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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.
Bipolar disorder (BD) is a complex mental disorder characterized by recurrent episodes of (hypo)mania and depression. It is a common condition affecting an estimated 40 to 50 million people worldwide1. This, combined with the typical onset in young adulthood, an often chronic course and increased risk of suicide2, makes BD a major public health concern and a major cause of global disability1. Clinically, BD is classified into two main subtypes: bipolar I disorder (BD I), in which manic episodes typically alternate with depressive episodes, and bipolar II disorder (BD II), characterized by the occurrence of at least one hypomanic and one depressive episode3. These subtypes have a lifetime prevalence of ~1% each in the population4,5.
Family and molecular genetic studies provide convincing evidence that BD is a multifactorial disorder, with genetic and environmental factors contributing to its development6. On the basis of twin and family studies, the heritability of BD is estimated at 60-85%7,8. Genome-wide association studies (GWASs)9-23 have led to valuable insights into the genetic etiology of BD. The largest such study has been conducted by the Psychiatric Genomics Consortium (PGC), in which genome-wide SNP data from 29,764 patients with BD and 169,118 controls were analyzed and 30 genome-wide significant loci were identified (PGC2)24. SNP-based heritability (h|NP) estimation using the same data suggested that common genetic variants genome-wide explain...