Genome-wide association study of over 40,000 bipolar disorder cases provides new insights into the underlying biology

Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathw...

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Published inNature genetics Vol. 53; no. 6; pp. 817 - 829
Main Authors Mullins, Niamh, Forstner, Andreas J., O’Connell, Kevin S., Coombes, Brandon, Coleman, Jonathan R. I., Qiao, Zhen, Als, Thomas D., Bigdeli, Tim B., Børte, Sigrid, Bryois, Julien, Charney, Alexander W., Drange, Ole Kristian, Gandal, Michael J., Hagenaars, Saskia P., Ikeda, Masashi, Kamitaki, Nolan, Kim, Minsoo, Krebs, Kristi, Panagiotaropoulou, Georgia, Schilder, Brian M., Sloofman, Laura G., Steinberg, Stacy, Trubetskoy, Vassily, Winsvold, Bendik S., Won, Hong-Hee, Abramova, Liliya, Adorjan, Kristina, Agerbo, Esben, Al Eissa, Mariam, Albani, Diego, Alliey-Rodriguez, Ney, Anjorin, Adebayo, Antilla, Verneri, Antoniou, Anastasia, Awasthi, Swapnil, Baek, Ji Hyun, Bækvad-Hansen, Marie, Bass, Nicholas, Bauer, Michael, Beins, Eva C., Bergen, Sarah E., Birner, Armin, Pedersen, Carsten Bøcker, Bøen, Erlend, Boks, Marco P., Bosch, Rosa, Brum, Murielle, Brumpton, Ben M., Brunkhorst-Kanaan, Nathalie, Budde, Monika, Bybjerg-Grauholm, Jonas, Byerley, William, Cairns, Murray, Casas, Miquel, Cervantes, Pablo, Clarke, Toni-Kim, Cruceanu, Cristiana, Cuellar-Barboza, Alfredo, Cunningham, Julie, Curtis, David, Czerski, Piotr M., Dale, Anders M., Dalkner, Nina, David, Friederike S., Degenhardt, Franziska, Djurovic, Srdjan, Dobbyn, Amanda L., Douzenis, Athanassios, Elvsåshagen, Torbjørn, Escott-Price, Valentina, Ferrier, I. Nicol, Fiorentino, Alessia, Foroud, Tatiana M., Forty, Liz, Frank, Josef, Frei, Oleksandr, Freimer, Nelson B., Frisén, Louise, Gade, Katrin, Garnham, Julie, Gelernter, Joel, Pedersen, Marianne Giørtz, Gizer, Ian R., Gordon, Scott D., Gordon-Smith, Katherine, Greenwood, Tiffany A., Grove, Jakob, Guzman-Parra, José, Ha, Kyooseob, Haraldsson, Magnus, Hautzinger, Martin, Heilbronner, Urs, Hellgren, Dennis, Herms, Stefan, Hoffmann, Per, Holmans, Peter A., Huckins, Laura, Jamain, Stéphane, Johnson, Jessica S., Kalman, Janos L.
Format Journal Article
LanguageEnglish
Published 17.05.2021
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Summary:Bipolar disorder (BD) is a heritable mental illness with complex etiology. We performed a genome-wide association study (GWAS) of 41,917 BD cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. BD risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics, and anesthetics. Integrating eQTL data implicated 15 genes robustly linked to BD via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of BD subtypes indicated high but imperfect genetic correlation between BD type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of BD, identify novel therapeutic leads, and prioritize genes for functional follow-up studies.
Bibliography:PGC BD PI group: A.J.F., M.I., H.-H.W., D.C., R.A., I.A., M.A., L. Alfredsson, G. Babadjanova, L.B., B.T.B., F.B., S. Bengesser, W.H.B., D.H.R.B., M. Boehnke, A.D.B., G. Breen, V.J.C., S. Catts, A.C., N.C., U.D., D.D., T. Esko, B.E., P.F., M.F., J.M.F., M.G., E.S.G., F.S.G., M.J. Green, M.G.-S., J. Hauser, F.H., J. Hillert, K.S.H., D.M.H., C.M.H., K. Hveem, N.I., A.V.J., I.J., L.A.J., R.S.K., J.R.K., G.K., M. Landén, M. Leboyer, C.M.L., Q.S.L., J. Lissowska, C. Lochner, C. Loughland, N.G.M., C.A.M., F.M., S.L.M., A.M.M., F.J.M., I.M., P. Michie, L. Milani, P.B. Mitchell, G.M., O.M., P.B. Mortensen, B.M., B.M.-M., R.M.M., B.M.N., C.M.N., M.N., M.M.N., M.C.O’D., K.J.O., T.O., M.J.O., S.A.P., C. Pantelis, C. Pato, M.T.P., G.P.P., R.H.P., D.P., J.A.R-Q., A.R., E.Z.R., M. Ribasés, M. Rietschel, S.R., G.A.R., T.S., U.S., M.S., P.R.S., T.G.S., L.J.S., R.J.S., A.S., C.S.W., J.W.S., H.S., K.S., E. Stordal, F. Streit, P.F.S., G.T., A.E.V., E.V., J.B.V., I.D.W., T.W.W., T.W., N.R.W., J-A.Z., J.M.B., J.I.N., S. Cichon, H.J.E., E.A.S., A. McQuillin, A.D.F., R.A.O., O.A.A.
Bioinformatics: N.M., A.J.F., J.R.I.C., S. Børte, M.J. Gandal, M. Kim, B.M.S., L.G.S., B.S.W., H.-H.W., N.A.-R., S.E.B., B.M.B., V.E.-P., S.H., P.A.H., Y.K., M. Koromina, M. Kubo, M. Leber, P.H.L., C. Liao, L.M.O.L., T.R., P.R., P.D.S., M.S.A., C. Terao, T.E.T., S.X., H.Y., P.P.Z., S. Bengesser, G. Breen, P.F., E.S.G., Q.S.L., G.A.R., H.S., T.W., E.A.S.
Writing group: N.M., A.J.F., K.S.O’C., B.C., J.R.I.C., J.M.B., J.I.N., S. Cichon, H.J.E., E.A.S., A. McQuillin, A.D.F., R.A.O., O.A.A.
Genomic assays/data generation: A.J.F., M.I., E.A., M.A.E., D.A., M.B.-H., E.C.B., C.B.P., J.B.-G., M. Cairns, T.-K.C., C.C., J.C., F.S.D., F.D., S.D., A.F., J.F., N.B.F., J. Gelernter, M.G.P., P.H., S.J., Y.K., H.R.K., M. Kubo, S.E.L., C. Liao, E.M., N.W.M., J.D.M., G.W.M., J.L.M., D.W.M., T.W.M., N.O’B., M. Rivera, C.S.-M., S. Sharp, C.S.H., C. Terao, C. Toma, E.-E.T., S.H.W., HUNT All-In Psychiatry, G. Breen, A.C., T. Esko, J.M.F., E.S.G., D.M.H., N.I., F.J.M., L. Milani, R.M.M., M.M.N., M. Ribasés, G.A.R., T.S., G.T., S. Cichon
Kevin S. O’Connell, Brandon Coombes, Jonathan R. I. Coleman, and Zhen Qiao contributed equally to this work and should be regarded as joint second authors.
Obtained funding for BD samples: M.I., M. Cairns, I.N.F., L. Frisén, S.J., Y.K., J.A.K., M. Kubo, C. Lavebratt, S.L., D.M., P. McGuffin, G.W.M., J.B.P., M.H.R., J.R.D., D.J. Stein, J.S.S., C. Terao, A.H.Y., P.P.Z., M.A., L. Alfredsson, L.B., B.T.B., F.B., W.H.B., M. Boehnke, A.D.B., G. Breen, A.C., N.C., B.E., M.F., J.M.F., E.S.G., M.J. Green, M.G.-S., K.S.H., K. Hveem, N.I., I.J., L.A.J., M. Landén, M. Leboyer, N.G.M., F.J.M., P.B. Mitchell, O.M., P.B. Mortensen, B.M.N., M.N., M.M.N., M.C.O’D., T.O., M.J.O., C. Pato, M.T.P., G.P.P., M. Rietschel, G.A.R., T.S., M.S., P.R.S., T.G.S., C.S.W., J.W.S., G.T., J.B.V., T.W.W., T.W., J.M.B., J.I.N., H.J.E., R.A.O.
Statistical analysis: N.M., K.S.O’C., B.C., J.R.I.C., Z.Q., T.D.A., T.B.B., S. Børte, J.B., A.W.C., O.K.D., M.J. Gandal, S.P.H., N.K., M. Kim, K.K., G.P., B.M.S., L.G.S., S. Steinberg, V.T., B.S.W., H.-H.W., V.A., S.A., S.E.B., B.M.B., A.M.D., A.L.D., V.E.-P., T.M.F., O.F., S.D.G., T.A.G., J. Grove, P.A.H., L.H., J.S.J., Y.K., M. Kubo, C. Lavebratt, M. Leber, P.H.L., S.H.M., A. Maihofer, M.M., S.A.M., S.E.M., L.M.O.L., A.F.P., T.R., P.R., D.M.R., O.B.S., C. Terao, T.E.T., J.T.R.W., W.X., J.M.K.Y., H.Y., P.P.Z., H.Z., A.D.B., G. Breen, E.S.G., F.S.G., Q.S.L., B.M.-M., C.M.N., D.P., S.R., H.S., P.F.S., T.W., N.R.W., J.M.B., E.A.S.
Clinical: O.K.D., M.I., L. Abramova, K.A., E.A., N.A.-R., A. Anjorin, A. Antoniou, J.H.B., N.B., M. Bauer, A.B., C.B.P., E.B., M.P.B., R.B., M. Brum, N.B.-K., M. Budde, W.B., M. Cairns, M. Casas, P.C., A.C.-B., D.C., P.M.C., N.D., A.D., T. Elvsåshagen, L. Forty, L. Frisén, K.G., J. Garnham, M.G.P., I.R.G., K.G.-S., J. Grove, J.G.-P., K. Ha, M. Haraldsson, M. Hautzinger, U.H., D.H., J.L. Kalman, J.L. Kennedy, S.K.-S., M. Kogevinas, T.M.K., R.K., S.A.K., J.L., H.-J.L., C. Lewis, S.L., M. Lundberg, D.J.M., W.M., D.M., L. Martinsson, M.M., P. McGuffin, H.M., V.M., C.O’D., L.O., S.P., A. Perry, A. Pfennig, E.P., J.B.P., D.Q., M.H.R., J.R.D., E.J.R., J.P.R., F.R., J.R., E.C.S., F. Senner, E. Sigurdsson, L.S., C.S., O.B.S., D.J. Smith, J.L.S., A.T.S., J.S.S., B.S., P.T., M.P.V., H.V., A.H.Y., L.Z., HUNT All-In Psychiatry, R.A., I.A., M.A., G. Babadjanova, L.B., B.T.B., F.B., S. Bengesser, D.H.R.B., A.D.B., A.C., N.C., U.D., D.D., B.E., P.F., M.F., M.G., E.S.G., F.S.G., M.J. Green, M.G.-S., J. Hauser, K.S.H., N.I., I.J., L.A.J., R.S.K., G.K., M. Landén, C.M.L., J. Lissowska, N.G.M., C.A.M., F.M., S.L.M., A.M.M., I.M., P.B. Mitchell, G.M., O.M., P.B. Mortensen, M.C.O’D., K.J.O., M.J.O., C. Pato, M.T.P., R.H.P., J.A.R.-Q., A.R., E.Z.R., M. Rietschel, T.S., T.G.S., A.S., C.S.W., J.W.S., E. Stordal, F. Streit, A.E.V., E.V., J.B.V., I.D.W., T.W.W., T.W., J.I.N., A. McQuillin, A.D.F.
Author contributions
ISSN:1061-4036
1546-1718
DOI:10.1038/s41588-021-00857-4