JAMA Psychiatry: Genetic Variants Are Associated with Risk for Bipolar Disorder

Bipolar disorder (BD) is a familial illness that is associated with functional impairment and increased risk for suicide and substance use. The disorder is highly heritable, and research has identified many common genetic variants associated with risk for the disorder. Studies including the Pittsburgh Bipolar Offspring Study (BIOS) have found that offspring of parents with BD are at elevated, specific risk to develop the disorder compared with individuals without a family history of BD. 

While parental early-onset bipolar disorder and symptoms of depression/anxiety, mood lability, and subclinical mania are associated with higher risk of BD, these factors alone are insufficient to predict the development of the disorder. The polygenic risk score, reflecting the combined effects of many genetic variants, is robustly associated with an individual’s risk to develop bipolar disorder. 

A team led by Boris Birmaher, MD (Distinguished Professor of Psychiatry and Endowed Chair in Early Onset Bipolar Disease); and including Danella Hafeman, MD, PhD (Assistant Professor of Psychiatry); Tina Goldstein, PhD (Associate Professor of Psychiatry and Psychology); Dara Sakolsky, MD (Associate Professor of Psychiatry); Rasim Diler, MD (Professor of Psychiatry); and Vishwajit Nimgaonkar, MD, PhD (Professor of Psychiatry and Human Genetics), examined bipolar disorder polygenic risk score in the offspring of patients with the disorder and published the findings in JAMA Psychiatry. 

Study participants, recruited from BIOS, comprised 336 parents, both with and without bipolar disorder I/II, and 409 offspring. Participants were prospectively evaluated using standardized interviews blind to parental diagnosis. The team extracted and genotyped participants’ DNA, and constructed polygenic risk scores based on independent, large-scale, and genome-wide association studies for bipolar disorder, unipolar major depressive disorder, attention deficit/hyperactivity disorder, and schizophrenia.

For both parents and their offspring, results of the analysis showed significantly and specifically higher bipolar disorder polygenic risk scores than those without BD. There were no between-group differences for the polygenic scores for the other psychiatric disorders. Parental and offspring bipolar disorder polygenic risk scores were associated with increased risk for offspring to develop BD, beyond the associations of parental bipolar diagnosis.

“Having compared the genetic structure of parents vs. their children, we found that both are very similar and, importantly, specific for bipolar disorder,” said Dr. Birmaher, the study’s corresponding author. “We believe that the results of this paper will add biological evidence to the current literature supporting the validity of pediatric bipolar disorder.”

Role of Polygenic Risk Score in the Familial Transmission of Bipolar Disorder in Youth
Birmaher B, Hafeman D, Merranko J, Zwicker A, Goldstein B, Goldstein T, Axelson D, Monk K, Hickey MB, Sakolsky D, Iyengar S, Diler R, Nimgaonkar V, Uher R.

JAMA Psychiatry. Published online December 22, 2021. doi:10.1001/jamapsychiatry.2021.3700