Genome-wide association study identifies 30 loci associated with bipolar disorder

Abstract

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10−4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10−8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

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Fig. 1: Manhattan plot for our primary genome-wide association analysis of 20,352 cases and 31,358 controls.
Fig. 2: Association of BD1 and BD2 subtypes with SCZ and DEPR PRS.

Data availability

The PGC’s policy is to make genome-wide summary results public. Summary statistics for our meta-analysis are available through the PGC (https://www.med.unc.edu/pgc/results-and-downloads). Data are accessible with collaborative analysis proposals through the Bipolar Disorder Working Group of the PGC (https://med.unc.edu/pgc).

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Acknowledgements

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar Disorder Working Group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org), hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu). PGC members have received major funding from the US National Institute of Mental Health. This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M. O’Neil and Betty C. Lynch. The views expressed are those of the authors and not necessarily those of their institutions or any funding or regulatory bodies. Additional acknowledgements, including funding sources, are presented in the Supplementary Note.

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Writing group: E.A.S., G.B., A.J.F., A. McQuillin, S.R., J.R.I.C., N.M., N.R.W., A.D.F., H.J.E., S.C., R.A.O., L.J.S., O.A.A. and J.K. PGC BD principal investigator group: E.A.S., G.B., A.J.F., A. McQuillin, D. Curtis, R.H.P., R.A., I.A., M.A., L.B., B.T.B., F.B., W.H.B., J.M.B., D.H.R.B., M. Boehnke, A.D.B., A.C., N.C., U.D., T. Esko, B.E., M. Frye, J.M.F., E.S.G., M.G., F.G., M.G.-S., J.H., D.M.H., C.M.H., I.J., L.A.J., R.S.K., M. Landén, M. Leboyer, C.M.L., Q.S.L., J. Lissowska, N.G.M., S.L.M., A.M.M., F.J.M., I.M., A. Metspalu, P.B. Mitchell, G.M., O.M., P.B. Mortensen, B.M.-M., R.M.M., B.M.N., V.N., M.N., M.M.N., M.C.O’D., K.J.O., M.J.O., S.A.P., C.P., M.T.P., J.A.R.-Q., M. Ribasés, M. Rietschel, G.A.R., M. Schalling, P.R.S., T.G.S., A.S., J.W.S., H.S., K.S., E. Stordal, G.T., A.E.V., E.V., J.B.V., T.W., J.I.N., A.D.F., H.J.E., S.C., R.A.O., L.J.S., O.A.A., J.K. and P.S. Bioinformatics: E.A.S., G.B., A.J.F., J.R.I.C., H.A.G., P.A.H., S.E.B., D.W.C., V.E.-P., C.G., M.L.H., S.H., R. Karlsson, M. Leber, C. Liu, F. Meng, L.M.O.L., A.P.S.O., C.S.R., P.R., P.D.S., M. Steffens, S. Szelinger, T.E.T., S.X., P. Zandi, eQTLGen Consortium, BIOS Consortium, T. Esko, E.S.G., Q.S.L., G.A.R. and H.S. Clinical: A. McQuillin, M.M., E.A., N.A.-R., A.A., N.B., M. Bauer, C.B.P., E.B., M.P.B., M. Budde, M. Burmeister, W. Byerley, M.C., P.C., W.C., D. Curtis, P.M.C., J.R.D., T. Elvsåshagen, L. Forty, C.F., K.G., J. Garnham, M.G.P., K.G.-S., M.J.G., J. Grove, J.G.-P., M. Hautzinger, U.H., M. Hipolito, A.J., J.L.K., S.K.-S., M.K., R. Kupka, C. Lavebratt, J. Lawrence, W.B.L., S.L., D.J.M., P.B. Mahon, W.M., L. Martinsson, P.M., M.G.M., H.M., A.N.A., E.A.N., C.O’D., L.O., U.Ö., R.H.P., A. Perry, A. Pfennig, J.B.P., E.J.R., A.R., J.P.R., F.R., M. Rivera, W.A.S., C.S.W., E. Sigurdsson, C.S., O.B.S., J.L.S., A.T.S., D.S.C., J.S.S., F.S., J.S., R.C.T., H.V., T.W.W., A.H.Y., R.A., I.A., M.A., B.T.B., F.B., D.H.R.B., A.D.B., A.C., N.C., U.D., B.E., M. Frye, E.S.G., M.G., F.G., M.G.-S., J.H., I.J., L.A.J., R.S.K., G.K., M. Landén, J. Lissowska, N.G.M., F. Mayoral, S.L.M., A.M.M., F.J.M., I.M., P.B. Mitchell, G.M., O.M., P.B. Mortensen, V.N., M.C.O’D., K.J.O., M.J.O., C.P., M.T.P., J.A.R.-Q., M. Rietschel, T.G.S., A.S., J.W.S., E. Stordal, A.E.V., E.V., J.I.N. and A.D.F. Genomic assays/data generation: G.B., A.J.F., E.A., D.A., M.B.-H., C.B.P., J.B.-G., T.-K.C., D.W.C., C. Cruceanu, F.D., J.D.-F., S.D., S.B.F., J.F., M.G.P., E.K.G., P.H., S.J., R. Kandaswamy, A.C.K., S.E.L., A. Maaser, J.D.M., L. Milani, G.W.M., D.W.M., T.W.M., E.R., C.S.-M., T.S., C.S.H., S. Szelinger, J.T., S.H.W., P. Zhang, A.C., T. Esko, J.M.F., E.S.G., M.G., D.M.H., R.M.M., M.M.N., M. Ribasés, G.A.R., G.T. and S.C. Obtained funding for BD samples: G.B., H.A., N.A.-R., J.D.B., W. Bunney, J.R.D., N.B.F., L. Frisén, M.J.G., S.J., J.A.K., C. Lavebratt, S.L., P.M., G.W.M., U.Ö., J.B.P., M. Rivera, A.F.S., C.S.W., S.J.W., T.W.W., A.H.Y., M.A., B.T.B., W.H.B., J.M.B., M.Boehnke, A.D.B., A.C., N.C., M. Frye, J.M.F., E.S.G., M.G., M.G.-S., I.J., L.A.J., M. Landén, M. Leboyer, C.M.L., N.G.M., A. Metspalu, P.B. Mitchell, O.M., P.B. Mortensen, B.M.N., M.N., M.M.N., M.C.O’D., M.J.O., C.P., M.T.P., M. Rietschel, G.A.R., P.R.S., T.G.S., J.W.S., G.T., J.B.V., T.W., J.I.N., H.J.E., R.A.O. and P.S. Statistical analysis: E.A.S., G.B., S.R., V.T., M.M., Y.W., J.R.I.C., H.A.G., C.A.d.L., S. Steinberg, J.M.W.P., M.T., E.M.B., T.H.P., P.A.H., A.L.R., L.A., N.A.-R., T.D.A., V.A., S.A., J.A.B., R.B., S.E.B., J.B., F.C., K.C., A.W.C., D. Chen, C. Churchhouse, A.M.D., S.d.J., A.L.D., A.D., V.E.-P., C.C.F., M. Flickinger, T.M.F., D.G., C.G., J. Goldstein, S.D.G., T.A.G., J. Grove, W.G., M.L.H., D.H., L.H., J.S.J., R. Karlsson, M. Leber, P.H.L., J.Z.L., S.M., S.E.M., D.W.M., N.M., H.N., C.M.N., L.M.O.L., A.P.S.O., S.M.P., C.S.R., P.R., D.M.R., N.J.S., O.B.S., T.E.T., W.W., W.X., P. Zandi, P. Zhang, S.Z., eQTLGen Consortium, BIOS Consortium, J.M.B., A.D.B., M.J.D., E.S.G., F.G., Q.S.L., B.M.-M., D.P., H.S., P.F.S., N.R.W. and P.S.

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Correspondence to Eli A. Stahl or John Kelsoe.

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T.E.T., S. Steinberg, H.S. and K.S. are employed by deCODE Genetics/Amgen. Multiple additional authors work for pharmaceutical or biotechnology companies in a manner directly analogous to academic co-authors and collaborators. A.H.Y. has given paid lectures and is on advisory boards for the following companies with drugs used in affective and related disorders: Astra Zeneca, Eli Lilly, Janssen, Lundbeck, Sunovion, Servier, Livanova. A.H.Y. is Lead Investigator for Embolden Study (Astra Zeneca), BCI Neuroplasticity Study and Aripiprazole Mania Study, which are investigator-initiated studies from Astra Zeneca, Eli Lilly, Lundbeck and Wyeth. J.N. is an investigator for Janssen. P.F.S. reports the following potentially competing interests: Lundbeck (advisory committee), Pfizer (Scientific Advisory Board member) and Roche (grant recipient, speaker reimbursement). G.B. reports consultancy and speaker fees from Eli Lilly and Illumina and grant funding from Eli Lilly. O.A.A. has received speaker fees from Lundbeck. J.A.R.-Q. was on the speakers’ bureau and/or acted as consultant for Eli Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab and Rubió in the last 5 years. He also received travel awards (air tickets and hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire and Eli Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli Lilly, Lundbeck, Janssen-Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious and Rubió. E.V. has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, Astra Zeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Catalan Government (AGAUR and PERIS), the Spanish Ministry of Science, Innovation, and Universities (AES and CIBERSAM), the Seventh European Framework Programme and Horizon 2020 and the Stanley Medical Research Institute. T. Elvsåshagen has received speaker fees from Lundbeck. All other authors declare no competing interests.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–7 and Supplementary Notes

Reporting Summary

Supplementary Tables

Supplementary Tables 1–18

Supplementary Data 1

Regional association plots for all 31 lead SNPs in the 30 genome-wide-significant loci.

Supplementary Data 2

Forest plots of the 32 primary GWAS datasets for all 31 lead SNPs in the 30 genome-wide-significant loci.

Supplementary Data 3

Forest plots of the 7 follow-up datasets for all 31 lead SNPs in the 30 genome-wide-significant loci.

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