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.
Bibliographical noteFunding Information:
We thank the participants who donated their time, life experiences and DNA to this research and the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who make up the PGC. 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. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Full acknowledgements are included in the Supplementary Note.
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 coauthors and collaborators. A.H.Y. has given paid lectures and served on advisory boards relating to drugs used in affective and related disorders for several companies (AstraZeneca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allergan, Bionomics and Sumitomo Dainippon Pharma), was Lead Investigator for Embolden Study (AstraZeneca), BCI Neuroplasticity study and Aripiprazole Mania Study, and is an investigator for Janssen, Lundbeck, Livanova and Compass. J.I.N. is an investigator for Janssen. P.F.S. reports the following potentially competing financial interests: Lundbeck (advisory committee), Pfizer (Scientific Advisory Board member) and Roche (grant recipient, speaker reimbursement). G. Breen reports consultancy and speaker fees from Eli Lilly and Illumina and grant funding from Eli Lilly. M. Landén has received speaker fees from Lundbeck. O.A.A. has received speaker fees from Lundbeck and Sunovion, and is a consultant to HealthLytix. 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 a consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, AstraZeneca, Bristol Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, GlaxoSmithKline, 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. S.K.-S. received author’s and consultant honoraria from Medice Arzneimittel Pütter GmbH and Shire/Takeda. A.S. is or has been a consultant/speaker for: Abbott, Abbvie, Angelini, AstraZeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier. J.R.D. has served as an unpaid consultant to Myriad – Neuroscience (formerly Assurex Health) in 2017 and 2019 and owns stock in CVS Health. H.R.K. serves as an advisory board member for Dicerna Pharmaceuticals, and is a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was sponsored in the past 3 years by AbbVie, Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka and Pfizer. H.R.K. is named as an inventor on PCT patent application no. 15/878,640 entitled: Genotype-guided dosing of opioid agonists, filed January 24, 2018. B.M.N. is a member of the scientific advisory board at Deep Genomics and consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen. All other authors declare no financial interests or potential conflicts of interest.
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.