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Genome-Wide Association Study of Bipolar Disorder In Molecular Psychiatry (2009) 14, 755–763 & 2009 Nature Publishing Group All rights reserved 1359-4184/09 $32.00 www.nature.com/mp IMMEDIATE COMMUNICATION Genome-wide association study of bipolar disorder in European American and African American individuals EN Smith1,2,24, CS Bloss1,3,24, JA Badner4, T Barrett5, PL Belmonte6, W Berrettini7, W Byerley8, W Coryell9, D Craig10, HJ Edenberg11,12, E Eskin13, T Foroud12, E Gershon4, TA Greenwood14, M Hipolito15, DL Koller16, WB Lawson15, C Liu4, F Lohoff7, MG McInnis17, FJ McMahon18, DB Mirel19, SS Murray1,2,3, C Nievergelt14, J Nurnberger16, EA Nwulia15, J Paschall20, JB Potash6, J Rice21, TG Schulze18, W Scheftner22, C Panganiban10, N Zaitlen13, PP Zandi6,SZo¨llner17, NJ Schork1,2,3 and JR Kelsoe14,23 1Scripps Genomic Medicine, Scripps Translational Science Institute, La Jolla, CA, USA; 2Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA; 3Scripps Health, La Jolla, CA, USA; 4Department of Psychiatry, University of Chicago, Chicago, IL, USA; 5Department of Psychiatry, Portland VA Medical Center, Portland, OR, USA; 6Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, USA; 7Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA; 8Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA; 9Department of Psychiatry, University of Iowa, Iowa City, IA, USA; 10Neurogenomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA; 11Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA; 12Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA; 13Department of Computer Science, University of California, Los Angeles, Los Angeles, CA, USA; 14Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; 15Department of Psychiatry, Howard University, Washington, DC, USA; 16Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA; 17Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA; 18Genetic Basis of Mood and Anxiety Disorders Unit, National Institute of Mental Health Intramural Research Program, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA; 19Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA, USA; 20National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA; 21Division of Biostatistics, Washington University, St Louis, MO, USA; 22Department of Psychiatry, Rush University, Chicago, IL, USA and 23Department of Psychiatry, VA San Diego Healthcare System, La Jolla, CA, USA To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n = 1001 cases; n = 1033 controls), and one involving a sample of individuals of African ancestry (AA; n = 345 cases; n = 670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P =1.6Â 10À6) and rs10193871 in NAP5 at 2q21.2 (P =9.8Â 10À6). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P =1.5Â 10À6) and rs2769605 in NTRK2 at 9q21.33 (P =4.5Â 10À5). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P =1.4Â 10À6), rs4657247 in RGS5 at 1q23.3 (P =4.1Â 10À6), and rs7078071 in BTBD16 at 10q26.13 (P =4.5Â 10À6). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry. Molecular Psychiatry (2009) 14, 755–763; doi:10.1038/mp.2009.43; published online 2 June 2009 Keywords: ANK3 ; Bipolar Genome Study; genetic background; allelic heterogeneity; GAIN Correspondence: Dr NJ Schork, Department of Molecular and Introduction Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Avenue, MEM 275, La Jolla, CA 92037, USA. Bipolar disorder (BD) is a paradigmatic complex E-mail: [email protected] 24These authors contributed equally to this work. phenotype with many genetic and nongenetic deter- Received 6 January 2009; revised 3 April 2009; accepted 13 April minants. BD is characterized by episodes of mania 2009; published online 2 June 2009 and depression.1 Onset is usually in late adolescence, GWA study of bipolar disorder EN Smith et al 756 although BD typically recurs and relapses throughout standard single locus analyses within the EA and AA life. BD affects approximately 1% of the world’s groups, we also assessed the extent to which single- population, and carries a lifetime risk for completed nucleotide polymorphisms (SNPs) exhibited evidence suicide as high as 17%. Family, twin and adoption of genetic background-dependent effects or allelic studies all support a substantial genetic component in heterogeneity across the EA and AA individuals. BD.2–4 The sibling recurrence risk is between 7 and 10, Although more than 190 GWA studies have been and heritability is estimated to be about 80%. Although performed to date,12 these studies have virtually all this is consistent with a strong genetic component, the been with EA subjects (NHGRI catalog of published identification of specific genetic variations that influ- GWA studies: http://www.genome.gov/gwastudies/), ence BD susceptibility has been difficult. raising important questions as to the generalizability Although some family studies have suggested that of the results to other populations. We assessed the BD has an autosomal dominant genetic determinant, consistency of the SNPs exhibiting the strongest the vast majority of genetic studies suggest that BD associations with BD in our study with previously has a high level of genetic heterogeneity and a published results of BD GWA studies. We tested substantial polygenic component.5,6 Linkage studies variation at ANK3, which is a candidate gene that was have identified a number of loci with inconsistent implicated in an earlier GWA study15 and identified replication. Although previous linkage studies were as genome-wide significant in a recent collaborative highly divergent,7 recent meta-analyses of linkage analysis.17 Finally, we genotyped a subset of SNPs in studies have found consistent supportive evidence for the regions exhibiting strongest association in a linkage to a few potential BD susceptibility loci,8–10 replication case–control group and tracked the co- notably 6q, 8q, 13q and 22q. A number of polymor- inheritance of these SNPs with disease in families. phisms in a variety of candidate genes have been tested for association with BD, but most have shown no statistically compelling associations; those that Materials and methods appear to be associated show odds ratios (OR) of 1.1– We provide detailed information in the Supplemen- 1.3, which is again consistent with a polygenic basis tary material regarding study subjects, genotyping 11 for BD. and quality control. The final number of BD cases In the last several years, the development of was 1001 EA subjects and 345 AA subjects; control genome-wide association (GWA) study designs and counts were 1033 EA subjects and 670 AA subjects. analysis methods have made it possible to search for The final data set consisted of 724 067 SNPs in the EA multiple genetic variations underlying a condition data set and 840 730 SNPs in the AA data set. The like BD without a priori assumptions about the genes two data sets had 702 044 SNPs in common, and or genomic regions that might harbor susceptibility these SNPs were used to perform analyses addressing 12 variations. The GWA study approach has revealed SNP and SNP Â genetic background interactions in a number of genetic variations that are unequivocally the combined sample. associated with many different traits and diseases.13,14 The US National Institutes of Mental Health– Statistical analysis sponsored Genetics Initiative for Bipolar Disorder Consortium (Bipolar Consortium) collected over Primary analyses. All genetic analyses were 3500 subjects with BD during 1990–2008. A genetic conducted using PLINK18 versions 1.03 and 1.04. component of the Bipolar Consortium, termed the Our primary analyses tested the association of each ‘Bipolar Genome Study’ (BiGS), was initiated in 2006 SNP (coded additively) with BD using three distinct to conduct a GWA study of BD. The initial BiGS GWA methods that control for genetic background study was funded through the Foundation for the heterogeneity (Table 1): (1) single locus, contingency National Institutes of Health Genetic Information table analysis with genomic control adjustment, (2) Association Network (GAIN) initiative (http://www. logistic regression using Local Ancestry in Admixed genome.gov/19518664) and we report the results of Populations (LAMP19)-derived estimates of ancestry this
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