The largest ever study of gene associations in bipolar disorder has been completed by Mount Sinai School of Medicine researchers and has identified 30 genome-wide significant loci, including 20 that are novel. More than 50,000 subjects in 14 countries and more than 200 collaborating institutions participated in this large-scale genome-wide association (GWAS) study. The group’s results were reported in the May 2019 issue of Nature Genetics.
Bipolar disorder is one of the most prevalent mental illnesses in the world, affecting over 60 million globally and causing significant morbidity and mortality. Typical symptoms are dramatic mood fluctuations with alternate episodes of elevation (mania) and depression, between periods of euthymia. The cause of this disease has not yet been elucidated, but there is significant evidence genetics and environmental factors play major roles. There some treatments for bipolar disorder, but diagnosis is difficult and patients’ responses to treatment vary.
This study included 20,352 cases and 31,358 controls of European descent. Follow-up analysis was carried out on 822 variants in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant in the discovery phase were found to be significant in the combined analysis. Combined analysis showed a total of 30 loci that were genome-wide significant, including 20 that were newly identified.
The genome-wide significant loci were associated with ion channels, neurotransmitter transporters, and synaptic components. Pathway analysis found nine significantly enriched gene sets. These included insulin secretion regulation and endocannabinoid signaling
Bipolar disorder is highly heritable, based on research including twin studies. But that effect is mostly attributable to common variants of small effect. “The crux of this international collaborative study was, in essence, to connect the dots,” said Eli Stahl, Ph.D., assistant professor of genetics and psychiatry, at the Icahn School of Medicine at Mount Sinai. “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.”
The researchers also looked at the relationship between bipolar disorder and other psychiatric illnesses, since such disorders often share symptoms. There are four types of bipolar disorder, each with different mixes of symptoms, including clyclothymic disorder and “other specified and unspecified bipolar and related disorders. Not much is known about the relationship of these conditions to other psychiatric illnesses, but Bipolar I disorder (driven by psychosis) is more strongly correlated with schizophrenia, whereas bipolar II disorder (which does not feature full-blown manic episodes) is more strongly correlated with major depressive disorders.
The Mount Sinai study found that eight of the genes they uncovered that were associated with bipolar disorder were also associated with schizophrenia. Depression, autism spectrum disorder, anorexia nervosa and other psychiatric conditions also had genetic ties to bipolar disorder.
“These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder,” the researchers wrote in their Nature paper.