Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10−7). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.
Vyšlo v časopise: Genome-Wide Association of Bipolar Disorder Suggests an Enrichment of Replicable Associations in Regions near Genes. PLoS Genet 7(6): e32767. doi:10.1371/journal.pgen.1002134 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002134
1. ManolioTA 2010 Genomewide association studies and assessment of the risk of disease. N Engl J Med 363 166 176
2. HindorffLASethupathyPJunkinsHARamosEMMehtaJP 2009 Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 106 9362 9367
3. ParkJHWacholderSGailMHPetersUJacobsKB 2010 Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat Genet 42 570 575
4. YangJBenyaminBMcEvoyBPGordonSHendersAK 2010 Common SNPs explain a large proportion of the heritability for human height. Nature genetics 42 565 569
5. Lango AllenHEstradaKLettreGBerndtSIWeedonMN 2010 Hundreds of variants clustered in genomic loci and biological pathways affect human height. Nature
6. SpeliotesEKWillerCJBerndtSIMondaKLThorleifssonG 2010 Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet
7. HeidIMJacksonAURandallJCWinklerTWQiL 2010 Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet
8. WTCCC 2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 661 678
9. RischNBotsteinD 1996 A manic depressive history. Nat Genet 12 351 353
10. BarnettJHSmollerJW 2009 The genetics of bipolar disorder. Neuroscience 164 331 343
11. BaumAEAkulaNCabaneroMCardonaICoronaW 2008 A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry 13 197 207
12. SmithENBlossCSBadnerJABarrettTBelmontePL 2009 Genome-wide association study of bipolar disorder in European American and African American individuals. Mol Psychiatry 14 755 763
13. ScottLJMugliaPKongXQGuanWFlickingerM 2009 Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry. Proc Natl Acad Sci U S A 106 7501 7506
14. SchulzeTGDetera-WadleighSDAkulaNGuptaAKassemL 2009 Two variants in Ankyrin 3 (ANK3) are independent genetic risk factors for bipolar disorder. Mol Psychiatry 14 487 491
15. FerreiraMAO'DonovanMCMengYAJonesIRRuderferDM 2008 Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40 1056 1058
16. McMahonFJAkulaNSchulzeTGMugliaPTozziF 2010 Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1. Nat Genet 42 128 131
17. PurcellSMWrayNRStoneJLVisscherPMO'DonovanMC 2009 Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460 748 752
18. StoreyJDTibshiraniR 2003 Statistical significance for genomewide studies. Proc Natl Acad Sci U S A 100 9440 9445
19. LanktreeMBGuoYMurtazaMGlessnerJTBaileySD 2011 Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height. Am J Hum Genet 88 6 18
20. KeatingBJTischfieldSMurraySSBhangaleTPriceTS 2008 Concept, design and implementation of a cardiovascular gene-centric 50 k SNP array for large-scale genomic association studies. PLoS ONE 3 e3583 doi:10.1371/journal.pone.0003583
21. DicksonSPWangKKrantzIHakonarsonHGoldsteinDB 2010 Rare variants create synthetic genome-wide associations. PLoS Biol 8 e1000294 doi:10.1371/journal.pbio.1000294
22. TorkamaniATopolEJSchorkNJ 2008 Pathway analysis of seven common diseases assessed by genome-wide association. Genomics 92 265 272
23. LiYWillerCSannaSAbecasisG 2009 Genotype imputation. Annu Rev Genomics Hum Genet 10 387 406
24. PurcellSNealeBTodd-BrownKThomasLFerreiraMA 2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575
25. R Development Core Team 2008 R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0, URL http://www.R-project.org
26. 2007 Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 661 678
27. KleinRJ 2007 Power analysis for genome-wide association studies. BMC Genet 8 58
28. FaulFErdfelderELangAGBuchnerA 2007 G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39 175 191
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