Onland-Moret, N. Charlotte

    2009-01-01

    Several genome-wide association studies (GWAS) have been published on various complex diseases. Although, new loci are found to be associated with these diseases, still only very little of the genetic risk for these diseases can be explained. As GWAS are still underpowered to find small main effects

  8. Genome-wide pathway analysis identifies oxidative stress related gene MSRA as rheumatoid arthritis susceptibility locus

    NARCIS (Netherlands)

    Martin, Jose Ezequiel; Alizadeh, Behrooz Z.; Gonzalez-Gay, Miguel A.; Balsa, Alejandro; Pascual-Salcedo, Dora; Fernandez-Gutierrez, Benjamín; Raya, Enrique

    2010-01-01

    Objective: Genome-wide association studies (GWASs) carried out in rheumatoid arthritis (RA) have led to the discovery of several genetic associations with this disease. Still, the current associated genetic variations can explain only part of the genetic risk involved in RA, and it is well recognise

  9. Genome-wide analysis of tandem repeats in plants and green algae

    Science.gov (United States)

    Zhixin Zhao; Cheng Guo; Sreeskandarajan Sutharzan; Pei Li; Craig Echt; Jie Zhang; Chun Liang

    2014-01-01

    Tandem repeats (TRs) extensively exist in the genomes of prokaryotes and eukaryotes. Based on the sequenced genomes and gene annotations of 31 plant and algal species in Phytozome version 8.0 (http://www.phytozome.net/), we examined TRs in a genome-wide scale, characterized their distributions and motif features, and explored their putative biological functions. Among...

  10. Meta-analysis of genome-wide association from genomic prediction models

    Science.gov (United States)

    A limitation of many genome-wide association studies (GWA) in animal breeding is that there are many loci with small effect sizes; thus, larger sample sizes (N) are required to guarantee suitable power of detection. To increase sample size, results from different GWA can be combined in a meta-analys...

  11. Implementing Meta-analysis for genome-wide association studies of pork quality traits

    Science.gov (United States)

    Pork quality is a critical concern in the meat industry. Implementation of genome-wide association studies (GWA) allows identification of genomic regions that explain a substantial portion of the variation of relevant traits. It is also important to determine the consistency of results of GWA across...

  12. Implementing meta-analysis from genome-wide association studies for pork quality traits

    Science.gov (United States)

    Pork quality plays an important role in the meat processing industry, thus different methodologies have been implemented to elucidate the genetic architecture of traits affecting meat quality. One of the most common and widely used approaches is to perform genome-wide association (GWA) studies. Howe...

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

    NARCIS (Netherlands)

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

    2012-01-01

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

  14. Genome-wide computational prediction and analysis of core promoter elements across plant monocots and dicots

    Science.gov (United States)

    Transcription initiation, essential to gene expression regulation, involves recruitment of basal transcription factors to the core promoter elements (CPEs). The distribution of currently known CPEs across plant genomes is largely unknown. This is the first large scale genome-wide report on the compu...

  15. Meta-analysis of Genome-Wide Association Studies for Extraversion

    DEFF Research Database (Denmark)

    van den Berg, Stéphanie M; de Moor, Marleen H M; Verweij, K. J. H.

    2016-01-01

    Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively ...

  16. 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.

  17. Genome-wide copy number variation analysis in a Chinese autism spectrum disorder cohort

    Science.gov (United States)

    Guo, Hui; Peng, Yu; Hu, Zhengmao; Li, Ying; Xun, Guanglei; Ou, Jianjun; Sun, Liangdan; Xiong, Zhimin; Liu, Yanling; Wang, Tianyun; Chen, Jingjing; Xia, Lu; Bai, Ting; Shen, Yidong; Tian, Qi; Hu, Yiqiao; Shen, Lu; Zhao, Rongjuan; Zhang, Xuejun; Zhang, Fengyu; Zhao, Jingping; Zou, Xiaobing; Xia, Kun

    2017-01-01

    Autism spectrum disorder (ASD) describes a group of neurodevelopmental disorders with high heritability, although the underlying genetic determinants of ASDs remain largely unknown. Large-scale whole-genome studies of copy number variation in Han Chinese samples are still lacking. We performed a genome-wide copy number variation analysis of 343 ASD trios, 203 patients with sporadic cases and 988 controls in a Chinese population using Illumina genotyping platforms to identify CNVs and related genes that may contribute to ASD risk. We identified 32 rare CNVs larger than 1 Mb in 31 patients. ASD patients were found to carry a higher global burden of rare, large CNVs than controls. Recurrent de novo or case-private CNVs were found at 15q11-13, Xp22.3, 15q13.1–13.2, 3p26.3 and 2p12. The de novo 15q11–13 duplication was more prevalent in this Chinese population than in those with European ancestry. Several genes, including GRAMD2 and STAM, were implicated as novel ASD risk genes when integrating whole-genome CNVs and whole-exome sequencing data. We also identified several CNVs that include known ASD genes (SHANK3, CDH10, CSMD1) or genes involved in nervous system development (NYAP2, ST6GAL2, GRM6). Besides, our study also implicated Contactins-NYAPs-WAVE1 pathway in ASD pathogenesis. Our findings identify ASD-related CNVs in a Chinese population and implicate novel ASD risk genes and related pathway for further study. PMID:28281572

  18. Genome-wide transcriptome analysis of gametophyte development in Physcomitrella patens

    Directory of Open Access Journals (Sweden)

    Xiao Lihong

    2011-12-01

    Full Text Available Abstract Background Regulation of gene expression plays a pivotal role in controlling the development of multicellular plants. To explore the molecular mechanism of plant developmental-stage transition and cell-fate determination, a genome-wide analysis was undertaken of sequential developmental time-points and individual tissue types in the model moss Physcomitrella patens because of the short life cycle and relative structural simplicity of this plant. Results Gene expression was analyzed by digital gene expression tag profiling of samples taken from P. patens protonema at 3, 14 and 24 days, and from leafy shoot tissues at 30 days, after protoplast isolation, and from 14-day-old caulonemal and chloronemal tissues. In total, 4333 genes were identified as differentially displayed. Among these genes, 4129 were developmental-stage specific and 423 were preferentially expressed in either chloronemal or caulonemal tissues. Most of the differentially displayed genes were assigned to functions in organic substance and energy metabolism or macromolecule biosynthetic and catabolic processes based on gene ontology descriptions. In addition, some regulatory genes identified as candidates might be involved in controlling the developmental-stage transition and cell differentiation, namely MYB-like, HB-8, AL3, zinc finger family proteins, bHLH superfamily, GATA superfamily, GATA and bZIP transcription factors, protein kinases, genes related to protein/amino acid methylation, and auxin, ethylene, and cytokinin signaling pathways. Conclusions These genes that show highly dynamic changes in expression during development in P. patens are potential targets for further functional characterization and evolutionary developmental biology studies.

  19. Genome-Wide Analysis of Salicylate and Dibenzofuran Metabolism in Sphingomonas wittichii RW1

    Directory of Open Access Journals (Sweden)

    Edith eCoronado

    2012-08-01

    Full Text Available Sphingomonas wittichii RW1 is a bacterium isolated for its ability to degrade the xenobiotic compounds dibenzodioxin and dibenzofuran (DBF. A number of genes involved in DBF degradation have been previously characterized, such as the dxn cluster, dbfB, and the electron transfer components fdx1, fdx3 and redA2. Here we use a combination of whole genome transcriptome analysis and transposon library screening to characterize RW1 catabolic and other genes implicated in the reaction to or degradation of DBF. To detect differentially expressed genes upon exposure to DBF, we applied three different growth exposure experiments, using either short DBF exposures to actively growing cells or growing them with DBF as sole carbon and energy source. Genome-wide gene expression was examined using a custom-made microarray. In addition, proportional abundance determination of transposon insertions in RW1 libraries grown on salicylate or DBF by ultra-high throughput sequencing was used to infer genes whose interruption caused a fitness loss for growth on DBF. Expression patterns showed that batch and chemostat growth conditions, and short or long exposure of cells to DBF produced very different responses. Numerous other uncharacterized catabolic gene clusters putatively involved in aromatic compound metabolism increased expression in response to DBF. In addition, only very few transposon insertions completely abolished growth on DBF. Some of those (e.g., in dxnA1 were expected, whereas others (in a gene cluster for phenylacetate degradation were not. Both transcriptomic data and transposon screening suggest operation of multiple redundant and parallel aromatic pathways, depending on DBF exposure. In addition, increased expression of other non-catabolic genes suggests that during initial exposure, S. wittichii RW1 perceives DBF as a stressor, whereas after longer exposure, the compound is recognized as a carbon source and metabolized using several pathways in

  20. Genome-wide analysis of alternative transcripts in human breast cancer

    Science.gov (United States)

    Wen, Ji; Toomer, Kevin H.

    2016-01-01

    Transcript variants play a critical role in diversifying gene expression. Alternative splicing is a major mechanism for generating transcript variants. A number of genes have been implicated in breast cancer pathogenesis with their aberrant expression of alternative transcripts. In this study, we performed genome-wide analyses of transcript variant expression in breast cancer. With RNA-Seq data from 105 patients, we characterized the transcriptome of breast tumors, by pairwise comparison of gene expression in the breast tumor versus matched healthy tissue from each patient. We identified 2839 genes, ~10 % of protein-coding genes in the human genome, that had differential expression of transcript variants between tumors and healthy tissues. The validity of the computational analysis was confirmed by quantitative RT-PCR assessment of transcript variant expression from four top candidate genes. The alternative transcript profiling led to classification of breast cancer into two subgroups and yielded a novel molecular signature that could be prognostic of patients’ tumor burden and survival. We uncovered nine splicing factors (FOX2, MBNL1, QKI, PTBP1, ELAVL1, HNRNPC, KHDRBS1, SFRS2, and TIAR) that were involved in aberrant splicing in breast cancer. Network analyses for the coordinative patterns of transcript variant expression identified twelve “hub” genes that differentiated the cancerous and normal transcriptomes. Dysregulated expression of alternative transcripts may reveal novel biomarkers for tumor development. It may also suggest new therapeutic targets, such as the “hub” genes identified through the network analyses of transcript variant expression, or splicing factors implicated in the formation of the tumor transcriptome. PMID:25913416

  1. Genome-wide association and admixture analysis of glaucoma in the Women's Health Initiative.

    Science.gov (United States)

    Hoffmann, Thomas J; Tang, Hua; Thornton, Timothy A; Caan, Bette; Haan, Mary; Millen, Amy E; Thomas, Fridtjof; Risch, Neil

    2014-12-15

    We report a genome-wide association study (GWAS) and admixture analysis of glaucoma in 12 008 African-American and Hispanic women (age 50-79 years) from the Women's Health Initiative (WHI). Although GWAS of glaucoma have been conducted on several populations, this is the first to look at glaucoma in individuals of African-American and Hispanic race/ethnicity. Prevalent and incident glaucoma was determined by self-report from study questionnaires administered at baseline (1993-1998) and annually through 2005. For African Americans, there was a total of 658 prevalent cases, 1062 incident cases and 6067 individuals who never progressed to glaucoma. For our replication cohort, we used the WHI Hispanics, including 153 prevalent cases, 336 incident cases and 2685 non-cases. We found an association of African ancestry with glaucoma incidence in African Americans (hazards ratio 1.62, 95% CI 1.023-2.56, P = 0.038) and in Hispanics (hazards ratio 3.21, 95% CI 1.32-7.80, P = 0.011). Although we found that no previously identified glaucoma SNPs replicated in either the WHI African Americans or Hispanics, a risk score combining all previously reported hits was significant in African-American prevalent cases (P = 0.0046), and was in the expected direction in the incident cases, as well as in the Hispanic incident cases. Additionally, after imputing to 1000 Genomes, two less common independent SNPs were suggestive in African Americans, but had too low of an allele frequency in Hispanics to test for replication. These results suggest the possibility of a distinct genetic architecture underlying glaucoma in individuals of African ancestry.

  2. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis

    Science.gov (United States)

    Joubert, Bonnie R.; Felix, Janine F.; Yousefi, Paul; Bakulski, Kelly M.; Just, Allan C.; Breton, Carrie; Reese, Sarah E.; Markunas, Christina A.; Richmond, Rebecca C.; Xu, Cheng-Jian; Küpers, Leanne K.; Oh, Sam S.; Hoyo, Cathrine; Gruzieva, Olena; Söderhäll, Cilla; Salas, Lucas A.; Baïz, Nour; Zhang, Hongmei; Lepeule, Johanna; Ruiz, Carlos; Ligthart, Symen; Wang, Tianyuan; Taylor, Jack A.; Duijts, Liesbeth; Sharp, Gemma C.; Jankipersadsing, Soesma A.; Nilsen, Roy M.; Vaez, Ahmad; Fallin, M. Daniele; Hu, Donglei; Litonjua, Augusto A.; Fuemmeler, Bernard F.; Huen, Karen; Kere, Juha; Kull, Inger; Munthe-Kaas, Monica Cheng; Gehring, Ulrike; Bustamante, Mariona; Saurel-Coubizolles, Marie José; Quraishi, Bilal M.; Ren, Jie; Tost, Jörg; Gonzalez, Juan R.; Peters, Marjolein J.; Håberg, Siri E.; Xu, Zongli; van Meurs, Joyce B.; Gaunt, Tom R.; Kerkhof, Marjan; Corpeleijn, Eva; Feinberg, Andrew P.; Eng, Celeste; Baccarelli, Andrea A.; Benjamin Neelon, Sara E.; Bradman, Asa; Merid, Simon Kebede; Bergström, Anna; Herceg, Zdenko; Hernandez-Vargas, Hector; Brunekreef, Bert; Pinart, Mariona; Heude, Barbara; Ewart, Susan; Yao, Jin; Lemonnier, Nathanaël; Franco, Oscar H.; Wu, Michael C.; Hofman, Albert; McArdle, Wendy; Van der Vlies, Pieter; Falahi, Fahimeh; Gillman, Matthew W.; Barcellos, Lisa F.; Kumar, Ashish; Wickman, Magnus; Guerra, Stefano; Charles, Marie-Aline; Holloway, John; Auffray, Charles; Tiemeier, Henning W.; Smith, George Davey; Postma, Dirkje; Hivert, Marie-France; Eskenazi, Brenda; Vrijheid, Martine; Arshad, Hasan; Antó, Josep M.; Dehghan, Abbas; Karmaus, Wilfried; Annesi-Maesano, Isabella; Sunyer, Jordi; Ghantous, Akram; Pershagen, Göran; Holland, Nina; Murphy, Susan K.; DeMeo, Dawn L.; Burchard, Esteban G.; Ladd-Acosta, Christine; Snieder, Harold; Nystad, Wenche; Koppelman, Gerard H.; Relton, Caroline L.; Jaddoe, Vincent W.V.; Wilcox, Allen; Melén, Erik; London, Stephanie J.

    2016-01-01

    Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value < 2.2 × 10−16). Results were robust to different normalization methods used across studies and cell type adjustment. In this large scale meta-analysis of methylation data, we identified numerous loci involved in response to maternal smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure. PMID:27040690

  3. A genome-wide association analysis of chromosomal aberrations and Hirschsprung disease.

    Science.gov (United States)

    Bae, Joon Seol; Koh, InSong; Cheong, Hyun Sub; Seo, Jeong-Meen; Kim, Dae-Yeon; Oh, Jung-Tak; Kim, Hyun-Young; Jung, Kyuwhan; Sul, Jae Hoon; Park, Woong-Yang; Kim, Jeong-Hyun; Shin, Hyoung Doo

    2016-11-01

    Hirschsprung disease (HSCR) is a neurocristopathy characterized by the absence of intramural ganglion cells along variable lengths of the gastrointestinal tract. Although the RET proto-oncogene is considered to be the main risk factor for HSCR, only about 30% of the HSCR cases can be explained by variations in previously known genes including RET. Recently, copy number variation (CNV) and loss of heterozygosity (LOH) have emerged as new ways to understand human genomic variation. The goal of this present study is to identify new HSCR genetic factors related to CNV in Korean patients. In the genome-wide genotyping, using Illumina's HumanOmni1-Quad BeadChip (1,140,419 markers), of 123 HSCR patients and 432 unaffected subjects (total n = 555), a total of 8,188 CNVs (1 kb ∼ 1 mb) were identified by CNVpartition. As a result, 16 CNV regions and 13 LOH regions were identified as associated with HSCR (minimum P = 0.0005). Two top CNV regions (deletions at chr6:32675155-32680480 and chr22:20733495-21607293) were successfully validated by additional real-time quantitative polymerase chain reaction analysis. In addition, 2 CNV regions (6p21.32 and 22q11.21) and 2 LOH regions (3p22.2 and 14q23.3) were discovered to be unique to the HSCR patients group. Regarding the large-scale chromosomal aberrations (>1 mb), 11 large aberrations in the HSCR patients group were identified, which suggests that they may be a risk factor for HSCR. Although further replication in a larger cohort is needed, our findings may contribute to the understanding of the etiology of HSCR.

  4. Genome-wide analysis of gene expression in primate taste buds reveals links to diverse processes.

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    Peter Hevezi

    Full Text Available Efforts to unravel the mechanisms underlying taste sensation (gustation have largely focused on rodents. Here we present the first comprehensive characterization of gene expression in primate taste buds. Our findings reveal unique new insights into the biology of taste buds. We generated a taste bud gene expression database using laser capture microdissection (LCM procured fungiform (FG and circumvallate (CV taste buds from primates. We also used LCM to collect the top and bottom portions of CV taste buds. Affymetrix genome wide arrays were used to analyze gene expression in all samples. Known taste receptors are preferentially expressed in the top portion of taste buds. Genes associated with the cell cycle and stem cells are preferentially expressed in the bottom portion of taste buds, suggesting that precursor cells are located there. Several chemokines including CXCL14 and CXCL8 are among the highest expressed genes in taste buds, indicating that immune system related processes are active in taste buds. Several genes expressed specifically in endocrine glands including growth hormone releasing hormone and its receptor are also strongly expressed in taste buds, suggesting a link between metabolism and taste. Cell type-specific expression of transcription factors and signaling molecules involved in cell fate, including KIT, reveals the taste bud as an active site of cell regeneration, differentiation, and development. IKBKAP, a gene mutated in familial dysautonomia, a disease that results in loss of taste buds, is expressed in taste cells that communicate with afferent nerve fibers via synaptic transmission. This database highlights the power of LCM coupled with transcriptional profiling to dissect the molecular composition of normal tissues, represents the most comprehensive molecular analysis of primate taste buds to date, and provides a foundation for further studies in diverse aspects of taste biology.

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

    Science.gov (United States)

    Schneider, J F; Rempel, L A; Snelling, W M; Wiedmann, R T; Nonneman, D J; Rohrer, G A

    2012-10-01

    Reproductive efficiency has a great impact on the economic success of pork (sus scrofa) 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) was undertaken. Samples of DNA were collected and tested using the Illumina PorcineSNP60 BeadChip from 1,152 first parity gilts. Traits included total number born (TNB), NBA, number born dead (NBD), number stillborn (NSB), number of mummies (MUM), total litter birth weight (LBW), and ABW. A total of 41,151 SNP were tested using a Bayesian approach. Beginning with the first 5 SNP on SSC1 and ending with the last 5 SNP on the SSCX, SNP were assigned to groups of 5 consecutive SNP by chromosome-position order and analyzed again using a Bayesian approach. From that analysis, 5-SNP groups were selected having no overlap with another 5-SNP groups and no overlap across chromosomes. These selected 5-SNP non-overlapping groups were defined as QTL. Of the available 8,814 QTL, 124 were found to be statistically significant (P ABW, 9 on SSC1, 3 on SSC2, 9 on SSC5, 5 on SSC6, 1 on SSC7, 2 on SSC8, 2 on SSC9, 3 on SSC10, 1 on SSC11, 3 on SSC12, 2 on SSC13, 8 on SSC14, 8 on SSC15, 1 on SSC17, and 8 on SSC18. Several candidate genes have been identified that overlap QTL locations among TNB, NBA, NBD, and ABW. These QTL when combined with information on genes found in the same regions should provide useful information that could be used for marker assisted selection, marker assisted management, or genomic selection applications in commercial pig populations.

  6. Genome-wide association analysis of oxidative stress resistance in Drosophila melanogaster.

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    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 analysis of eating disorder-related symptoms, behaviors, and personality traits.

    Science.gov (United States)

    Boraska, Vesna; Davis, Oliver S P; Cherkas, Lynn F; Helder, Sietske G; Harris, Juliette; Krug, Isabel; Liao, Thomas Pei-Chi; Treasure, Janet; Ntalla, Ioanna; Karhunen, Leila; Keski-Rahkonen, Anna; Christakopoulou, Danai; Raevuori, Anu; Shin, So-Youn; Dedoussis, George V; Kaprio, Jaakko; Soranzo, Nicole; Spector, Tim D; Collier, David A; Zeggini, Eleftheria

    2012-10-01

    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, Breakfast Skipping behavior and Childhood Obsessive-Compulsive Personality Disorder trait (CHIRP). Investigated traits were derived from standardized self-report questionnaires completed by the TwinsUK population-based cohort. We tested 283,744 directly typed SNPs across six phenotypes of interest in the TwinsUK discovery dataset and followed-up signals from various strata using a two-stage replication strategy in two independent cohorts of European ancestry. We meta-analyzed a total of 2,698 individuals for DT, 2,680 for BD, 2,789 (821 cases/1,968 controls) for Bulimia, 1,360 (633 cases/727 controls) for Childhood Obsessive-Compulsive Personality Disorder trait, 2,773 (761 cases/2,012 controls) for Breakfast Skipping, and 2,967 (798 cases/2,169 controls) for Weight Fluctuation symptom. In this GWAS analysis of six ED-related phenotypes, we detected association of eight genetic variants with P < 10(-5) . Genetic variants that showed suggestive evidence of association were previously associated with several psychiatric disorders and ED-related phenotypes. Our study indicates that larger-scale collaborative studies will be needed to achieve the necessary power to detect loci underlying ED-related traits.

  8. Escherichia coli genome-wide promoter analysis: Identification of additional AtoC binding target elements

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    Kolisis Fragiskos N

    2011-05-01

    Full Text Available Abstract Background Studies on bacterial signal transduction systems have revealed complex networks of functional interactions, where the response regulators play a pivotal role. The AtoSC system of E. coli activates the expression of atoDAEB operon genes, and the subsequent catabolism of short-chain fatty acids, upon acetoacetate induction. Transcriptome and phenotypic analyses suggested that atoSC is also involved in several other cellular activities, although we have recently reported a palindromic repeat within the atoDAEB promoter as the single, cis-regulatory binding site of the AtoC response regulator. In this work, we used a computational approach to explore the presence of yet unidentified AtoC binding sites within other parts of the E. coli genome. Results Through the implementation of a computational de novo motif detection workflow, a set of candidate motifs was generated, representing putative AtoC binding targets within the E. coli genome. In order to assess the biological relevance of the motifs and to select for experimental validation of those sequences related robustly with distinct cellular functions, we implemented a novel approach that applies Gene Ontology Term Analysis to the motif hits and selected those that were qualified through this procedure. The computational results were validated using Chromatin Immunoprecipitation assays to assess the in vivo binding of AtoC to the predicted sites. This process verified twenty-two additional AtoC binding sites, located not only within intergenic regions, but also within gene-encoding sequences. Conclusions This study, by tracing a number of putative AtoC binding sites, has indicated an AtoC-related cross-regulatory function. This highlights the significance of computational genome-wide approaches in elucidating complex patterns of bacterial cell regulation.

  9. Genome wide transcriptional profile analysis of Vitis amurensis and Vitis vinifera in response to cold stress.

    Science.gov (United States)

    Xin, Haiping; Zhu, Wei; Wang, Lina; Xiang, Yue; Fang, Linchuan; Li, Jitao; Sun, Xiaoming; Wang, Nian; Londo, Jason P; Li, Shaohua

    2013-01-01

    Grape is one of the most important fruit crops worldwide. The suitable geographical locations and productivity of grapes are largely limited by temperature. Vitis amurensis is a wild grapevine species with remarkable cold-tolerance, exceeding that of Vitis vinifera, the dominant cultivated species of grapevine. However, the molecular mechanisms that contribute to the enhanced freezing tolerance of V. amurensis remain unknown. Here we used deep sequencing data from restriction endonuclease-generated cDNA fragments to evaluate the whole genome wide modification of transcriptome of V. amurensis under cold treatment. Vitis vinifera cv. Muscat of Hamburg was used as control to help investigate the distinctive features of V. amruensis in responding to cold stress. Approximately 9 million tags were sequenced from non-cold treatment (NCT) and cold treatment (CT) cDNA libraries in each species of grapevine sampled from shoot apices. Alignment of tags into V. vinifera cv. Pinot noir (PN40024) annotated genome identified over 15,000 transcripts in each library in V. amruensis and more than 16,000 in Muscat of Hamburg. Comparative analysis between NCT and CT libraries indicate that V. amurensis has fewer differential expressed genes (DEGs, 1314 transcripts) than Muscat of Hamburg (2307 transcripts) when exposed to cold stress. Common DEGs (408 transcripts) suggest that some genes provide fundamental roles during cold stress in grapes. The most robust DEGs (more than 20-fold change) also demonstrated significant differences between two kinds of grapevine, indicating that cold stress may trigger species specific pathways in V. amurensis. Functional categories of DEGs indicated that the proportion of up-regulated transcripts related to metabolism, transport, signal transduction and transcription were more abundant in V. amurensis. Several highly expressed transcripts that were found uniquely accumulated in V. amurensis are discussed in detail. This subset of unique candidate

  10. Genome-wide DNA methylation analysis in obsessive-compulsive disorder patients.

    Science.gov (United States)

    Yue, Weihua; Cheng, Weiqiu; Liu, Zhaorui; Tang, Yi; Lu, Tianlan; Zhang, Dai; Tang, Muni; Huang, Yueqin

    2016-08-16

    Literatures have suggested that not only genetic but also environmental factors, interactively accounted for susceptibility of obsessive-compulsive disorder (OCD). DNA methylation may regulate expression of genes as the heritable epigenetic modification. The examination for genome-wide DNA methylation was performed on blood samples from 65 patients with OCD, as well as 96 healthy control subjects. The DNA methylation was examined at over 485,000 CpG sites using the Illumina Infinium Human Methylation450 BeadChip. As a result, 8,417 probes corresponding to 2,190 unique genes were found to be differentially methylated between OCD and healthy control subjects. Of those genes, 4,013 loci were located in CpG islands and 2,478 were in promoter regions. These included BCYRN1, BCOR, FGF13, HLA-DRB1, ARX, etc., which have previously been reported to be associated with OCD. Pathway analyses indicated that regulation of actin cytoskeleton, cell adhesion molecules (CAMs), actin binding, transcription regulator activity, and other pathways might be further associated with risk of OCD. Unsupervised clustering analysis of the top 3,000 most variable probes revealed two distinct groups with significantly more people with OCD in cluster one compared with controls (67.74% of cases v.s. 27.13% of controls, Chi-square = 26.011, df = 1, P = 3.41E-07). These results strongly suggested that differential DNA methylation might play an important role in etiology of OCD.

  11. Genome-wide analysis of esophageal adenocarcinoma yields specific copy number aberrations that correlate with prognosis.

    Science.gov (United States)

    Frankel, Adam; Armour, Nicola; Nancarrow, Derek; Krause, Lutz; Hayward, Nicholas; Lampe, Guy; Smithers, B Mark; Barbour, Andrew

    2014-04-01

    The incidence of esophageal adenocarcinoma (EAC) has been increasing rapidly for the past 3 decades in Western (Caucasian) populations. Curative treatment is based around esophagectomy, which has a major impact on quality of life. For those suitable for treatment with curative intent, 5-year survival is ∼30%. More accurate prognostic tools are therefore needed, and copy number aberrations (CNAs) may offer the ability to act as prospective biomarkers in this regard. We performed a genome-wide examination of CNAs in 54 samples of EAC using single-nucleotide polymorphism (SNP) arrays. Our aims were to describe frequent regions of CNA, to define driver CNAs, and to identify CNAs that correlated with survival. Regions of frequent amplification included oncogenes such as EGFR, MYC, KLF12, and ERBB2, while frequently deleted regions included tumor suppressor genes such as CDKN2A/B, PTPRD, FHIT, and SMAD4. The genomic identification of significant targets in cancer (GISTIC) algorithm identified 24 regions of gain and 28 regions of loss that were likely to contain driver changes. We discovered 61 genes in five regions that, when stratified by CNA type (gain or loss), correlated with a statistically significant difference in survival. Pathway analysis of the genes residing in both the GISTIC and prognostic regions showed they were significantly enriched for cancer-related networks. Finally, we discovered that copy-neutral loss of heterozygosity is a frequent mechanism of CNA in genes currently targetable by chemotherapy, potentially leading to under-reporting of cases suitable for such treatment. Copyright © 2014 Wiley Periodicals, Inc.

  12. Implementing meta-analysis from genome-wide association studies for pork quality traits.

    Science.gov (United States)

    Bernal Rubio, Y L; Gualdrón Duarte, J L; Bates, R O; Ernst, C W; Nonneman, D; Rohrer, G A; King, D A; Shackelford, S D; Wheeler, T L; Cantet, R J C; Steibel, J P

    2015-12-01

    Pork quality plays an important role in the meat processing industry. Thus, different methodologies have been implemented to elucidate the genetic architecture of traits affecting meat quality. One of the most common and widely used approaches is to perform genome-wide association (GWA) studies. However, a limitation of many GWA in animal breeding is the limited power due to small sample sizes in animal populations. One alternative is to implement a meta-analysis of GWA (MA-GWA) combining results from independent association studies. The objective of this study was to identify significant genomic regions associated with meat quality traits by performing MA-GWA for 8 different traits in 3 independent pig populations. Results from MA-GWA were used to search for genes possibly associated with the set of evaluated traits. Data from 3 pig data sets (U.S. Meat Animal Research Center, commercial, and Michigan State University Pig Resource Population) were used. A MA was implemented by combining -scores derived for each SNP in every population and then weighting them using the inverse of estimated variance of SNP effects. A search for annotated genes retrieved genes previously reported as candidates for shear force (calpain-1 catalytic subunit [] and calpastatin []), as well as for ultimate pH, purge loss, and cook loss (protein kinase, AMP-activated, γ 3 noncatalytic subunit []). In addition, novel candidate genes were identified for intramuscular fat and cook loss (acyl-CoA synthetase family member 3 mitochondrial []) and for the objective measure of muscle redness, CIE a* (glycogen synthase 1, muscle [] and ferritin, light polypeptide []). Thus, implementation of MA-GWA allowed integration of results for economically relevant traits and identified novel genes to be tested as candidates for meat quality traits in pig populations.

  13. 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

  14. Genome-wide analysis of ionotropic receptors provides insight into their evolution in Heliconius butterflies.

    Science.gov (United States)

    van Schooten, Bas; Jiggins, Chris D; Briscoe, Adriana D; Papa, Riccardo

    2016-03-22

    In a world of chemical cues, smell and taste are essential senses for survival. Here we focused on Heliconius, a diverse group of butterflies that exhibit variation in pre- and post-zygotic isolation and chemically-mediated behaviors across their phylogeny. Our study examined the ionotropic receptors, a recently discovered class of receptors that are some of the most ancient chemical receptors. We found more ionotropic receptors in Heliconius (31) than in Bombyx mori (25) or in Danaus plexippus (27). Sixteen genes in Lepidoptera were not present in Diptera. Only IR7d4 was exclusively found in butterflies and two expansions of IR60a were exclusive to Heliconius. A genome-wide comparison between 11 Heliconius species revealed instances of pseudogenization, gene gain, and signatures of positive selection across the phylogeny. IR60a2b and IR60a2d are unique to the H. melpomene, H. cydno, and H. timareta clade, a group where chemosensing is likely involved in pre-zygotic isolation. IR60a2b also displayed copy number variations (CNVs) in distinct populations of H. melpomene and was the only gene significantly higher expressed in legs and mouthparts than in antennae, which suggests a gustatory function. dN/dS analysis suggests more frequent positive selection in some intronless IR genes and in particular in the sara/sapho and melpomene/cydno/timareta clades. IR60a1 was the only gene with an elevated dN/dS along a major phylogenetic branch associated with pupal mating. Only IR93a was differentially expressed between sexes. All together these data make Heliconius butterflies one of the very few insects outside Drosophila where IRs have been characterized in detail. Our work outlines a dynamic pattern of IR gene evolution throughout the Heliconius radiation which could be the result of selective pressure to find potential mates or host-plants.

  15. Genome-wide analysis and molecular dissection of the SPL gene family in Salvia miltiorrhiza

    Institute of Scientific and Technical Information of China (English)

    Linsu Zhang; Bin Wu; Degang Zhao; Caili Li; Fenjuan Shao; Shanfa Lu

    2014-01-01

    SQUAMOSA promoter binding protein-likes (SPLs) are plant-specific transcription factors playing vital regulatory roles in plant growth and development. There is no information about SPLs in Salvia miltiorrhiza (Danshen), a significant medicinal plant widely used in Traditional Chinese medicine (TCM) for>1,700 years and an emerging model plant for TCM studies. Through genome-wide identification and subsequent molecular cloning, we identified a total 15 SmSPLs with divergent sequence features, gene structures, and motifs. Comparative analysis showed sequence conservation between SmSPLs and their Arabidopsis counterparts. A phylogenetic tree clusters SmSPLs into six groups. Many of the motifs identified commonly exist in a group/subgroup, implying their functional redundancy. Eight SmSPLs were predicted and experimental y validated to be targets of miR156/157. SmSPLs were differen-tial y expressed in various tissues of S. milltiorrhiza. The expression of miR156/157-targeted SmSPLs was increased with the maturation of S. miltiorrhiza, whereas the expression of miR156/157 was decreased, confirming the regulatory roles of miR156/157 in SmSPLs and suggesting the functions of SmSPLs in S. miltiorrhiza development. The expression of miR156/157 was negatively correlated with miR172 during the maturation of S. miltiorrhiza. The results indicate the significance and complexity of SmSPL-, miR156-, and miR172-mediated regula-tion of developmental timing in S. miltiorrhiza.

  16. Genome-Wide Analysis and Characterization of Aux/IAA Family Genes in Brassica rapa.

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    Parameswari Paul

    Full Text Available Auxins are the key players in plant growth development involving leaf formation, phototropism, root, fruit and embryo development. Auxin/Indole-3-Acetic Acid (Aux/IAA are early auxin response genes noted as transcriptional repressors in plant auxin signaling. However, many studies focus on Aux/ARF gene families and much less is known about the Aux/IAA gene family in Brassica rapa (B. rapa. Here we performed a comprehensive genome-wide analysis and identified 55 Aux/IAA genes in B. rapa using four conserved motifs of Aux/IAA family (PF02309. Chromosomal mapping of the B. rapa Aux/IAA (BrIAA genes facilitated understanding cluster rearrangement of the crucifer building blocks in the genome. Phylogenetic analysis of BrIAA with Arabidopsis thaliana, Oryza sativa and Zea mays identified 51 sister pairs including 15 same species (BrIAA-BrIAA and 36 cross species (BrIAA-AtIAA IAA genes. Among the 55 BrIAA genes, expression of 43 and 45 genes were verified using Genebank B. rapa ESTs and in home developed microarray data from mature leaves of Chiifu and RcBr lines. Despite their huge morphological difference, tissue specific expression analysis of BrIAA genes between the parental lines Chiifu and RcBr showed that the genes followed a similar pattern of expression during leaf development and a different pattern during bud, flower and siliqua development stages. The response of the BrIAA genes to abiotic and auxin stress at different time intervals revealed their involvement in stress response. Single Nucleotide Polymorphisms between IAA genes of reference genome Chiifu and RcBr were focused and identified. Our study examines the scope of conservation and divergence of Aux/IAA genes and their structures in B. rapa. Analyzing the expression and structural variation between two parental lines will significantly contribute to functional genomics of Brassica crops and we belive our study would provide a foundation in understanding the Aux/IAA genes in B. rapa.

  17. A genome-wide association meta-analysis on apolipoprotein A-IV concentrations.

    Science.gov (United States)

    Lamina, Claudia; Friedel, Salome; Coassin, Stefan; Rueedi, Rico; Yousri, Noha A; Seppälä, Ilkka; Gieger, Christian; Schönherr, Sebastian; Forer, Lukas; Erhart, Gertraud; Kollerits, Barbara; Marques-Vidal, Pedro; Ried, Janina; Waeber, Gerard; Bergmann, Sven; Dähnhardt, Doreen; Stöckl, Andrea; Kiechl, Stefan; Raitakari, Olli T; Kähönen, Mika; Willeit, Johann; Kedenko, Ludmilla; Paulweber, Bernhard; Peters, Annette; Meitinger, Thomas; Strauch, Konstantin; Study Group, Kora; Lehtimäki, Terho; Hunt, Steven C; Vollenweider, Peter; Kronenberg, Florian

    2016-08-15

    Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n = 13,813) followed by two additional replication studies (n = 2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (P = 6.77 × 10 (-)  (44)), rs5104 in APOA4 (P = 1.79 × 10(-)(24)) and rs4241819 in KLKB1 (P = 5.6 × 10(-)(14)). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 × 10 (-)  (07)). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and an inverse association for kidney function with apoA-IV concentrations (P = 5.5 × 10(-)(05)). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (P = 0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1 The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations.

  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. Genome-wide location analysis reveals a role for Sub1 in RNA polymerase III transcription

    Science.gov (United States)

    Tavenet, Arounie; Suleau, Audrey; Dubreuil, Géraldine; Ferrari, Roberto; Ducrot, Cécile; Michaut, Magali; Aude, Jean-Christophe; Dieci, Giorgio; Lefebvre, Olivier; Conesa, Christine; Acker, Joël

    2009-01-01

    Human PC4 and the yeast ortholog Sub1 have multiple functions in RNA polymerase II transcription. Genome-wide mapping revealed that Sub1 is present on Pol III-transcribed genes. Sub1 was found to interact with components of the Pol III transcription system and to stimulate the initiation and reinitiation steps in a system reconstituted with all recombinant factors. Sub1 was required for optimal Pol III gene transcription in exponentially growing cells. PMID:19706510

  20. Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease

    DEFF Research Database (Denmark)

    Kim, Deog Kyeom; Cho, Michael H; Hersh, Craig P

    2012-01-01

    Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility. Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic d...... quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552)....

  1. 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

    the 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...

  2. 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.

  3. Genome-wide analysis of regions similar to promoters of histone genes

    KAUST Repository

    Chowdhary, Rajesh

    2010-05-28

    Background: The purpose of this study is to: i) develop a computational model of promoters of human histone-encoding genes (shortly histone genes), an important class of genes that participate in various critical cellular processes, ii) use the model so developed to identify regions across the human genome that have similar structure as promoters of histone genes; such regions could represent potential genomic regulatory regions, e.g. promoters, of genes that may be coregulated with histone genes, and iii/ identify in this way genes that have high likelihood of being coregulated with the histone genes.Results: We successfully developed a histone promoter model using a comprehensive collection of histone genes. Based on leave-one-out cross-validation test, the model produced good prediction accuracy (94.1% sensitivity, 92.6% specificity, and 92.8% positive predictive value). We used this model to predict across the genome a number of genes that shared similar promoter structures with the histone gene promoters. We thus hypothesize that these predicted genes could be coregulated with histone genes. This hypothesis matches well with the available gene expression, gene ontology, and pathways data. Jointly with promoters of the above-mentioned genes, we found a large number of intergenic regions with similar structure as histone promoters.Conclusions: This study represents one of the most comprehensive computational analyses conducted thus far on a genome-wide scale of promoters of human histone genes. Our analysis suggests a number of other human genes that share a high similarity of promoter structure with the histone genes and thus are highly likely to be coregulated, and consequently coexpressed, with the histone genes. We also found that there are a large number of intergenic regions across the genome with their structures similar to promoters of histone genes. These regions may be promoters of yet unidentified genes, or may represent remote control regions that

  4. Analysis of binary responses with outcome-specific misclassification probability in genome-wide association studies

    Directory of Open Access Journals (Sweden)

    Rekaya R

    2016-11-01

    Full Text Available Romdhane Rekaya,1–3 Shannon Smith,4 El Hamidi Hay,5 Nourhene Farhat,6 Samuel E Aggrey3,7 1Department of Animal and Dairy Science, College of Agricultural and Environmental Sciences, 2Department of Statistics, Franklin College of Arts and Sciences, 3Institute of Bioinformatics, The University of Georgia, Athens, GA, 4Zoetis, Kalamazoo, MI, 5United States Department of Agriculture, Agricultural Research Service, Beltsville, MD, 6Carolinas HealthCare System Blue Ridge, Morganton, NC, 7Department of Poultry Science, College of Agricultural and Environmental Sciences, University of Georgia, Athens, GA, USA Abstract: Errors in the binary status of some response traits are frequent in human, animal, and plant applications. These error rates tend to differ between cases and controls because diagnostic and screening tests have different sensitivity and specificity. This increases the inaccuracies of classifying individuals into correct groups, giving rise to both false-positive and false-negative cases. The analysis of these noisy binary responses due to misclassification will undoubtedly reduce the statistical power of genome-wide association studies (GWAS. A threshold model that accommodates varying diagnostic errors between cases and controls was investigated. A simulation study was carried out where several binary data sets (case–control were generated with varying effects for the most influential single nucleotide polymorphisms (SNPs and different diagnostic error rate for cases and controls. Each simulated data set consisted of 2000 individuals. Ignoring misclassification resulted in biased estimates of true influential SNP effects and inflated estimates for true noninfluential markers. A substantial reduction in bias and increase in accuracy ranging from 12% to 32% was observed when the misclassification procedure was invoked. In fact, the majority of influential SNPs that were not identified using the noisy data were captured using the

  5. Genome-wide analysis of signal peptide functionality in Lactobacillus plantarum WCFS1

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    Axelsson Lars

    2009-09-01

    Full Text Available Abstract Background Lactobacillus plantarum is a normal, potentially probiotic, inhabitant of the human gastrointestinal (GI tract. The bacterium has great potential as food-grade cell factory and for in situ delivery of biomolecules. Since protein secretion is important both for probiotic activity and in biotechnological applications, we have carried out a genome-wide experimental study of signal peptide (SP functionality. Results We have constructed a library of 76 Sec-type signal peptides from L. plantarum WCFS1 that were predicted to be cleaved by signal peptidase I. SP functionality was studied using staphylococcal nuclease (NucA as a reporter protein. 82% of the SPs gave significant extracellular NucA activity. Levels of secreted NucA varied by a dramatic 1800-fold and this variation was shown not to be the result of different mRNA levels. For the best-performing SPs all produced NucA was detected in the culture supernatant, but the secretion efficiency decreased for the less well performing SPs. Sequence analyses of the SPs and their cognate proteins revealed four properties that correlated positively with SP performance for NucA: high hydrophobicity, the presence of a transmembrane helix predicted by TMHMM, the absence of an anchoring motif in the cognate protein, and the length of the H+C domain. Analysis of a subset of SPs with a lactobacillal amylase (AmyA showed large variation in production levels and secretion efficiencies. Importantly, there was no correlation between SP performance with NucA and the performance with AmyA. Conclusion This is the first comprehensive experimental study showing that predicted SPs in the L. plantarum genome actually are capable of driving protein secretion. The results reveal considerable variation between the SPs that is at least in part dependent on the protein that is secreted. Several SPs stand out as promising candidates for efficient secretion of heterologous proteins in L. plantarum. The

  6. Genome-Wide Association Analysis of Young-Onset Stroke Identifies a Locus on Chromosome 10q25 Near HABP2.

    Science.gov (United States)

    Cheng, Yu-Ching; Stanne, Tara M; Giese, Anne-Katrin; Ho, Weang Kee; Traylor, Matthew; Amouyel, Philippe; Holliday, Elizabeth G; Malik, Rainer; Xu, Huichun; Kittner, Steven J; Cole, John W; O'Connell, Jeffrey R; Danesh, John; Rasheed, Asif; Zhao, Wei; Engelter, Stefan; Grond-Ginsbach, Caspar; Kamatani, Yoichiro; Lathrop, Mark; Leys, Didier; Thijs, Vincent; Metso, Tiina M; Tatlisumak, Turgut; Pezzini, Alessandro; Parati, Eugenio A; Norrving, Bo; Bevan, Steve; Rothwell, Peter M; Sudlow, Cathie; Slowik, Agnieszka; Lindgren, Arne; Walters, Matthew R; Jannes, Jim; Shen, Jess; Crosslin, David; Doheny, Kimberly; Laurie, Cathy C; Kanse, Sandip M; Bis, Joshua C; Fornage, Myriam; Mosley, Thomas H; Hopewell, Jemma C; Strauch, Konstantin; Müller-Nurasyid, Martina; Gieger, Christian; Waldenberger, Melanie; Peters, Annette; Meisinger, Christine; Ikram, M Arfan; Longstreth, W T; Meschia, James F; Seshadri, Sudha; Sharma, Pankaj; Worrall, Bradford; Jern, Christina; Levi, Christopher; Dichgans, Martin; Boncoraglio, Giorgio B; Markus, Hugh S; Debette, Stephanie; Rolfs, Arndt; Saleheen, Danish; Mitchell, Braxton D

    2016-02-01

    Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early- versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset genetic variants at loci with association Pstroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2. HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke. © 2016 American Heart Association, Inc.

  7. Genome-wide identification of the regulatory targets of a transcription factor using biochemical characterization and computational genomic analysis

    Directory of Open Access Journals (Sweden)

    Jolly Emmitt R

    2005-11-01

    Full Text Available Abstract Background A major challenge in computational genomics is the development of methodologies that allow accurate genome-wide prediction of the regulatory targets of a transcription factor. We present a method for target identification that combines experimental characterization of binding requirements with computational genomic analysis. Results Our method identified potential target genes of the transcription factor Ndt80, a key transcriptional regulator involved in yeast sporulation, using the combined information of binding affinity, positional distribution, and conservation of the binding sites across multiple species. We have also developed a mathematical approach to compute the false positive rate and the total number of targets in the genome based on the multiple selection criteria. Conclusion We have shown that combining biochemical characterization and computational genomic analysis leads to accurate identification of the genome-wide targets of a transcription factor. The method can be extended to other transcription factors and can complement other genomic approaches to transcriptional regulation.

  8. Genome-wide association study to identify common variants associated with brachial circumference: a meta-analysis of 14 cohorts.

    Directory of Open Access Journals (Sweden)

    Vesna Boraska

    Full Text Available Brachial circumference (BC, also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05 in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.

  9. Genome-wide meta-analysis for serum calcium identifies significantly associated SNPs near the calcium-sensing receptor (CASR gene.

    Directory of Open Access Journals (Sweden)

    Karen Kapur

    2010-07-01

    Full Text Available Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR gene on 3q13. The top hit with a p-value of 6.3 x 10(-37 is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1 x 10(-21, a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02 x 10(-4. This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.

  10. Genome-Wide Identification and Evolutionary Analysis of the Animal Specific ETS Transcription Factor Family

    OpenAIRE

    Wang, Zhipeng; Zhang, Qin

    2009-01-01

    The ETS proteins are a family of transcription factors (TFs) that regulate a variety of biological processes. We made genome-wide analyses to explore the classification of the ETS gene family. We identified 207 ETS genes which encode 321 ETS TFs from ten animal species. Of the 321 ETS TFs, 155 contain only an ETS domain, about 50% contain a ETS_PEA3_N or a SAM_PNT domain in addition to an ETS domain, the rest (only four) contain a second ETS domain or a second ETS_PEA3_N domain or an another ...

  11. A genome-wide tree- and forest-based association analysis of comorbidity of alcoholism and smoking

    OpenAIRE

    Ye, Yuanqing; Zhong, Xiaoyun; Zhang, Heping

    2005-01-01

    Genetic mechanisms underlying alcoholism are complex. Understanding the etiology of alcohol dependence and its comorbid conditions such as smoking is important because of the significant health concerns. In this report, we describe a method based on classification trees and deterministic forests for association studies to perform a genome-wide joint association analysis of alcoholism and smoking. This approach is used to analyze the single-nucleotide polymorphism data from the Collaborative S...

  12. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies

    NARCIS (Netherlands)

    C.E. Elks (Cathy); J.R.B. Perry (John); P. Sulem (Patrick); D.I. Chasman (Daniel); N. Franceschini (Nora); C. He (Chunyan); K.L. Lunetta (Kathryn); J.A. Visser (Jenny); E.M. Byrne (Enda); D.L. Cousminer (Diana); D.F. Gudbjartsson (Daniel); T. Esko (Tõnu); B. Feenstra (Bjarke); J.J. Hottenga (Jouke Jan); D.L. Koller (Daniel); Z. Kutalik (Zoltán); P. Lin (Peng); M. Mangino (Massimo); M. Marongiu (Mara); P.F. McArdle (Patrick); A.V. Smith (Albert Vernon); L. Stolk (Lisette); S. van Wingerden (Sophie); J.H. Zhao; E. Albrecht (Eva); T. Corre (Tanguy); E. Ingelsson (Erik); C. Hayward (Caroline); P.K. Magnusson (Patrik); S. Ulivi (Shelia); N. Warrington (Nicole); L. Zgaga (Lina); H. Alavere (Helene); N. Amin (Najaf); T. Aspelund (Thor); S. Bandinelli (Stefania); I. Barroso (Inês); G. Berenson (Gerald); S.M. Bergmann (Sven); H. Blackburn (Hannah); E.A. Boerwinkle (Eric); J.E. Buring (Julie); F. Busonero; H. Campbell (Harry); S.J. Chanock (Stephen); W. Chen (Wei); M. Cornelis (Marilyn); D.J. Couper (David); A.D. Coviello (Andrea); P. d' Adamo (Pio); U. de Faire (Ulf); E.J.C. de Geus (Eco); P. Deloukas (Panagiotis); A. Döring (Angela); D.F. Easton (Douglas); G. Eiriksdottir (Gudny); V. Emilsson (Valur); J.G. Eriksson (Johan); L. Ferrucci (Luigi); A.R. Folsom (Aaron); T. Foroud (Tatiana); M. Garcia (Melissa); P. Gasparini (Paolo); F. Geller (Frank); C. Gieger (Christian); V. Gudnason (Vilmundur); A.S. Hall (Alistair); S.E. Hankinson (Susan); L. Ferreli (Liana); A.C. Heath (Andrew); D.G. Hernandez (Dena); A. Hofman (Albert); F.B. Hu (Frank); T. Illig (Thomas); M.R. Järvelin; A.D. Johnson (Andrew); D. Karasik (David); K-T. Khaw (Kay-Tee); D.P. Kiel (Douglas); T.O. Kilpelänen (Tuomas); I. Kolcic (Ivana); P. Kraft (Peter); L.J. Launer (Lenore); J.S.E. Laven (Joop); S. Li (Shengxu); J. Liu (Jianjun); D. Levy (Daniel); N.G. Martin (Nicholas); M. Melbye (Mads); V. Mooser (Vincent); J.C. Murray (Jeffrey); M.A. Nalls (Michael); P. Navarro (Pau); M. Nelis (Mari); A.R. Ness (Andrew); K. Northstone (Kate); B.A. Oostra (Ben); M. Peacock (Munro); C. Palmer (Cameron); A. Palotie (Aarno); G. Paré (Guillaume); A.N. Parker (Alex); N.L. Pedersen (Nancy); L. Peltonen (Leena Johanna); C.E. Pennell (Craig); P.D.P. Pharoah (Paul); O. Polasek (Ozren); A.S. Plump (Andrew); A. Pouta (Anneli); E. Porcu (Eleonora); T. Rafnar (Thorunn); J.P. Rice (John); S.M. Ring (Susan); F. Rivadeneira Ramirez (Fernando); I. Rudan (Igor); C. Sala (Cinzia); V. Salomaa (Veikko); S. Sanna (Serena); D. Schlessinger; N.J. Schork (Nicholas); A. Scuteri (Angelo); A.V. Segrè (Ayellet); A.R. Shuldiner (Alan); N. Soranzo (Nicole); U. Sovio (Ulla); S.R. Srinivasan (Sathanur); D.P. Strachan (David); M.L. Tammesoo; E. Tikkanen (Emmi); D. Toniolo (Daniela); K. Tsui (Kim); L. Tryggvadottir (Laufey); J.P. Tyrer (Jonathan); M. Uda (Manuela); R.M. van Dam (Rob); J.B.J. van Meurs (Joyce); P. Vollenweider (Peter); G. Waeber (Gérard); N.J. Wareham (Nick); D. Waterworth (Dawn); H.E. Wichmann (Heinz Erich); G.A.H.M. Willemsen (Gonneke); J.F. Wilson (James); A.F. Wright (Alan); L. Young (Lauren); G. Zhai (Guangju); W.V. Zhuang; L.J. Bierut (Laura); D.I. Boomsma (Dorret); H.A. Boyd (Heather); L. Crisponi (Laura); E.W. Demerath (Ellen); P. Tikka-Kleemola (Päivi); M.J. Econs (Michael); T.B. Harris (Tamara); D. Hunter (David); R.J.F. Loos (Ruth); A. Metspalu (Andres); G.W. Montgomery (Grant); P.M. Ridker (Paul); T.D. Spector (Tim); E.A. Streeten (Elizabeth); K. Stefansson (Kari); U. Thorsteinsdottir (Unnur); A.G. Uitterlinden (André); E. Widen (Elisabeth); J. Murabito (Joanne); K. Ong (Ken); M.N. Weedon (Michael)

    2010-01-01

    textabstractTo identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10 -60) and 9q31.2 (P = 2.2 × 10 -33), we identified 30

  13. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies

    NARCIS (Netherlands)

    C.E. Elks (Cathy); J.R.B. Perry (John); P. Sulem (Patrick); D.I. Chasman (Daniel); N. Franceschini (Nora); C. He (Chunyan); K.L. Lunetta (Kathryn); J.A. Visser (Jenny); E.M. Byrne (Enda); D.L. Cousminer (Diana); D.F. Gudbjartsson (Daniel); T. Esko (Tõnu); B. Feenstra (Bjarke); J.J. Hottenga (Jouke Jan); D.L. Koller (Daniel); Z. Kutalik (Zoltán); P. Lin (Peng); M. Mangino (Massimo); M. Marongiu (Mara); P.F. McArdle (Patrick); A.V. Smith (Albert Vernon); L. Stolk (Lisette); S. van Wingerden (Sophie); J.H. Zhao; E. Albrecht (Eva); T. Corre (Tanguy); E. Ingelsson (Erik); C. Hayward (Caroline); P.K. Magnusson (Patrik); S. Ulivi (Shelia); N.M. Warrington (Nicole); L. Zgaga (Lina); H. Alavere (Helene); N. Amin (Najaf); T. Aspelund (Thor); S. Bandinelli (Stefania); I. Barroso (Inês); G. Berenson (Gerald); S.M. Bergmann (Sven); H. Blackburn (Hannah); E.A. Boerwinkle (Eric); J.E. Buring (Julie); F. Busonero; H. Campbell (Harry); S.J. Chanock (Stephen); W. Chen (Wei); M. Cornelis (Marilyn); D.J. Couper (David); A.D. Coviello (Andrea); P. d' Adamo (Pio); U. de Faire (Ulf); E.J.C. de Geus (Eco); P. Deloukas (Panagiotis); A. Döring (Angela); D.F. Easton (Douglas); G. Eiriksdottir (Gudny); V. Emilsson (Valur); J.G. Eriksson (Johan); L. Ferrucci (Luigi); A.R. Folsom (Aaron); T. Foroud (Tatiana); M. Garcia (Melissa); P. Gasparini (Paolo); F. Geller (Frank); C. Gieger (Christian); V. Gudnason (Vilmundur); A.S. Hall (Alistair); S.E. Hankinson (Susan); L. Ferreli (Liana); A.C. Heath (Andrew); D.G. Hernandez (Dena); A. Hofman (Albert); F.B. Hu (Frank); T. Illig (Thomas); M.R. Järvelin; A.D. Johnson (Andrew); D. Karasik (David); K-T. Khaw (Kay-Tee); D.P. Kiel (Douglas); T.O. Kilpelänen (Tuomas); I. Kolcic (Ivana); P. Kraft (Peter); L.J. Launer (Lenore); J.S.E. Laven (Joop); S. Li (Shengxu); J. Liu (Jianjun); D. Levy (Daniel); N.G. Martin (Nicholas); M. Melbye (Mads); V. Mooser (Vincent); J.C. Murray (Jeffrey); M.A. Nalls (Michael); P. Navarro (Pau); M. Nelis (Mari); A.R. Ness (Andrew); K. Northstone (Kate); B.A. Oostra (Ben); M. Peacock (Munro); C. Palmer (Cameron); A. Palotie (Aarno); G. Paré (Guillaume); A.N. Parker (Alex); N.L. Pedersen (Nancy); L. Peltonen (Leena Johanna); C.E. Pennell (Craig); P.D.P. Pharoah (Paul); O. Polasek (Ozren); A.S. Plump (Andrew); A. Pouta (Anneli); E. Porcu (Eleonora); T. Rafnar (Thorunn); J.P. Rice (John); S.M. Ring (Susan); F. Rivadeneira Ramirez (Fernando); I. Rudan (Igor); C. Sala (Cinzia); V. Salomaa (Veikko); S. Sanna (Serena); D. Schlessinger; N.J. Schork (Nicholas); A. Scuteri (Angelo); A.V. Segrè (Ayellet); A.R. Shuldiner (Alan); N. Soranzo (Nicole); U. Sovio (Ulla); S.R. Srinivasan (Sathanur); D.P. Strachan (David); M.L. Tammesoo; E. Tikkanen (Emmi); D. Toniolo (Daniela); K. Tsui (Kim); L. Tryggvadottir (Laufey); J.P. Tyrer (Jonathan); M. Uda (Manuela); R.M. van Dam (Rob); J.B.J. van Meurs (Joyce); P. Vollenweider (Peter); G. Waeber (Gérard); N.J. Wareham (Nick); D. Waterworth (Dawn); H.E. Wichmann (Heinz Erich); G.A.H.M. Willemsen (Gonneke); J.F. Wilson (James); A.F. Wright (Alan); L. Young (Lauren); G. Zhai (Guangju); W.V. Zhuang; L.J. Bierut (Laura); D.I. Boomsma (Dorret); H.A. Boyd (Heather); L. Crisponi (Laura); E.W. Demerath (Ellen); P. Tikka-Kleemola (Päivi); M.J. Econs (Michael); T.B. Harris (Tamara); D. Hunter (David); R.J.F. Loos (Ruth); A. Metspalu (Andres); G.W. Montgomery (Grant); P.M. Ridker (Paul); T.D. Spector (Tim); E.A. Streeten (Elizabeth); K. Stefansson (Kari); U. Thorsteinsdottir (Unnur); A.G. Uitterlinden (André); E. Widen (Elisabeth); J. Murabito (Joanne); K. Ong (Ken); M.N. Weedon (Michael)

    2010-01-01

    textabstractTo identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10 -60) and 9q31.2 (P = 2.2 × 10 -33), we identified 30

  14. Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies

    DEFF Research Database (Denmark)

    Elks, Cathy E; Perry, John R B; Sulem, Patrick

    2010-01-01

    To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarc...

  15. Genome-wide analysis of multiethnic cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

    OpenAIRE

    Hysi, Pirro G.; Cheng, Ching-Yu; Springelkamp, Henri?t; MacGregor, Stuart; Bailey, Jessica N. Cooke; Wojciechowski, Robert; Vitart, Veronique; Nag, Abhishek; Hewitt, Alex W.; H?hn, Ren?; Venturini, Cristina; Mirshahi, Alireza; Wishal D Ramdas; Thorleifsson, Gudmar; Vithana, Eranga

    2014-01-01

    Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma and IOP variability may herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multiethnic participants for IOP. We confirm genetic association of known loci for IOP and primary open angle glaucoma (POAG) and identify four new IOP loci located...

  16. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma

    OpenAIRE

    Hysi, Pirro G.; Cheng, Ching-Yu; Springelkamp, Henriët; MacGregor, Stuart; Bailey, Jessica N. Cooke; Wojciechowski, Robert; Vitart, Veronique; Nag, Abhishek; Hewitt, Alex W.; Höhn, René; Venturini, Cristina; Mirshahi, Alireza; Wishal D Ramdas; Thorleifsson, Gudmar; Vithana, Eranga

    2014-01-01

    Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-ass...

  17. Genome-wide association studies of mri-defined brain infarcts: Meta-analysis from the charge consortium

    OpenAIRE

    2010-01-01

    textabstractBackground and Purpose-Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods-Using 2.2 mi...

  18. 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

  19. GenoGAM: genome-wide generalized additive models for ChIP-Seq analysis.

    Science.gov (United States)

    Stricker, Georg; Engelhardt, Alexander; Schulz, Daniel; Schmid, Matthias; Tresch, Achim; Gagneur, Julien

    2017-08-01

    Chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) is a widely used approach to study protein-DNA interactions. Often, the quantities of interest are the differential occupancies relative to controls, between genetic backgrounds, treatments, or combinations thereof. Current methods for differential occupancy of ChIP-Seq data rely however on binning or sliding window techniques, for which the choice of the window and bin sizes are subjective. Here, we present GenoGAM (Genome-wide Generalized Additive Model), which brings the well-established and flexible generalized additive models framework to genomic applications using a data parallelism strategy. We model ChIP-Seq read count frequencies as products of smooth functions along chromosomes. Smoothing parameters are objectively estimated from the data by cross-validation, eliminating ad hoc binning and windowing needed by current approaches. GenoGAM provides base-level and region-level significance testing for full factorial designs. Application to a ChIP-Seq dataset in yeast showed increased sensitivity over existing differential occupancy methods while controlling for type I error rate. By analyzing a set of DNA methylation data and illustrating an extension to a peak caller, we further demonstrate the potential of GenoGAM as a generic statistical modeling tool for genome-wide assays. Software is available from Bioconductor: https://www.bioconductor.org/packages/release/bioc/html/GenoGAM.html . gagneur@in.tum.de. Supplementary information is available at Bioinformatics online.

  20. Epigenetic Variation in Monozygotic Twins: A Genome-Wide Analysis of DNA Methylation in Buccal Cells

    Directory of Open Access Journals (Sweden)

    Jenny van Dongen

    2014-05-01

    Full Text Available DNA methylation is one of the most extensively studied epigenetic marks in humans. Yet, it is largely unknown what causes variation in DNA methylation between individuals. The comparison of DNA methylation profiles of monozygotic (MZ twins offers a unique experimental design to examine the extent to which such variation is related to individual-specific environmental influences and stochastic events or to familial factors (DNA sequence and shared environment. We measured genome-wide DNA methylation in buccal samples from ten MZ pairs (age 8–19 using the Illumina 450k array and examined twin correlations for methylation level at 420,921 CpGs after QC. After selecting CpGs showing the most variation in the methylation level between subjects, the mean genome-wide correlation (rho was 0.54. The correlation was higher, on average, for CpGs within CpG islands (CGIs, compared to CGI shores, shelves and non-CGI regions, particularly at hypomethylated CpGs. This finding suggests that individual-specific environmental and stochastic influences account for more variation in DNA methylation in CpG-poor regions. Our findings also indicate that it is worthwhile to examine heritable and shared environmental influences on buccal DNA methylation in larger studies that also include dizygotic twins.

  1. Topological Data Analysis Generates High-Resolution, Genome-wide Maps of Human Recombination.

    Science.gov (United States)

    Camara, Pablo G; Rosenbloom, Daniel I S; Emmett, Kevin J; Levine, Arnold J; Rabadan, Raul

    2016-07-01

    Meiotic recombination is a fundamental evolutionary process driving diversity in eukaryotes. In mammals, recombination is known to occur preferentially at specific genomic regions. Using topological data analysis (TDA), a branch of applied topology that extracts global features from large data sets, we developed an efficient method for mapping recombination at fine scales. When compared to standard linkage-based methods, TDA can deal with a larger number of SNPs and genomes without incurring prohibitive computational costs. We applied TDA to 1,000 Genomes Project data and constructed high-resolution whole-genome recombination maps of seven human populations. Our analysis shows that recombination is generally under-represented within transcription start sites. However, the binding sites of specific transcription factors are enriched for sites of recombination. These include transcription factors that regulate the expression of meiosis- and gametogenesis-specific genes, cell cycle progression, and differentiation blockage. Additionally, our analysis identifies an enrichment for sites of recombination at repeat-derived loci matched by piwi-interacting RNAs.

  2. Genome-Wide Analysis of the NAC Gene Family in Physic Nut (Jatropha curcas L.).

    Science.gov (United States)

    Wu, Zhenying; Xu, Xueqin; Xiong, Wangdan; Wu, Pingzhi; Chen, Yaping; Li, Meiru; Wu, Guojiang; Jiang, Huawu

    2015-01-01

    The NAC proteins (NAM, ATAF1/2 and CUC2) are plant-specific transcriptional regulators that have a conserved NAM domain in the N-terminus. They are involved in various biological processes, including both biotic and abiotic stress responses. In the present study, a total of 100 NAC genes (JcNAC) were identified in physic nut (Jatropha curcas L.). Based on phylogenetic analysis and gene structures, 83 JcNAC genes were classified as members of, or proposed to be diverged from, 39 previously predicted orthologous groups (OGs) of NAC sequences. Physic nut has a single intron-containing NAC gene subfamily that has been lost in many plants. The JcNAC genes are non-randomly distributed across the 11 linkage groups of the physic nut genome, and appear to be preferentially retained duplicates that arose from both ancient and recent duplication events. Digital gene expression analysis indicates that some of the JcNAC genes have tissue-specific expression profiles (e.g. in leaves, roots, stem cortex or seeds), and 29 genes differentially respond to abiotic stresses (drought, salinity, phosphorus deficiency and nitrogen deficiency). Our results will be helpful for further functional analysis of the NAC genes in physic nut.

  3. Effects of environment, genetics and data analysis pitfalls in an esophageal cancer genome-wide association study.

    Directory of Open Access Journals (Sweden)

    Alexander Statnikov

    Full Text Available BACKGROUND: The development of new high-throughput genotyping technologies has allowed fast evaluation of single nucleotide polymorphisms (SNPs on a genome-wide scale. Several recent genome-wide association studies employing these technologies suggest that panels of SNPs can be a useful tool for predicting cancer susceptibility and discovery of potentially important new disease loci. METHODOLOGY/PRINCIPAL FINDINGS: In the present paper we undertake a careful examination of the relative significance of genetics, environmental factors, and biases of the data analysis protocol that was used in a previously published genome-wide association study. That prior study reported a nearly perfect discrimination of esophageal cancer patients and healthy controls on the basis of only genetic information. On the other hand, our results strongly suggest that SNPs in this dataset are not statistically linked to the phenotype, while several environmental factors and especially family history of esophageal cancer (a proxy to both environmental and genetic factors have only a modest association with the disease. CONCLUSIONS/SIGNIFICANCE: The main component of the previously claimed strong discriminatory signal is due to several data analysis pitfalls that in combination led to the strongly optimistic results. Such pitfalls are preventable and should be avoided in future studies since they create misleading conclusions and generate many false leads for subsequent research.

  4. The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels.

    Science.gov (United States)

    van Leeuwen, Elisabeth M; Smouter, Françoise A S; Kam-Thong, Tony; Karbalai, Nazanin; Smith, Albert V; Harris, Tamara B; Launer, Lenore J; Sitlani, Colleen M; Li, Guo; Brody, Jennifer A; Bis, Joshua C; White, Charles C; Jaiswal, Alok; Oostra, Ben A; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G; Boerwinkle, Eric; Ballantyne, Christie M; Gudnason, Vilmundur; Psaty, Bruce M; Cupples, L Adrienne; Järvelin, Marjo-Riitta; Ripatti, Samuli; Isaacs, Aaron; Müller-Myhsok, Bertram; Karssen, Lennart C; van Duijn, Cornelia M

    2014-01-01

    Genome-wide association studies (GWAS) have revealed 74 single nucleotide polymorphisms (SNPs) associated with high-density lipoprotein cholesterol (HDL) blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS) to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS) cohort I (RS-I) using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs) to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III), we were able to filter 181 interaction terms with a p-valueSPATA8 (ENSG00000185594) being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.

  5. A method for detecting epistasis in genome-wide studies using case-control multi-locus association analysis

    Directory of Open Access Journals (Sweden)

    Galan Jose

    2008-07-01

    Full Text Available Abstract Background The difficulty in elucidating the genetic basis of complex diseases roots in the many factors that can affect the development of a disease. Some of these genetic effects may interact in complex ways, proving undetectable by current single-locus methodology. Results We have developed an analysis tool called Hypothesis Free Clinical Cloning (HFCC to search for genome-wide epistasis in a case-control design. HFCC combines a relatively fast computing algorithm for genome-wide epistasis detection, with the flexibility to test a variety of different epistatic models in multi-locus combinations. HFCC has good power to detect multi-locus interactions simulated under a variety of genetic models and noise conditions. Most importantly, HFCC can accomplish exhaustive genome-wide epistasis search with large datasets as demonstrated with a 400,000 SNP set typed on a cohort of Parkinson's disease patients and controls. Conclusion With the current availability of genetic studies with large numbers of individuals and genetic markers, HFCC can have a great impact in the identification of epistatic effects that escape the standard single-locus association analyses.

  6. Mapping of fertility traits in Finnish Ayrshire by genome-wide association analysis

    DEFF Research Database (Denmark)

    Schulmann, Nina F; Sahana, Goutam; Iso-Touru, T

    2011-01-01

    A whole-genome scan using single marker association was used to detect chromosome regions associated with seven female fertility traits in Finnish Ayrshire dairy cattle. The phenotypic data consisted of de-regressed estimated breeding values for 340 bulls which were estimated using a single trait...... effect. We detected eleven genome-wide significant associations on eight different chromosomes. With at least chromosome-wise significance after Bonferroni correction, sixteen SNPs on nine chromosomes showed significant associations with one or more fertility traits. The results confirmed quantitative...... trait loci on three chromosomes (1, 2 and 20) for fertility traits previously reported for the same breed and one on chromosome four previously detected in Holstein cattle....

  7. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

    DEFF Research Database (Denmark)

    Kilpeläinen, Tuomas O; Carli, Jayne F Martin; Skowronski, Alicja A

    2016-01-01

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered....... Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching Pleptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO....... Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown...

  8. Identification of a novel susceptibility locus for juvenile idiopathic arthritis by genome-wide association analysis

    Science.gov (United States)

    Hinks, Anne; Barton, Anne; Shephard, Neil; Eyre, Steve; Bowes, John; Cargill, Michele; Wang, Eric; Ke, Xiayi; Kennedy, Giulia C; John, Sally; Worthington, Jane; Thomson, Wendy

    2009-01-01

    Objective Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease of childhood. Two well-established genetic factors known to contribute to JIA susceptibility, HLA and PTPN22, account for less than half of the genetic susceptibility to disease; therefore, additional genetic factors have yet to be identified. The purpose of this study was to perform a systematic search of the genome to identify novel susceptibility loci for JIA. Methods A genome-wide association study using Affymetrix GeneChip 100K arrays was performed in a discovery cohort (279 cases and 184 controls). Single-nucleotide polymorphisms (SNPs) showing the most significant differences between cases and controls were then genotyped in a validation sample of cases (n = 321) and controls, combined with control data from the 1958 UK birth cohort (n = 2,024). In one region in which association was confirmed, fine-mapping was performed (654 cases and 1,847 controls). Results Of the 112 SNPs that were significantly associated with JIA in the discovery cohort, 6 SNPs were associated with JIA in the independent validation cohort. The most strongly associated SNP mapped to the HLA region, while the second strongest association was with a SNP within the VTCN1 gene. Fine-mapping of that gene was performed, and 10 SNPs were found to be associated with JIA. Conclusion This study is the first to successfully apply a SNP-based genome-wide association approach to the investigation of JIA. The replicated association with markers in the VTCN1 gene defined an additional susceptibility locus for JIA and implicates a novel pathway in the pathogenesis of this chronic disease of childhood. PMID:19116933

  9. Impact of vitamin D on immune function: lessons learned from genome-wide analysis.

    Science.gov (United States)

    Chun, Rene F; Liu, Philip T; Modlin, Robert L; Adams, John S; Hewison, Martin

    2014-01-01

    Immunomodulatory responses to the active form of vitamin D (1,25-dihydroxyvitamin D, 1,25D) have been recognized for many years, but it is only in the last 5 years that the potential role of this in normal human immune function has been recognized. Genome-wide analyses have played a pivotal role in redefining our perspective on vitamin D and immunity. The description of increased vitamin D receptor (VDR) and 1α-hydroxylase (CYP27B1) expression in macrophages following a pathogen challenge, has underlined the importance of intracrine vitamin D as key mediator of innate immune function. It is now clear that both macrophages and dendritic cells (DCs) are able to respond to 25-hydroxyvitamin D (25D), the major circulating vitamin D metabolite, thereby providing a link between the function of these cells and the variations in vitamin D status common to many humans. The identification of hundreds of primary 1,25D target genes in immune cells has also provided new insight into the role of vitamin D in the adaptive immune system, such as the modulation of antigen-presentation and T cells proliferation and phenotype, with the over-arching effects being to suppress inflammation and promote immune tolerance. In macrophages 1,25D promotes antimicrobial responses through the induction of antibacterial proteins, and stimulation of autophagy and autophagosome activity. In this way variations in 25D levels have the potential to influence both innate and adaptive immune responses. More recent genome-wide analyses have highlighted how cytokine signaling pathways can influence the intracrine vitamin D system and either enhance or abrogate responses to 25D. The current review will discuss the impact of intracrine vitamin D metabolism on both innate and adaptive immunity, whilst introducing the concept of disease-specific corruption of vitamin D metabolism and how this may alter the requirements for vitamin D in maintaining a healthy immune system in humans.

  10. Genome-wide SNP discovery in tetraploid alfalfa using 454 sequencing and high resolution melting analysis

    Directory of Open Access Journals (Sweden)

    Zhao Patrick X

    2011-07-01

    Full Text Available Abstract Background Single nucleotide polymorphisms (SNPs are the most common type of sequence variation among plants and are often functionally important. We describe the use of 454 technology and high resolution melting analysis (HRM for high throughput SNP discovery in tetraploid alfalfa (Medicago sativa L., a species with high economic value but limited genomic resources. Results The alfalfa genotypes selected from M. sativa subsp. sativa var. 'Chilean' and M. sativa subsp. falcata var. 'Wisfal', which differ in water stress sensitivity, were used to prepare cDNA from tissue of clonally-propagated plants grown under either well-watered or water-stressed conditions, and then pooled for 454 sequencing. Based on 125.2 Mb of raw sequence, a total of 54,216 unique sequences were obtained including 24,144 tentative consensus (TCs sequences and 30,072 singletons, ranging from 100 bp to 6,662 bp in length, with an average length of 541 bp. We identified 40,661 candidate SNPs distributed throughout the genome. A sample of candidate SNPs were evaluated and validated using high resolution melting (HRM analysis. A total of 3,491 TCs harboring 20,270 candidate SNPs were located on the M. truncatula (MT 3.5.1 chromosomes. Gene Ontology assignments indicate that sequences obtained cover a broad range of GO categories. Conclusions We describe an efficient method to identify thousands of SNPs distributed throughout the alfalfa genome covering a broad range of GO categories. Validated SNPs represent valuable molecular marker resources that can be used to enhance marker density in linkage maps, identify potential factors involved in heterosis and genetic variation, and as tools for association mapping and genomic selection in alfalfa.

  11. Genome-wide analysis of the MYB gene family in physic nut (Jatropha curcas L.).

    Science.gov (United States)

    Zhou, Changpin; Chen, Yanbo; Wu, Zhenying; Lu, Wenjia; Han, Jinli; Wu, Pingzhi; Chen, Yaping; Li, Meiru; Jiang, Huawu; Wu, Guojiang

    2015-11-01

    The MYB proteins comprise one of the largest transcription factor families in plants, and play key roles in regulatory networks controlling development, metabolism, and stress responses. A total of 125 MYB genes (JcMYB) have been identified in the physic nut (Jatropha curcas L.) genome, including 120 2R-type MYB, 4 3R-MYB, and 1 4R-MYB genes. Based on exon-intron arrangement of MYBs from both lower (Physcomitrella patens) and higher (physic nut, Arabidopsis, and rice) plants, we can classify plant MYB genes into ten groups (MI-X), except for MIX genes which are nonexistent in higher plants. We also observed that MVIII genes may be one of the most ancient MYB types which consist of both R2R3- and 3R-MYB genes. Most MYB genes (76.8% in physic nut) belong to the MI group which can be divided into 34 subgroups. The JcMYB genes were nonrandomly distributed on its 11 linkage groups (LGs). The expansion of MYB genes across several subgroups was observed and resulted from genome triplication of ancient dicotyledons and from both ancient and recent tandem duplication events in the physic nut genome. The expression patterns of several MYB duplicates in the physic nut showed differences in four tissues (root, stem, leaf, and seed), and 34 MYB genes responded to at least one abiotic stressor (drought, salinity, phosphate starvation, and nitrogen starvation) in leaves and/or roots based on the data analysis of digital gene expression tags. Overexpression of the JcMYB001 gene in Arabidopsis increased its sensitivity to drought and salinity stresses.

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

    Science.gov (United States)

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

    2013-01-01

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

  13. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

    Science.gov (United States)

    Kilpeläinen, Tuomas O; Carli, Jayne F Martin; Skowronski, Alicja A; Sun, Qi; Kriebel, Jennifer; Feitosa, Mary F; Hedman, Åsa K; Drong, Alexander W; Hayes, James E; Zhao, Jinghua; Pers, Tune H; Schick, Ursula; Grarup, Niels; Kutalik, Zoltán; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikäinen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Del Greco M, Fabiola; Pasko, Dorota; Renström, Frida; Willems, Sara M; Mahajan, Anubha; Rose, Lynda M; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E; Pérusse, Louis; Gaunt, Tom; Ahluwalia, Tarunveer S; Ju Sung, Yun; Ramos, Yolande F; Amin, Najaf; Amuzu, Antoinette; Barroso, Inês; Bellis, Claire; Blangero, John; Buckley, Brendan M; Böhringer, Stefan; I Chen, Yii-Der; de Craen, Anton J N; Crosslin, David R; Dale, Caroline E; Dastani, Zari; Day, Felix R; Deelen, Joris; Delgado, Graciela E; Demirkan, Ayse; Finucane, Francis M; Ford, Ian; Garcia, Melissa E; Gieger, Christian; Gustafsson, Stefan; Hallmans, Göran; Hankinson, Susan E; Havulinna, Aki S; Herder, Christian; Hernandez, Dena; Hicks, Andrew A; Hunter, David J; Illig, Thomas; Ingelsson, Erik; Ioan-Facsinay, Andreea; Jansson, John-Olov; Jenny, Nancy S; Jørgensen, Marit E; Jørgensen, Torben; Karlsson, Magnus; Koenig, Wolfgang; Kraft, Peter; Kwekkeboom, Joanneke; Laatikainen, Tiina; Ladwig, Karl-Heinz; LeDuc, Charles A; Lowe, Gordon; Lu, Yingchang; Marques-Vidal, Pedro; Meisinger, Christa; Menni, Cristina; Morris, Andrew P; Myers, Richard H; Männistö, Satu; Nalls, Mike A; Paternoster, Lavinia; Peters, Annette; Pradhan, Aruna D; Rankinen, Tuomo; Rasmussen-Torvik, Laura J; Rathmann, Wolfgang; Rice, Treva K; Brent Richards, J; Ridker, Paul M; Sattar, Naveed; Savage, David B; Söderberg, Stefan; Timpson, Nicholas J; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widén, Elisabeth; Wood, Andrew R; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sørensen, Thorkild I A; Sarzynski, Mark A; Rao, D C; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G; Heliövaara, Markku; Knekt, Paul B; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K; Viikari, Jorma S; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T; Mellström, Dan; Lorentzon, Mattias; Casas, Juan P; Bandinelli, Stefanie; März, Winfried; Isaacs, Aaron; van Dijk, Ko W; van Duijn, Cornelia M; Harris, Tamara B; Bouchard, Claude; Allison, Matthew A; Chasman, Daniel I; Ohlsson, Claes; Lind, Lars; Scott, Robert A; Langenberg, Claudia; Wareham, Nicholas J; Ferrucci, Luigi; Frayling, Timothy M; Pramstaller, Peter P; Borecki, Ingrid B; Waterworth, Dawn M; Bergmann, Sven; Waeber, Gérard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B; Eline Slagboom, P; Grallert, Harald; Spector, Tim D; Jukema, J W; Klein, Robert J; Schadt, Erik E; Franks, Paul W; Lindgren, Cecilia M; Leibel, Rudolph L; Loos, Ruth J F

    2016-02-01

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

  14. Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels

    Science.gov (United States)

    Kilpeläinen, Tuomas O.; Carli, Jayne F. Martin; Skowronski, Alicja A.; Sun, Qi; Kriebel, Jennifer; Feitosa, Mary F; Hedman, Åsa K.; Drong, Alexander W.; Hayes, James E.; Zhao, Jinghua; Pers, Tune H.; Schick, Ursula; Grarup, Niels; Kutalik, Zoltán; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikäinen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Greco M, Fabiola Del; Pasko, Dorota; Renström, Frida; Willems, Sara M.; Mahajan, Anubha; Rose, Lynda M.; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E.; Pérusse, Louis; Gaunt, Tom; Ahluwalia, Tarunveer S.; Ju Sung, Yun; Ramos, Yolande F.; Amin, Najaf; Amuzu, Antoinette; Barroso, Inês; Bellis, Claire; Blangero, John; Buckley, Brendan M.; Böhringer, Stefan; I Chen, Yii-Der; de Craen, Anton J. N.; Crosslin, David R.; Dale, Caroline E.; Dastani, Zari; Day, Felix R.; Deelen, Joris; Delgado, Graciela E.; Demirkan, Ayse; Finucane, Francis M.; Ford, Ian; Garcia, Melissa E.; Gieger, Christian; Gustafsson, Stefan; Hallmans, Göran; Hankinson, Susan E.; Havulinna, Aki S; Herder, Christian; Hernandez, Dena; Hicks, Andrew A.; Hunter, David J.; Illig, Thomas; Ingelsson, Erik; Ioan-Facsinay, Andreea; Jansson, John-Olov; Jenny, Nancy S.; Jørgensen, Marit E.; Jørgensen, Torben; Karlsson, Magnus; Koenig, Wolfgang; Kraft, Peter; Kwekkeboom, Joanneke; Laatikainen, Tiina; Ladwig, Karl-Heinz; LeDuc, Charles A.; Lowe, Gordon; Lu, Yingchang; Marques-Vidal, Pedro; Meisinger, Christa; Menni, Cristina; Morris, Andrew P.; Myers, Richard H.; Männistö, Satu; Nalls, Mike A.; Paternoster, Lavinia; Peters, Annette; Pradhan, Aruna D.; Rankinen, Tuomo; Rasmussen-Torvik, Laura J.; Rathmann, Wolfgang; Rice, Treva K.; Brent Richards, J; Ridker, Paul M.; Sattar, Naveed; Savage, David B.; Söderberg, Stefan; Timpson, Nicholas J.; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widén, Elisabeth; Wood, Andrew R.; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sørensen, Thorkild I. A.; Sarzynski, Mark A.; Rao, D. C.; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G.; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G.; Heliövaara, Markku; Knekt, Paul B.; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K.; Viikari, Jorma S.; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T.; Mellström, Dan; Lorentzon, Mattias; Casas, Juan P.; Bandinelli, Stefanie; März, Winfried; Isaacs, Aaron; van Dijk, Ko W.; van Duijn, Cornelia M.; Harris, Tamara B.; Bouchard, Claude; Allison, Matthew A.; Chasman, Daniel I.; Ohlsson, Claes; Lind, Lars; Scott, Robert A.; Langenberg, Claudia; Wareham, Nicholas J.; Ferrucci, Luigi; Frayling, Timothy M.; Pramstaller, Peter P.; Borecki, Ingrid B.; Waterworth, Dawn M.; Bergmann, Sven; Waeber, Gérard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B.; Eline Slagboom, P; Grallert, Harald; Spector, Tim D.; Jukema, J.W.; Klein, Robert J.; Schadt, Erik E; Franks, Paul W.; Lindgren, Cecilia M.; Leibel, Rudolph L.; Loos, Ruth J. F.

    2016-01-01

    Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10−6 in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10−8) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health. PMID:26833098

  15. Deep genome-wide measurement of meiotic gene conversion using tetrad analysis in Arabidopsis thaliana.

    Directory of Open Access Journals (Sweden)

    Yujin Sun

    Full Text Available Gene conversion, the non-reciprocal exchange of genetic information, is one of the potential products of meiotic recombination. It can shape genome structure by acting on repetitive DNA elements, influence allele frequencies at the population level, and is known to be implicated in human disease. But gene conversion is hard to detect directly except in organisms, like fungi, that group their gametes following meiosis. We have developed a novel visual assay that enables us to detect gene conversion events directly in the gametes of the flowering plant Arabidopsis thaliana. Using this assay we measured gene conversion events across the genome of more than one million meioses and determined that the genome-wide average frequency is 3.5×10(-4 conversions per locus per meiosis. We also detected significant locus-to-locus variation in conversion frequency but no intra-locus variation. Significantly, we found one locus on the short arm of chromosome 4 that experienced 3-fold to 6-fold more gene conversions than the other loci tested. Finally, we demonstrated that we could modulate conversion frequency by varying experimental conditions.

  16. Genome-wide analysis demonstrates conserved localization of messenger RNAs to mitotic microtubules.

    Science.gov (United States)

    Blower, Michael D; Feric, Elma; Weis, Karsten; Heald, Rebecca

    2007-12-31

    RNA localization is of critical importance in many fundamental cell biological and developmental processes by regulating the spatial control of gene expression. To investigate how spindle-localized RNAs might influence mitosis, we comprehensively surveyed all messenger RNAs (mRNAs) that bound to microtubules during metaphase in both Xenopus laevis egg extracts and mitotic human cell extracts. We identify conserved classes of mRNAs that are enriched on microtubules in both human and X. laevis. Active mitotic translation occurs on X. laevis meiotic spindles, and a subset of microtubule-bound mRNAs (MT-mRNAs) associate with polyribosomes. Although many MT-mRNAs associate with polyribosomes, we find that active translation is not required for mRNA localization to mitotic microtubules. Our results represent the first genome-wide survey of mRNAs localized to a specific cytoskeletal component and suggest that microtubule localization of specific mRNAs is likely to function in mitotic regulation and mRNA segregation during cell division.

  17. Genome-wide analysis of DNA methylation in five tissues of Zhikong scallop, Chlamys farreri.

    Directory of Open Access Journals (Sweden)

    Yan Sun

    Full Text Available DNA methylation plays a vital role in tissue development and differentiation in eukaryotes. Epigenetic studies have been seldom conducted in the extremely diverse and evolutionarily highly successful bilaterian lineage Mollusca. In the present study, we conducted the genome-wide profiling of DNA methylation for five tissues of a bivalve mollusc, Chlamys farreri using the methylation-sensitive amplification polymorphism (MSAP technique. The methylation levels were quite similar among tissues, ranging from 20.9% to 21.7%. CG methylation was the dominant type (14.9%-16.5% in the C. farreri genome, but CHG methylation also accounted for a substantial fraction of total methylation (5.1%-6.3%. Relatively high methylation diversity was observed within tissues. Methylation differentiation between tissues was evaluated and 460 tissue-specific epiloci were identified. Kidney differs from the other tissues in DNA methylation profiles. Our study presents the first look at the tissue-specific DNA methylation patterns in a bivalve mollusc and represents an initial step towards understanding of epigenetic regulatory mechanism underlying tissue development and differentiation in bivalves.

  18. Genome-Wide Identification and in Silico Analysis of Poplar Peptide Deformylases

    Directory of Open Access Journals (Sweden)

    Chuan-Ping Yang

    2012-04-01

    Full Text Available Peptide deformylases (PDF behave as monomeric metal cation hydrolases for the removal of the N-formyl group (Fo. This is an essential step in the N-terminal Met excision (NME that occurs in these proteins from eukaryotic mitochondria or chloroplasts. Although PDFs have been identified and their structure and function have been characterized in several herbaceous species, it remains as yet unexplored in poplar. Here, we report on the first identification of two genes (PtrPDF1A and PtrPDF1B respectively encoding two putative PDF polypeptides in Populus trichocarpa by genome-wide investigation. One of them (XP_002300047.1 encoded by PtrPDF1B (XM_002300011.1 was truncated, and then revised into a complete sequence based on its ESTs support with high confidence. We document that the two PDF1s of Populus are evolutionarily divergent, likely as a result of independent duplicated events. Furthermore, in silico simulations demonstrated that PtrPDF1A and PtrPDF1B should act as similar PDF catalytic activities to their corresponding PDF orthologs in Arabidopsis. This result would be value of for further assessment of their biological activities in poplar, and further experiments are now required to confirm them.

  19. DNA Methylation in Newborns and Maternal Smoking in Pregnancy: Genome-wide Consortium Meta-analysis.

    Science.gov (United States)

    Joubert, Bonnie R; Felix, Janine F; Yousefi, Paul; Bakulski, Kelly M; Just, Allan C; Breton, Carrie; Reese, Sarah E; Markunas, Christina A; Richmond, Rebecca C; Xu, Cheng-Jian; Küpers, Leanne K; Oh, Sam S; Hoyo, Cathrine; Gruzieva, Olena; Söderhäll, Cilla; Salas, Lucas A; Baïz, Nour; Zhang, Hongmei; Lepeule, Johanna; Ruiz, Carlos; Ligthart, Symen; Wang, Tianyuan; Taylor, Jack A; Duijts, Liesbeth; Sharp, Gemma C; Jankipersadsing, Soesma A; Nilsen, Roy M; Vaez, Ahmad; Fallin, M Daniele; Hu, Donglei; Litonjua, Augusto A; Fuemmeler, Bernard F; Huen, Karen; Kere, Juha; Kull, Inger; Munthe-Kaas, Monica Cheng; Gehring, Ulrike; Bustamante, Mariona; Saurel-Coubizolles, Marie José; Quraishi, Bilal M; Ren, Jie; Tost, Jörg; Gonzalez, Juan R; Peters, Marjolein J; Håberg, Siri E; Xu, Zongli; van Meurs, Joyce B; Gaunt, Tom R; Kerkhof, Marjan; Corpeleijn, Eva; Feinberg, Andrew P; Eng, Celeste; Baccarelli, Andrea A; Benjamin Neelon, Sara E; Bradman, Asa; Merid, Simon Kebede; Bergström, Anna; Herceg, Zdenko; Hernandez-Vargas, Hector; Brunekreef, Bert; Pinart, Mariona; Heude, Barbara; Ewart, Susan; Yao, Jin; Lemonnier, Nathanaël; Franco, Oscar H; Wu, Michael C; Hofman, Albert; McArdle, Wendy; Van der Vlies, Pieter; Falahi, Fahimeh; Gillman, Matthew W; Barcellos, Lisa F; Kumar, Ashish; Wickman, Magnus; Guerra, Stefano; Charles, Marie-Aline; Holloway, John; Auffray, Charles; Tiemeier, Henning W; Smith, George Davey; Postma, Dirkje; Hivert, Marie-France; Eskenazi, Brenda; Vrijheid, Martine; Arshad, Hasan; Antó, Josep M; Dehghan, Abbas; Karmaus, Wilfried; Annesi-Maesano, Isabella; Sunyer, Jordi; Ghantous, Akram; Pershagen, Göran; Holland, Nina; Murphy, Susan K; DeMeo, Dawn L; Burchard, Esteban G; Ladd-Acosta, Christine; Snieder, Harold; Nystad, Wenche; Koppelman, Gerard H; Relton, Caroline L; Jaddoe, Vincent W V; Wilcox, Allen; Melén, Erik; London, Stephanie J

    2016-04-01

    Epigenetic modifications, including DNA methylation, represent a potential mechanism for environmental impacts on human disease. Maternal smoking in pregnancy remains an important public health problem that impacts child health in a myriad of ways and has potential lifelong consequences. The mechanisms are largely unknown, but epigenetics most likely plays a role. We formed the Pregnancy And Childhood Epigenetics (PACE) consortium and meta-analyzed, across 13 cohorts (n = 6,685), the association between maternal smoking in pregnancy and newborn blood DNA methylation at over 450,000 CpG sites (CpGs) by using the Illumina 450K BeadChip. Over 6,000 CpGs were differentially methylated in relation to maternal smoking at genome-wide statistical significance (false discovery rate, 5%), including 2,965 CpGs corresponding to 2,017 genes not previously related to smoking and methylation in either newborns or adults. Several genes are relevant to diseases that can be caused by maternal smoking (e.g., orofacial clefts and asthma) or adult smoking (e.g., certain cancers). A number of differentially methylated CpGs were associated with gene expression. We observed enrichment in pathways and processes critical to development. In older children (5 cohorts, n = 3,187), 100% of CpGs gave at least nominal levels of significance, far more than expected by chance (p value smoking in pregnancy with persistence into later childhood and provide insights into mechanisms underlying effects of this important exposure.

  20. Genome-wide SNP analysis explains coral diversity and recovery in the Ryukyu Archipelago.

    Science.gov (United States)

    Shinzato, Chuya; Mungpakdee, Sutada; Arakaki, Nana; Satoh, Noriyuki

    2015-12-10

    Following a global coral bleaching event in 1998, Acropora corals surrounding most of Okinawa island (OI) were devastated, although they are now gradually recovering. In contrast, the Kerama Islands (KIs) only 30 km west of OI, have continuously hosted a great variety of healthy corals. Taking advantage of the decoded Acropora digitifera genome and using genome-wide SNP analyses, we clarified Acropora population structure in the southern Ryukyu Archipelago (sRA). Despite small genetic distances, we identified distinct clusters corresponding to specific island groups, suggesting infrequent long-distance dispersal within the sRA. Although the KIs were believed to supply coral larvae to OI, admixture analyses showed that such dispersal is much more limited than previously realized, indicating independent recovery of OI coral populations and the necessity of local conservation efforts for each region. We detected strong historical migration from the Yaeyama Islands (YIs) to OI, and suggest that the YIs are the original source of OI corals. In addition, migration edges to the KIs suggest that they are a historical sink population in the sRA, resulting in high diversity. This population genomics study provides the highest resolution data to date regarding coral population structure and history.

  1. Genome-wide analysis reveals coating of the mitochondrial genome by TFAM.

    Directory of Open Access Journals (Sweden)

    Yun E Wang

    Full Text Available Mitochondria contain a 16.6 kb circular genome encoding 13 proteins as well as mitochondrial tRNAs and rRNAs. Copies of the genome are organized into nucleoids containing both DNA and proteins, including the machinery required for mtDNA replication and transcription. The transcription factor TFAM is critical for initiation of transcription and replication of the genome, and is also thought to perform a packaging function. Although specific binding sites required for initiation of transcription have been identified in the D-loop, little is known about the characteristics of TFAM binding in its nonspecific packaging state. In addition, it is unclear whether TFAM also plays a role in the regulation of nuclear gene expression. Here we investigate these questions by using ChIP-seq to directly localize TFAM binding to DNA in human cells. Our results demonstrate that TFAM uniformly coats the whole mitochondrial genome, with no evidence of robust TFAM binding to the nuclear genome. Our study represents the first high-resolution assessment of TFAM binding on a genome-wide scale in human cells.

  2. P-value based analysis for shared controls design in genome-wide association studies.

    Science.gov (United States)

    Zaykin, Dmitri V; Kozbur, Damian O

    2010-11-01

    An appealing genome-wide association study design compares one large control group against several disease samples. A pioneering study by the Wellcome Trust Case Control Consortium that employed such a design has identified multiple susceptibility regions, many of which have been independently replicated. While reusing a control sample provides effective utilization of data, it also creates correlation between association statistics across diseases. An observation of a large association statistic for one of the diseases may greatly increase chances of observing a spuriously large association for a different disease. Accounting for the correlation is also particularly important when screening for SNPs that might be involved in a set of diseases with overlapping etiology. We describe methods that correct association statistics for dependency due to shared controls, and we describe ways to obtain a measure of overall evidence and to combine association signals across multiple diseases. The methods we describe require no access to individual subject data, instead, they efficiently utilize information contained in P-values for association reported for individual diseases. P-value based combined tests for association are flexible and essentially as powerful as the approach based on aggregating the individual subject data.

  3. Genome-wide analysis of LXRα activation reveals new transcriptional networks in human atherosclerotic foam cells.

    Science.gov (United States)

    Feldmann, Radmila; Fischer, Cornelius; Kodelja, Vitam; Behrens, Sarah; Haas, Stefan; Vingron, Martin; Timmermann, Bernd; Geikowski, Anne; Sauer, Sascha

    2013-04-01

    Increased physiological levels of oxysterols are major risk factors for developing atherosclerosis and cardiovascular disease. Lipid-loaded macrophages, termed foam cells, are important during the early development of atherosclerotic plaques. To pursue the hypothesis that ligand-based modulation of the nuclear receptor LXRα is crucial for cell homeostasis during atherosclerotic processes, we analysed genome-wide the action of LXRα in foam cells and macrophages. By integrating chromatin immunoprecipitation-sequencing (ChIP-seq) and gene expression profile analyses, we generated a highly stringent set of 186 LXRα target genes. Treatment with the nanomolar-binding ligand T0901317 and subsequent auto-regulatory LXRα activation resulted in sequence-dependent sharpening of the genome-binding patterns of LXRα. LXRα-binding loci that correlated with differential gene expression revealed 32 novel target genes with potential beneficial effects, which in part explained the implications of disease-associated genetic variation data. These observations identified highly integrated LXRα ligand-dependent transcriptional networks, including the APOE/C1/C4/C2-gene cluster, which contribute to the reversal of cholesterol efflux and the dampening of inflammation processes in foam cells to prevent atherogenesis.

  4. Genome-wide analysis of light- and temperature-entrained circadian transcripts in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Alexander M van der Linden

    Full Text Available Most organisms have an endogenous circadian clock that is synchronized to environmental signals such as light and temperature. Although circadian rhythms have been described in the nematode Caenorhabditis elegans at the behavioral level, these rhythms appear to be relatively non-robust. Moreover, in contrast to other animal models, no circadian transcriptional rhythms have been identified. Thus, whether this organism contains a bona fide circadian clock remains an open question. Here we use genome-wide expression profiling experiments to identify light- and temperature-entrained oscillating transcripts in C. elegans. These transcripts exhibit rhythmic expression with temperature-compensated 24-h periods. In addition, their expression is sustained under constant conditions, suggesting that they are under circadian regulation. Light and temperature cycles strongly drive gene expression and appear to entrain largely nonoverlapping gene sets. We show that mutations in a cyclic nucleotide-gated channel required for sensory transduction abolish both light- and temperature-entrained gene expression, implying that environmental cues act cell nonautonomously to entrain circadian rhythms. Together, these findings demonstrate circadian-regulated transcriptional rhythms in C. elegans and suggest that further analyses in this organism will provide new information about the evolution and function of this biological clock.

  5. Genome-wide association analysis of feed intake and residual feed intake in Nellore cattle.

    Science.gov (United States)

    Santana, Miguel H A; Utsunomiya, Yuri T; Neves, Haroldo H R; Gomes, Rodrigo C; Garcia, José F; Fukumasu, Heidge; Silva, Saulo L; Oliveira Junior, Gerson A; Alexandre, Pâmela A; Leme, Paulo R; Brassaloti, Ricardo A; Coutinho, Luiz L; Lopes, Thiago G; Meirelles, Flávio V; Eler, Joanir P; Ferraz, José B S

    2014-02-11

    Feed intake plays an important economic role in beef cattle, and is related with feed efficiency, weight gain and carcass traits. However, the phenotypes collected for dry matter intake and feed efficiency are scarce when compared with other measures such as weight gain and carcass traits. The use of genomic information can improve the power of inference of studies on these measures, identifying genomic regions that affect these phenotypes. This work performed the genome-wide association study (GWAS) for dry matter intake (DMI) and residual feed intake (RFI) of 720 Nellore cattle (Bos taurus indicus). In general, no genomic region extremely associated with both phenotypic traits was observed, as expected for the variables that have their regulation controlled by many genes. Three SNPs surpassed the threshold for the Bonferroni multiple test for DMI and two SNPs for RFI. These markers are located on chromosomes 4, 8, 14 and 21 in regions near genes regulating appetite and ion transport and close to important QTL as previously reported to RFI and DMI, thus corroborating the literature that points these two processes as important in the physiological regulation of intake and feed efficiency. This study showed the first GWAS of DMI to identify genomic regions associated with feed intake and efficiency in Nellore cattle. Some genes and QTLs previously described for DMI and RFI, in other subspecies (Bos taurus taurus), that influences these phenotypes are confirmed in this study.

  6. Genome-wide chromatin occupancy analysis reveals a role for ASH2 in transcriptional pausing.

    Science.gov (United States)

    Pérez-Lluch, Sílvia; Blanco, Enrique; Carbonell, Albert; Raha, Debasish; Snyder, Michael; Serras, Florenci; Corominas, Montserrat

    2011-06-01

    An important mechanism for gene regulation involves chromatin changes via histone modification. One such modification is histone H3 lysine 4 trimethylation (H3K4me3), which requires histone methyltranferase complexes (HMT) containing the trithorax-group (trxG) protein ASH2. Mutations in ash2 cause a variety of pattern formation defects in the Drosophila wing. We have identified genome-wide binding of ASH2 in wing imaginal discs using chromatin immunoprecipitation combined with sequencing (ChIP-Seq). Our results show that genes with functions in development and transcriptional regulation are activated by ASH2 via H3K4 trimethylation in nearby nucleosomes. We have characterized the occupancy of phosphorylated forms of RNA Polymerase II and histone marks associated with activation and repression of transcription. ASH2 occupancy correlates with phosphorylated forms of RNA Polymerase II and histone activating marks in expressed genes. Additionally, RNA Polymerase II phosphorylation on serine 5 and H3K4me3 are reduced in ash2 mutants in comparison to wild-type flies. Finally, we have identified specific motifs associated with ASH2 binding in genes that are differentially expressed in ash2 mutants. Our data suggest that recruitment of the ASH2-containing HMT complexes is context specific and points to a function of ASH2 and H3K4me3 in transcriptional pausing control.

  7. Efficient Genome-Wide Sequencing and Low-Coverage Pedigree Analysis from Noninvasively Collected Samples.

    Science.gov (United States)

    Snyder-Mackler, Noah; Majoros, William H; Yuan, Michael L; Shaver, Amanda O; Gordon, Jacob B; Kopp, Gisela H; Schlebusch, Stephen A; Wall, Jeffrey D; Alberts, Susan C; Mukherjee, Sayan; Zhou, Xiang; Tung, Jenny

    2016-06-01

    Research on the genetics of natural populations was revolutionized in the 1990s by methods for genotyping noninvasively collected samples. However, these methods have remained largely unchanged for the past 20 years and lag far behind the genomics era. To close this gap, here we report an optimized laboratory protocol for genome-wide capture of endogenous DNA from noninvasively collected samples, coupled with a novel computational approach to reconstruct pedigree links from the resulting low-coverage data. We validated both methods using fecal samples from 62 wild baboons, including 48 from an independently constructed extended pedigree. We enriched fecal-derived DNA samples up to 40-fold for endogenous baboon DNA and reconstructed near-perfect pedigree relationships even with extremely low-coverage sequencing. We anticipate that these methods will be broadly applicable to the many research systems for which only noninvasive samples are available. The lab protocol and software ("WHODAD") are freely available at www.tung-lab.org/protocols-and-software.html and www.xzlab.org/software.html, respectively. Copyright © 2016 by the Genetics Society of America.

  8. Genome wide analysis of drug-induced torsades de pointes: lack of common variants with large effect sizes.

    Directory of Open Access Journals (Sweden)

    Elijah R Behr

    Full Text Available Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP, treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p  =  3×10(-7, odds ratio = 2, 95% confidence intervals: 1.5-2.6. The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p  =  3×10(-9. Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.

  9. Genome Wide Analysis of Drug-Induced Torsades de Pointes: Lack of Common Variants with Large Effect Sizes

    Science.gov (United States)

    Behr, Elijah R.; Ritchie, Marylyn D.; Tanaka, Toshihiro; Kääb, Stefan; Crawford, Dana C.; Nicoletti, Paola; Floratos, Aris; Sinner, Moritz F.; Kannankeril, Prince J.; Wilde, Arthur A. M.; Bezzina, Connie R.; Schulze-Bahr, Eric; Zumhagen, Sven; Guicheney, Pascale; Bishopric, Nanette H.; Marshall, Vanessa; Shakir, Saad; Dalageorgou, Chrysoula; Bevan, Steve; Jamshidi, Yalda; Bastiaenen, Rachel; Myerburg, Robert J.; Schott, Jean-Jacques; Camm, A. John; Steinbeck, Gerhard; Norris, Kris; Altman, Russ B.; Tatonetti, Nicholas P.; Jeffery, Steve; Kubo, Michiaki; Nakamura, Yusuke; Shen, Yufeng; George, Alfred L.; Roden, Dan M.

    2013-01-01

    Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p  =  3×10−7, odds ratio = 2, 95% confidence intervals: 1.5–2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p  =  3×10−9). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs. PMID:24223155

  10. Genome-wide Association Studies of MRI-defined Brain Infarcts: Meta-analysis from the CHARGE Consortium

    Science.gov (United States)

    Debette, Stephanie; Bis, Joshua C.; Fornage, Myriam; Schmidt, Helena; Ikram, M. Arfan; Sigurdsson, Sigurdur; Heiss, Gerardo; Struchalin, Maksim; Smith, Albert V.; van der Lugt, Aad; DeCarli, Charles; Lumley, Thomas; Knopman, David S.; Enzinger, Christian; Eiriksdottir, Gudny; Koudstaal, Peter J.; DeStefano, Anita L.; Psaty, Bruce M.; Dufouil, Carole; Catellier, Diane J.; Fazekas, Franz; Aspelund, Thor; Aulchenko, Yurii S.; Beiser, Alexa; Rotter, Jerome I.; Tzourio, Christophe; Shibata, Dean K.; Tscherner, Maria; Harris, Tamara B.; Rivadeneira, Fernando; Atwood, Larry D.; Rice, Kenneth; Gottesman, Rebecca F.; van Buchem, Mark A.; Uitterlinden, Andre G.; Kelly-Hayes, Margaret; Cushman, Mary; Zhu, Yicheng; Boerwinkle, Eric; Gudnason, Vilmundur; Hofman, Albert; Romero, Jose R.; Lopez, Oscar; van Duijn, Cornelia M.; Au, Rhoda; Heckbert, Susan R.; Wolf, Philip A.; Mosley, Thomas H.; Seshadri, Sudha; Breteler, Monique M.B.; Schmidt, Reinhold; Launer, Lenore J.; Longstreth, WT

    2010-01-01

    Background Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI-infarct, in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods Using 2.2 million genotyped and imputed SNPs, each study performed cross-sectional genome-wide association analysis of MRI-infarct using age and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance weighted meta-analysis, including 9401 participants with mean age 69.7, 19.4% of whom had ≥1 MRI-infarct. Results The most significant association was found with rs2208454 (minor allele frequency: 20%), located in intron 3 of MACRO Domain Containing 2 gene and in the downstream region of Fibronectin Leucine Rich Transmembrane Protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI-infarcts: odds ratio=0.76, 95% confidence interval=0.68–0.84, p=4.64×10−7. Highly suggestive associations (p0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 African-American participants, although 4 SNPs within 200kb from rs2208454 were associated with MRI-infarcts in African-American sample. Conclusions This first community-based, genome-wide association study on covert MRI-infarcts uncovered novel associations. Although replication of the association with top SNP failed, possibly due to insufficient power, results in the African American sample are encouraging, and further efforts at replication are needed. PMID:20044523

  11. 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

    Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16......(-8)). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis...

  12. Genome-wide DNA methylation analysis of transient neonatal diabetes type 1 patients with mutations in ZFP57

    DEFF Research Database (Denmark)

    Bak, Mads; Boonen, Susanne E; Dahl, Christina;

    2016-01-01

    involved in establishment and maintenance of methylation of imprinted loci. Our objective was to investigate whether additional regions are aberrantly methylated in ZFP57 mutation carriers. METHODS: Genome-wide DNA methylation analysis was performed on four individuals with homozygous or compound...... and HYMAI. A subset of patients with maternal hypomethylation at PLAGL1 have hypomethylation at additional imprinted loci throughout the genome, including GRB10, ZIM2 (PEG3), MEST (PEG1), KCNQ1OT1 and NESPAS (GNAS-AS1). About half of the TNDM1 patients carry mutations in ZFP57, a transcription factor...

  13. Genome-wide association and biological pathway analysis for milk-fat composition in Danish Holstein and Danish Jersey cattle

    DEFF Research Database (Denmark)

    Buitenhuis, Bart; Janss, Luc L G; Poulsen, Nina Aagaard;

    2014-01-01

    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 acid (FA) profile using the HD bovine SNP array and subsequently a biological pathway analysis based on the SNP...

  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. The challenges of genome-wide interaction studies: lessons to learn from the analysis of HDL blood levels.

    Directory of Open Access Journals (Sweden)

    Elisabeth M van Leeuwen

    Full Text Available Genome-wide association studies (GWAS have revealed 74 single nucleotide polymorphisms (SNPs associated with high-density lipoprotein cholesterol (HDL blood levels. This study is, to our knowledge, the first genome-wide interaction study (GWIS to identify SNP×SNP interactions associated with HDL levels. We performed a GWIS in the Rotterdam Study (RS cohort I (RS-I using the GLIDE tool which leverages the massively parallel computing power of Graphics Processing Units (GPUs to perform linear regression on all genome-wide pairs of SNPs. By performing a meta-analysis together with Rotterdam Study cohorts II and III (RS-II and RS-III, we were able to filter 181 interaction terms with a p-value<1 · 10-8 that replicated in the two independent cohorts. We were not able to replicate any of these interaction term in the AGES, ARIC, CHS, ERF, FHS and NFBC-66 cohorts (Ntotal = 30,011 when adjusting for multiple testing. Our GWIS resulted in the consistent finding of a possible interaction between rs774801 in ARMC8 (ENSG00000114098 and rs12442098 in SPATA8 (ENSG00000185594 being associated with HDL levels. However, p-values do not reach the preset Bonferroni correction of the p-values. Our study suggest that even for highly genetically determined traits such as HDL the sample sizes needed to detect SNP×SNP interactions are large and the 2-step filtering approaches do not yield a solution. Here we present our analysis plan and our reservations concerning GWIS.

  16. Genome-wide identification and analysis of the SGR gene family in Cucumis melo L.

    Science.gov (United States)

    Bade, R G; Bao, M L; Jin, W Y; Ma, Y; Niu, Y D; Hasi, A

    2016-10-17

    Chlorophyll (CHL) is present in many plant organs, and its metabolism is strongly regulated throughout plant development. Understanding the fate of CHL in senescent leaves or during fruit ripening is a complex process. The stay-green (SGR) protein has been shown to affect CHL degradation. In this study, we used the conserved sequences of STAY-GREEN domain protein (NP_567673) in Arabidopsis thaliana as a probe to search SGR family genes in the genome-wide melon protein database. Four candidate SGR family genes were identified in melon (Cucumis melo L. Hetao). The phylogenetic evolution, gene structure, and conserved motifs were subsequently analyzed. In order to verify the function of CmSGR genes in CHL degradation, CmSGR1 and CmSGR2 were transiently overexpressed and silenced using different plasmids in melon. Overexpression of CmSGR1 or CmSGR2 induced leaf yellowing or fruit ripening, while silencing of CmSGR1 or CmSGR2 via RNA interference delayed CHL breakdown during fruit ripening or leaf senescence compared with the wild type. Next, the expression profile was analyzed, and we found that CmSGR genes were expressed ubiquitously. Moreover, CmSGR1 and CmSGR2 were upregulated, and promoted fruit ripening. CmSGR3 and CmSGR4 were more highly expressed in leaves, cotyledon, and stem compared with CmSGR1 or CmSGR2. Thus, we conclude that CmSGR genes are crucial for fruit ripening and leaf senescence. CmSGR protein structure and function were further clarified to provide a theoretical foundation and valuable information for improved performance of melon.

  17. Genomic-wide analysis of lymphatic metastasis-associated genes in human hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Chun-Feng Lee; Zhi-Qiang Ling; Ting Zhao; Shih-Hua Fang; Weng-Cheng Chang; San-Chih Lee; Kuan-Rong Lee

    2009-01-01

    AIM: To identify the genes related to lymph node metastasis in human hepatocellular carcinoma (HCC), 32 HCC patients with or without lymph node metastasis were investigated by high-throughput microarray comprising 886 genes.METHODS: The samples of cancerous and non-cancerouspaired tissue were taken from 32 patients with HCC who underwent hepatectomy with lymph node dissection. Total RNA was extracted from the cells obtained by means of laser microdissection (LCM) and was amplified by the T7-based amplification system. Then, the amplified samples were applied in the cDNA microarray comprising of 886 genes.RESULTS: The results demonstrated that 25 upregulated genes such as cell membrane receptor,intracellular signaling and cell adhesion related genes,and 48 down-regulated genes such as intracellular signaling and cell cycle regulator-related genes,were correlated with lymph node metastasis in HCC. Amongst them were included some interesting genes, such as MET, EPHA2, CCND1, MMP2, MMP13,CASP3, CDH1, and PTPN2. Expression of 16 genes ( MET, CCND1, CCND2, VEGF, KRT18, RFC4, BIRC5,CDC6, MMP2, BCL2A1, CDH1, VIM, PDGFRA, PTPN2,SLC25A5 and DSP) were further confirmed by real-time quantitative reverse transcriptional polymerase chain reaction (RT-PCR).CONCLUSION: Tumor metastasis is an important biological characteristic, which involves multiple genetic changes and cumulation. This genome-wide information contributes to an improved understanding of molecular alterations during lymph node metastasis in HCC. It may help clinicians to predict metastasis of lymph nodes and assist researchers in identifying novel therapeutic targets for metastatic HCC patients.

  18. Genome-wide association analysis of forage quality in maize mature stalk.

    Science.gov (United States)

    Wang, Hongwu; Li, Kun; Hu, Xiaojiao; Liu, Zhifang; Wu, Yujin; Huang, Changling

    2016-10-21

    Plant digestibility of silage maize (Zea mays L.) has a large influence on nutrition intake for animal feeding. Improving forage quality will enhance the utilization efficiency and feeding value of forage maize. Dissecting the genetic basis of forage quality will improve our understanding of the complex nature of cell wall biosynthesis and degradation, which is also helpful for breeding good quality silage maize. Acid detergent fiber (ADF), neutral detergent fiber (NDF) and in vitro dry matter digestibility (IVDMD) of stalk were evaluated in a diverse maize population, which is comprised of 368 inbred lines and planted across seven environments. Using a mixed model accounting for population structure and polygenic background effects, a genome-wide association study was conducted to identify single nucleotide polymorphisms (SNPs) significantly associated with forage quality. Scanning 559,285 SNPs across the whole genome, 73, 41 and 82 SNPs were found to be associated with ADF, NDF, and IVDMD, respectively. Each significant SNP explained 4.2 %-6.2 % of the phenotypic variation. Underlying these associated loci, 56 genes were proposed as candidate genes for forage quality. Of all the candidate genes proposed by GWAS, we only found a C3H gene (ZmC3H2) that is directly involved in cell wall component biosynthesis. The candidate genes found in this study are mainly involved in signal transduction, stress resistance, and transcriptional regulation of cell wall biosynthetic gene expression. Adding high digestibility maize into the association panel would be helpful for increasing genetic variability and identifying more genes associated with forage quality traits. Cloning and functional validation of these genes would be helpful for understanding the molecular mechanism of the fiber content and digestibility. These findings provide us new insights into cell wall formation and deposition.

  19. Genome-wide analysis reveals the vacuolar pH-stat of Saccharomyces cerevisiae.

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    Christopher L Brett

    Full Text Available Protons, the smallest and most ubiquitous of ions, are central to physiological processes. Transmembrane proton gradients drive ATP synthesis, metabolite transport, receptor recycling and vesicle trafficking, while compartmental pH controls enzyme function. Despite this fundamental importance, the mechanisms underlying pH homeostasis are not entirely accounted for in any organelle or organism. We undertook a genome-wide survey of vacuole pH (pH(v in 4,606 single-gene deletion mutants of Saccharomyces cerevisiae under control, acid and alkali stress conditions to reveal the vacuolar pH-stat. Median pH(v (5.27±0.13 was resistant to acid stress (5.28±0.14 but shifted significantly in response to alkali stress (5.83±0.13. Of 107 mutants that displayed aberrant pH(v under more than one external pH condition, functional categories of transporters, membrane biogenesis and trafficking machinery were significantly enriched. Phospholipid flippases, encoded by the family of P4-type ATPases, emerged as pH regulators, as did the yeast ortholog of Niemann Pick Type C protein, implicated in sterol trafficking. An independent genetic screen revealed that correction of pH(v dysregulation in a neo1(ts mutant restored viability whereas cholesterol accumulation in human NPC1(-/- fibroblasts diminished upon treatment with a proton ionophore. Furthermore, while it is established that lumenal pH affects trafficking, this study revealed a reciprocal link with many mutants defective in anterograde pathways being hyperacidic and retrograde pathway mutants with alkaline vacuoles. In these and other examples, pH perturbations emerge as a hitherto unrecognized phenotype that may contribute to the cellular basis of disease and offer potential therapeutic intervention throu