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. 2025 Apr 1;8(4):e255331.
doi: 10.1001/jamanetworkopen.2025.5331.

Polygenic Scores and Mood Disorder Onsets in the Context of Family History and Early Psychopathology

Kathryn Freeman  1   2 , Alyson Zwicker  2   3   4 , Janice M Fullerton  5   6 , Danella M Hafeman  7 , Neeltje E M van Haren  8   9 , John Merranko  7 , Benjamin I Goldstein  10 , Emma K Stapp  11 , Elena de la Serna  12   13   14 , Dolores Moreno  13   15 , Gisela Sugranyes  12   13   14 , Sergi Mas  12   13   16 , Gloria Roberts  17 , Claudio Toma  5   6   18 , Peter R Schofield  5   6 , Howard J Edenberg  19 , Holly C Wilcox  20   21 , Melvin G McInnis  22 , Lukas Propper  3   23 , Barbara Pavlova  2   3 , Samuel A Stewart  24 , Eileen M Denovan-Wright  25 , Guy A Rouleau  26 , Josefina Castro-Fornieles  12   13   14   27 , Manon H J Hillegers  8 , Boris Birmaher  7 , Philip B Mitchell  17 , Martin Alda  2   3 , John I Nurnberger  28   29 , Rudolf Uher  1   2   3
Affiliations

Polygenic Scores and Mood Disorder Onsets in the Context of Family History and Early Psychopathology

Kathryn Freeman et al. JAMA Netw Open. .

Abstract

Importance: Bipolar disorder (BD) and major depressive disorder (MDD) aggregate within families, with risk often first manifesting as early psychopathology, including attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders.

Objective: To determine whether polygenic scores (PGS) are associated with mood disorder onset independent of familial high risk for BD (FHR-BD) and early psychopathology.

Design, setting, and participants: This cohort study used data from 7 prospective cohorts enriched in FHR-BD from Australia, Canada, the Netherlands, Spain, and the US. Participants with FHR-BD, defined as having at least 1 first-degree relative with BD, were compared with participants without FHR for any mood disorder. Participants were repeatedly assessed with variable follow-up intervals from July 1992 to July 2023. Data were analyzed from August 2023 to August 2024.

Exposures: PGS indexed genetic liability for MDD, BD, anxiety, neuroticism, subjective well-being, ADHD, self-regulation, and addiction risk factor. Semistructured diagnostic interviews with relatives established FHR-BD. ADHD or anxiety disorder diagnoses before mood disorder onset constituted early psychopathology.

Main outcomes and measures: The outcome of interest, mood disorder onset, was defined as a consensus-confirmed new diagnosis of MDD or BD. Cox regression examined associations of PGS, FHR-BD, ADHD, and anxiety with mood disorder onset. Kaplan-Meier curves and log-rank tests evaluated the probability of onset by PGS quartile and familial risk status.

Results: A total of 1064 participants (546 [51.3%] female; mean [SD] age at last assessment, 21.7 [5.1] years), including 660 with FHR-BD and 404 without FHR for any mood disorder, were repeatedly assessed for mental disorders. A total of 399 mood disorder onsets occurred over a variable mean (SD) follow-up interval of 6.3 (5.7) years. Multiple PGS were associated with onset after correcting for FHR-BD and early psychopathology, including PGS for ADHD (hazard ratio [HR], 1.19; 95% CI, 1.06-1.34), self-regulation (HR, 1.19; 95% CI, 1.06-1.34), neuroticism (HR, 1.18; 95% CI, 1.06-1.32), MDD (HR, 1.17; 95% CI, 1.04-1.31), addiction risk factor (HR, 1.16; 95% CI, 1.04-1.30), anxiety (HR, 1.15; 95% CI, 1.02-1.28), BD (HR, 1.14; 95% CI, 1.02-1.28), and subjective well-being (HR, 0.89; 95% CI, 0.79-0.99). High PGS for addiction risk factor, anxiety, BD, and MDD were associated with increased probability of onset in the control group. High PGS for ADHD and self-regulation increased rates of onset among participants with FHR-BD. PGS for self-regulation, ADHD, and addiction risk factors showed stronger associations with onsets of BD than MDD.

Conclusions and relevance: In this cohort study, multiple PGS were associated with mood disorder onset independent of family history of BD and premorbid diagnoses of ADHD or anxiety. The association between PGS and mood disorder risk varied depending on family history status.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Fullerton reported personal fees from Illumina outside the submitted work. Dr Hafeman reported grants from National Institutes of Mental Health, Substance Abuse and Mental Health Services Administration, and Baszucki Group and personal fees from UpToDate outside the submitted work. Dr van Haren reported grants from National Institute of Mental Health and Vrienden van Sophia outside the submitted work. Dr Schofield reported grants from the Dutch Research Council eHealth and Stress in Action Gravitation, and Convergence PROTECtME outside the submitted work. Dr Nurnberger reported funding from Janssen ending in 2021. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Associations of Polygenic Scores With Risk of Mood Disorder Onset
ADHD indicates attention-deficit/hyperactivity disorder; FHR-BD, familial high-risk for bipolar disorder; HR, hazard ratio. Dot indicates estimate was significant; circle, estimate was not significant.
Figure 2.
Figure 2.. Kaplan-Meier Plots of Associations of Polygenic Score (PGS), Familial High Risk of Bipolar Disorder (FHR-BD), and Mood Disorder Onsets
PGS were split into quartiles (Q) and stratified by FHR-BD: Q1 is the lowest PGS; Q4, highest PGS. ADHD indicates attention-deficit/hyperactivity disorder.
Figure 3.
Figure 3.. Associations of Polygenic Scores (PGS) With Bipolar Disorder Onset Compared With Mood Disorder Onsets
ADHD indicates attention-deficit/hyperactivity disorder; HR, hazard ratio. Bars represent confidence intervals of mood disorder onset estimate (α = .05); dots, estimates were statistically significant; circles, estimates were not statistically significant.
See this image and copyright information in PMC

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