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

Mullins, N. et al. (2021) Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology. Nature Genetics, 53(6), pp. 817-829. (doi: 10.1038/s41588-021-00857-4) (PMID:34002096)

Abstract

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder 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 expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

• Item Type: Articles
• Additional Information: The PGC has received major funding from the US National Institute of Mental Health (PGC3: U01 MH109528; PGC2: U01 MH094421; PGC1: U01 MH085520). Statistical 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), which is supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Smith, Professor Daniel
• Authors: Mullins, N., Forstner, A. J., O'Connell, K. S., Coombes, B., Coleman, J. R.I., Qiao, Z., Als, T. D., Bigdeli, T. B., Børte, S., Bryois, J., Charney, A. W., Drange, O. K., Gandal, M. J., Hagenaars, S. P., Ikeda, M., Kamitaki, N., Kim, M., Krebs, K., Panagiotaropoulou, G., Schilder, B. M., Sloofman, L. G., Steinberg, S., Trubetskoy, V., Winsvold, B. S., Won, H.-H., Abramova, L., Adorjan, K., Agerbo, E., Al Eissa, M., Albani, D., Alliey-Rodriguez, N., Anjorin, A., Antilla, V., Antoniou, A., Awasthi, S., Hyun Baek, J., Bækvad-Hansen, M., Bass, N., Bauer, M., Beins, E. C., Bergen, S. E., Birner, A., Bøcker Pedersen, C., Bøen, E., Boks, M. P., Bosch, R., Brum, M., Brumpton, B. M., Brunkhorst-Kanaan, N., Budde, M., Bybjerg-Grauholm, J., Byerley, W., Cairns, M., Casas, M., Cervantes, P., Clarke, T.-K., Cruceanu, C., Cuellar-Barboza, A., Cunningham, J., Curtis, D., Czerski, P. M., Dale, A. M., Dalkner, N., David, F. S., Degenhardt, F., Djurovic, S., Dobbyn, A. L., Douzenis, A., Elvsåshagen, T., Escott-Price, V., Nicol Ferrier, I., Fiorentino, A., Foroud, T. M., Forty, L., Frank, J., Frei, O., Freimer, N. B., Frisén, L., Gade, K., Garnham, J., Gelernter, J., Marianne Giørtz Pedersen, M., Gizer, I. R., Gordon, S. D., Gordon-Smith, K., Greenwood, T. A., Grove, J., Guzman-Parra, J., Ha, K., Haraldsson, M., Hautzinger, M., Heilbronner, U., Hellgren, D., Herms, S., Hoffmann, P., Holmans, P. A., Huckins, L., Jamain, S., Johnson, J. S., Kalman, J. L., Kamatani, Y., Kennedy, J. L., Kittel-Schneider, S., Knowles, J. A., Kogevinas, M., Koromina, M., Kranz, T. M., Kranzler, H. R., Kubo, M., Kupka, R., Kushner, S. A., Lavebratt, C., Lawrence, J., Leber, M., Lee, H.-J., Lee, P. H., Levy, S. E., Lewis, C., Liao, C., Lucae, S., Lundberg, M., MacIntyre, D. J., Maier, W., Maihofer, A., Malaspina, D., Maratou, E., Martinsson, L., Mattheisen, M., McGregor, N. W., McGuffin, P., McKay, J. D., Medeiros, H., Medland, S. E., Millischer, V., Montgomery, G. W., Moran, J. L., Morris, D. W., Mühleisen, T. W., O'Brien, N., O'Donovan, C., Olde Loohuis, L. M., Oruc, L., Papiol, S., Pardiñas, A. F., Perry, A., Pfennig, A., Porichi, E., Potash, J. B., Quested, D., Raj, T., Rapaport, M. H., DePaulo, J. R., Regeer, E. J., Rice, J. P., Rivas, F., Rivera, M., Roth, J., Roussos, P., Ruderfer, D. M., Sánchez-Mora, C., Schulte, E. C., Senner, F., Sharp, S., Shilling, P. D., Sigurdsson, E., Sirignano, L., Slaney, C., Smeland, O. B., Sobell, J. L., Hansen, C. S., Artigas, M. S., Spijker, A. T., Stein, D. J., Strauss, J. S., Beata Świątkowska, B., Terao, C., Thorgeirsson, T. E., Toma, C., Tooney, P., Tsermpini, E.-E., Vawter, M. P., Vedder, H., Walters, J. T.R., Witt, S. H., Xi, S., Xu, W., Young, H., Young, A. H., Zandi, P. P., Zhou, H., Zillich, L., Adolfsson, R., Agartz, I., Alda, M., Alfredsson, L., Babadjanova, G., Backlund, L., Baune, B. T., Bellivier, F., Bengesser, S., Berrettini, W. H., Blackwood, D. H.R., Boehnke, M., Børglum, A. D., Breen, G., Carr, V. J., Catts, S., Corvin, A., Craddock, N., Dannlowski, U., Dikeos, D., Esko, T., Etain, B., Ferentinos, P., Frye, M., Fullerton, J. M., Gawlik, M., Gershon, E. S., Goes, F., Green, M. J., Grigoroiu-Serbanescu, M., Hauser, J., Henskens, F., Hillert, J., Hong, K. S., Hougaard, D. M., Hultman, C. M., Hveem, K., Iwata, N., Jablensky, A. V., Jones, I., Jones, L. A., Kahn, R. S., Kelsoe, J. R., Kirov, G., Mikael Landén, M., Leboyer, M., Lewis, C. M., Li, Q. S., Lissowska, J., Lochner, C., Loughland, C., Martin, N. G., Mathews, C. A., Mayoral, F., McElroy, S. L., McIntosh, A. M., McMahon, F. J., Melle, I., Michie, P., Milani, L., Mitchell, P. B., Morken, G., Mors, O., Bo Mortensen, P., Mowry, B., Müller-Myhsok, B., Myers, R. M., Neale, B. M., Nievergelt, C. M., Nordentoft, M., Nöthen, M. M., O'Donovan, M. C., Smith, D., Oedegaard, K. J., Olsson, T., Owen, M. J., Paciga, S. A., Pantelis, C., Pato, C., Pato, M. T., Patrinos, G. P., Perlis, R. H., Posthuma, D., Ramos-Quiroga, J. A., Reif, A., Reininghaus, E. Z., Ribasés, M., Rietschel, M., Rouleau, G. A., Ripke, S., Saito, T., Schall, U., Schalling, M., Schofield, P. R., Schulze, T. G., Scott, R. J., Scott, L. J., Serretti, A., Weickert, C. S., Smoller, J. W., Stefansson, H., Stefansson, K., Stordal, E., Streit, F., Turecki, G., Sullivan, P. F., Vaaler, A. E., Vieta, E., Vincent, J. B., Waldman, I. D., Weickert, T. W., Werge, T., Wray, N. R., Zwart, J.-A., Biernacka, J. M., Nurnberger, J. I., Cichon, S., Edenberg, H. J., Stahl, E. A., McQuillin, A., Di Florio, A., Ophoff, R. A., and Andreassen, O. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
• Journal Name: Nature Genetics
• Publisher: Nature Research
• ISSN: 1061-4036
• ISSN (Online): 1546-1718
• Published Online: 17 May 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Genetics 53(6): 817-829
• Publisher Policy: Reproduced in accordance with the publisher copyright policy