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Bipolar Disorder Risk Loci Reported From Psychiatric Genomics Consortium GWAS

NEW YORK (GenomeWeb) – Members of the Psychiatric Genomics Consortium's Bipolar Disorder Working Group have tracked down dozens of common genetic contributors to bipolar disorder in a genome-wide association study involving tens of thousands of cases and controls from around the world.

"By discovering new genes associated with bipolar disorder and demonstrating their overlap with genes found in other psychiatric disorders, we bring ourselves closer to finding the true genetic underpinnings of the disease and improving patient outcomes," co-first author Eli Stahl, a genetics, genomics, psychiatry, and population genetics researcher affiliated with the Icahn School of Medicine at Mount Sinai and the Broad Institute, said in a statement.

As they reported online today in Nature Genetics, the researchers started with a discovery GWAS that included 20,352 individuals with bipolar disorder and 31,358 unaffected controls of European descent from 14 countries, including Australia and sites in Europe and North America. Following a validation step to assess 822 suspicious variants in another 9,412 cases and 137,769 unaffected controls, along with a combined analysis of the discovery and validation data, they were left with significant bipolar disorder associations for variants at 10 known and 20 new loci.

The team's subsequent functional enrichment and pathway analyses suggest that sites in and around genes from insulin secretion and endocannabinoid signaling pathways were particularly over-represented among the bipolar disease risk loci. The analysis also highlighted subtle differences in the loci coinciding with the type I, type II, or schizoaffective disorder subtypes of bipolar disorder, along with distinct genetic overlap with other neuropsychiatric conditions depending on the type of bipolar disorder involved.

The authors saw overlap with schizophrenia at eight risk loci, though three of those sites showed independent ties to each of the neuropsychiatric conditions, for example. They noted that shared and distinct associations for bipolar disorder and schizophrenia "may represent opportunities to understand the genetic distinctions between these closely related and sometimes clinically difficult to distinguish disorders."

Genetic overlap appeared to be particularly prominent for the subset of almost 14,900 individuals with type I bipolar disorder — a form of the disease characterized by alternating depressive and manic episodes.

On the other hand, the team did not detect loci with genome-wide significant ties to bipolar disorder subtype in the more than 3,400 individuals with bipolar disorder who reported hypomanic episodes and depressive symptoms that lined up with type II forms of the disease, or in the 977 individuals with schizoaffective disorder-bipolar type, in part due to the smaller sample sizes. The results hinted that type II bipolar disorder may overlap to some extent with major depressive disorder, though the GWAS analysis did not pick up genome-wide significant associations with depression-associated loci reported in the past. 

The authors concluded that these and other findings from the study "reveal an extensive polygenic genetic architecture of the disease, implicate brain calcium channels and neurotransmitter function in [bipolar disorder] etiology, and confirm that [bipolar disorder] is part of a spectrum of highly correlated psychiatric and mood disorders."