Psychiatric Polygenic Risk Scores Across Youth With Bipolar Disorder, Youth at High Risk for Bipolar Disorder, and Controls

Objective: There is a pronounced gap in knowledge regarding polygenic underpinnings of youth bipolar disorder (BD). This study aimed to compare polygenic risk scores (PRSs) in youth with BD, youth at high clinical and/or familial risk for BD (HR), and controls. Method: Participants were 344 youths of European ancestry (13-20 years old), including 136 youths with BD, 121 HR youths, and 87 controls. PRSs for BD, schizophrenia, major depressive disorder, and attention-deficit/hyperactivity disorder were constructed using independent genome-wide summary statistics from adult cohorts. Multinomial logistic regression was used to examine the association between each PRS and diagnostic status (BD vs HR vs controls). All genetic analyses controlled for age, sex, and 2 genetic principal components. Results: The BD group showed significantly higher BD-PRS than the control group (odds ratio = 1.54, 95% CI = 1.13-2.10, p = .006), with the HR group numerically intermediate. BD-PRS explained 7.9% of phenotypic variance. PRSs for schizophrenia, major depressive disorder, and attentiondeficit/hyperactivity disorder were not significantly different among groups. In the BD group, BD-PRS did not significantly differ in relation to BD subtype, age of onset, psychosis, or family history of BD. Conclusion: BD-PRS derived from adult genome-wide summary statistics is elevated in youth with BD. Absence of significant between-group differences in PRSs for other psychiatric disorders supports the specificity of BD-PRS in youth. These fi ndings add to the biological validation of BD in youth and could have implications for early identification and diagnosis. To enhance clinical utility, future genome-wide association studies that focus specifically on early-onset BD are warranted, as are studies integrating additional genetic and environmental factors. Plain language summary: Polygenic risk scores estimate an individual's genetic susceptibility to develop a disorder, such as bipolar disorder (BD). In this study, the authors constructed polygenic risk scores from previous adult studies. Youth with BD had elevated polygenic risk scores for BD compared to youth without bipolar disorder. Youth at high risk for BD had intermediate polygenic risk scores. To evaluate the specificity of polygenic risk scores for BD, the authors estimated risk scores for other mental health disorders including schizophrenia, major depressive disorder, and attentiondeficit/hyperactivity disorder. These other polygenic risk scores did not differ between youth with and without BD. These fi ndings support the biological validation of BD in youth, with potential implications for early identification and diagnosis. Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who in the data collection, and/or of the work.