Meta-analysis of genome-wide association data identifies a risk locus for major mood disorders on 3p21.1

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The major mood disorders, which include bipolar disorder and major depressive disorder (MDD), are considered heritable traits, although previous genetic association studies have had limited success in robustly identifying risk loci. We performed a meta-analysis of five case-control cohorts for major mood disorder, including over 13,600 individuals genotyped on high-density SNP arrays. We identified SNPs at 3p21.1 associated with major mood disorders (rs2251219, P = 3.63 × 10−8; odds ratio = 0.87; 95% confidence interval, 0.83–0.92), with supportive evidence for association observed in two out of three independent replication cohorts. These results provide an example of a shared genetic susceptibility locus for bipolar disorder and MDD.

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Figure 1: Genome-wide association results and detail of peak association region.

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Genotyping of the GAIN major depression and NIMH bipolar disorder samples was provided through the Genetic Association Information Network (GAIN), Foundation for NIH (the US National Institutes of Health). The data sets used for the analyses described in this manuscript were obtained from the Database of Genotypes and Phenotypes (dbGaP). Samples and associated phenotype data were provided by the contributing studies. We thank the Wellcome Trust Case Control Consortium, the STEP-BD group, the Netherlands Study of Depression and Anxiety and the Netherlands Twin Registry for making data or results available for analysis. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH. Postmortem brain tissue was supplied by the Stanley Medical Research Institute. Additional acknowledgments are included in the Supplementary Note. Funded by the US NIMH Intramural Research Program, Deutsche Forschungsgemeinschaft (DFG), the National Genome Research Network (NGFN) of the Federal German Ministry of Education and Research, NARSAD (Independent Investigator Award to F.J.M. and Young Investigator Award to T.G.S.), the National German Genome Research Network Plus (NGFNplus) and the MooDS-Net (grant 01GS08144 to S.C. and M.M.N., grant 01GS08147 to M.R.) of the Federal German Ministry of Education and Research, the Heinz Nixdorf Foundation (G. Schmidt, chairman), the Alfried Krupp von Bohlen und Halbach-Stiftung, the DFG Graduate College 793, University of Heidelberg and grants from the NIMH and US National Human Genome Research Institute to J.R.K. (MH078151, MH081804, MH059567 supplement). This research was also supported in part by the Intramural Research Program of the National Library of Medicine, NIH. The replication samples were supported by the Swiss National Science Foundation (3200B0–105993, 32003B-118308 and 33CSCO-122661) and GlaxoSmithKline (Psychiatry Center of Excellence for Drug Discovery and Genetics Division, Verona).

Author information

F.J.M. designed the study, led the analysis and wrote the manuscript. N.A., T.G.S. and C.J.M.S. contributed to the data management and analysis. S.D.D.-W., T.G.S., P.M., W.M., F.H., M.R., J.I.N. and H.J.E. (the latter two are members of the BiGS Consortium) edited the manuscript. J.R.W. performed the gene expression experiments. P.M., F.T., R.B., J.S., M.M., T.W.M., W.M, M.M.N., S.C., A.F., J.B.V., F.H., M.P., M.R. and BiGS Consortium members collected samples and/or shared genetic association results. All authors reviewed the manuscript.

Correspondence to Francis J McMahon.

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A full membership list is provided in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2, Supplementary Tables 2–5 and Supplementary Note (PDF 597 kb)

Supplementary Table 1

Complete results of meta-analysis for 317,889 SNPs in five study samples. (XLS 13555 kb)

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