Mood disorders are disabling and prevalent, especially among individuals with a family history of major depressive disorder (MDD) or bipolar disorder (BD). Early psychopathology, specifically childhood-onset disorders like anxiety and attention-deficit/hyperactivity disorder (ADHD), is a major risk factor associated with mood disorders. Genome-wide association studies (GWAS) generate a polygenic score (PGS), which can measure the genetic risk score for behavioral and psychiatric traits for an individual’s genotype.
A cohort study published in JAMA Network Open aimed to determine if PGS is more strongly associated with the onset of mood disorder than early psychopathology and BD family history. The study also examined the specificity of PGS in predicting BD compared to any onset of mood disorder and the effect of family high-risk (FHR) history on PGS.
In this retrospective cohort study, data from 7 cohort studies from Canada, Spain, the Netherlands, the United States, and Australia were collected. The study was approved by the Nova Scotia Health Authority Research Ethics Board. Informed written consent was provided by participants. Principal component analysis and genotype preparation were conducted independently by separate teams. By using EIGENSOFT version 8.0.0 smartpca, the top 10 eigenvectors were identified from the oldest offspring in each. Participants without FHR for mood disorder were compared to participants who had FHR-BD. They were continuously assessed at different intervals from July 1992 to July 2023.
The statistical analysis was conducted using four Cox regressions to estimate the link for each PGS, anxiety, ADHD, and FHR-BD with mood disorder onset. The long-rank test and Kaplan-Meier curves were used to evaluate the onset probability by familial risk status and PGS quartile. Data were analyzed from August 2023 to August 2024 using R software version 4.3.0.
The total of 1064 participants (546 females, 54.3%) with an average age of 21.7 years (standard deviation [SD]) were assessed repeatedly for mental disorders. This included 404 without FHR and 660 with FHR-BD. Over an average follow-up time of 6.3 years, 399 participants developed a mood disorder onset. Multiple PGS were linked with onset after controlling for early psychopathology and FHR-BD. This included PGS for self-regulation [Hazard Ratio (HR) = 1.19; 95% Confidence Interval (CI) = 1.06 to 1.34], ADHD (HR=1.19, 95% CI=1.06 to 1.34), MDD (HR=1.17; 95% CI= 1.04 to1.31), neuroticism (HR=1.18, 95% CI=1.06 to 1.32), addiction risk factor (HR=1.16, 95% CI=1.04 to 1.30), BD (HR=1.14, 95% CI= 1.02 to 1.28), subjective well-being (HR=0.89, 95% CI=0.79 to 0.99) and anxiety (HR=1.15, 95% CI= 1.02 to 1.28). In the control group with no FHR, increased PGS for anxiety, MDD, BD, and addiction risk were linked with an increased risk of developing mood disorders. Those with FHR-BD, increased PGS for ADHD, and self-regulation were linked with a high rate of onset. PGS for ADHD, self-regulation, and addiction risk had a stronger link with BD onset than MDD.
The limitation of this study is that it involves young participants without a family history of mood disorder and possible right censoring bias. FHR status did not significantly influence results during young adulthood and adolescence. More validation in clinical cohorts is necessary to assess the specificity and sensitivity of PGS.
In conclusion, the research of 1064 participants showed that the genetic risk of psychopathology-related PGS was linked with mood disorder over FHR for early psychopathology and BD of pre-morbid anxiety and ADHD.
Reference: Freeman K, Zwicker A, Fullerton JM, et al. Polygenic Scores and Mood Disorder Onsets in the Context of Family History and Early Psychopathology. JAMA Netw Open. 2025;8(4):e255331. doi:10.1001/jamanetworkopen.2025.5331
