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

• Type of Material: Article
• Authors: Irwin Waldman, Emory University; Mark Rapaport, Emory University
• Language: English
• Date: 2021-05-17
• Publisher: Nature Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use
• Final Published Version (URL): http://dx.doi.org/10.1038/s41588-021-00857-4
• Title of Journal or Parent Work: NATURE GENETICS
• Volume: 53
• Issue: 6
• Start Page: 817
• End Page: 829
• Grant/Funding 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. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Research Categories: Psychology, Cognitive; Psychology, Behavioral; Biology, Genetics

Abstract

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.