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 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. ### Competing Interest Statement T.E. Thorgeirsson, S. Steinberg, H. Stefansson and K. Stefansson 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. Young has given paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Astrazenaca, Eli Lilly, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma. A.H. Young was Lead Investigator for Embolden Study (Astra Zeneca), BCI Neuroplasticity study and Aripiprazole Mania Study. Also an investigator for Janssen, Lundbeck, Livanova, Compass. J. Nurnberger is an investigator for Janssen. P.F. Sullivan 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. Landen has received speaker fees from Lundbeck. O.A. Andreassen has received speaker fees from Lundbeck. J.Antoni Ramos-Quiroga was on the speakers bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab, and Rubio in the last 5 years. He also received travel awards (air tickets + hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubio, 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 Rubio. Dr. E. Vieta has received grants and served as 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, 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. Elvsashagen has received speaker fees from Lundbeck. S. Kittel-Schneider received author and consultant honoraria from Medice Arzneimittel Putter GmbH and Shire/Takeda. Prof. Serretti is or has been consultant/speaker for: Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier. J.R. DePaulo has served as an unpaid consultant to Myriad-Neuroscience (formerly Assurex Health) in 2017 and 2019 and owns stock in CVS Health. H.R. Kranzler serves as an advisory board member for Dicerna Pharmaceuticals, is a member of the American Society of Clinical Psychopharmacology Alcohol Clinical Trials Initiative, which was sponsored in the past three years by AbbVie, Alkermes, Amygdala Neurosciences, Arbor Pharmaceuticals, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, and Pfizer. HRK is named as an inventor on PCT patent application #15/878,640 entitled: "Genotype-guided dosing of opioid agonists," filed January 24, 2018. ALM and CL are employees of Indivior, Inc. AA was an employee of Indivior, Inc. at the time the work was performed. All other authors declare no financial interests or potential conflicts of interest. ### Funding Statement 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 () hosted by SURFsara and the Mount Sinai high performance computing cluster (), which is supported by the Office of Research Infrastructure of the National Institutes of Health under award numbers S10OD018522 and S10OD026880. Full details of all funding sources are included in the Supplementary Note. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Boards that provided approval or exemption for each cohort are given in Supplementary Table 1. All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes GWAS summary statistics are publicly available on the PGC website (). Individual-level data are accessible through collaborative analysis proposals to the Bipolar Disorder Working Group of the PGC (). This study included some publicly available datasets accessed through dbGaP (PGC bundle phs001254.v1.p1) and the Haplotype Reference Consortium reference panel v1.0 (). Databases used: Drug-Gene Interaction Database DGIdb v.2 Psychoactive Drug Screening Database Ki DB DrugBank 5.0 [www.drugbank.ca][1] LDHub FUMA [1]: http://www.drugbank.ca