Freeman Kathryn, Zwicker Alyson, Fullerton Janice M, Hafeman Danella M, van Haren Neeltje E M, Merranko John, Goldstein Benjamin I, Stapp Emma K, de la Serna Elena, Moreno Dolores, Sugranyes Gisela, Mas Sergi, Roberts Gloria, Toma Claudio, Schofield Peter R, Edenberg Howard J, Wilcox Holly C, McInnis Melvin G, Propper Lukas, Pavlova Barbara, Stewart Samuel A, Denovan-Wright Eileen M, Rouleau Guy A, Castro-Fornieles Josefina, Hillegers Manon H J, Birmaher Boris, Mitchell Philip B, Alda Martin, Nurnberger John I, Uher Rudolf
Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada.
Nova Scotia Health Authority, Halifax, Nova Scotia, Canada.
JAMA Netw Open. 2025 Apr 1;8(4):e255331. doi: 10.1001/jamanetworkopen.2025.5331.
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.
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.
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.
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.
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.
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.
双相情感障碍（BD）和重度抑郁症（MDD）在家族中聚集，风险通常首先表现为早期精神病理学症状，包括注意力缺陷多动障碍（ADHD）和焦虑症。
确定多基因评分（PGS）是否与情绪障碍发病相关，独立于BD家族高风险（FHR - BD）和早期精神病理学症状。
设计、设置和参与者：这项队列研究使用了来自澳大利亚、加拿大、荷兰、西班牙和美国的7个富含FHR - BD的前瞻性队列的数据。将FHR - BD定义为至少有1名BD一级亲属的参与者与无任何情绪障碍FHR的参与者进行比较。从1992年7月至2023年7月，对参与者进行了不同随访间隔的反复评估。数据于2023年8月至2024年8月进行分析。
PGS对MDD、BD、焦虑、神经质、主观幸福感、ADHD、自我调节和成瘾风险因素的遗传易感性进行索引。与亲属进行的半结构化诊断访谈确定了FHR - BD。情绪障碍发病前的ADHD或焦虑症诊断构成早期精神病理学症状。
感兴趣的结局，即情绪障碍发病，定义为经共识确认的MDD或BD新诊断。Cox回归分析了PGS、FHR - BD、ADHD和焦虑与情绪障碍发病的关联。Kaplan - Meier曲线和对数秩检验评估了按PGS四分位数和家族风险状态的发病概率。
共有1064名参与者（546名[51.3%]女性；最后一次评估时的平均[标准差]年龄为21.7[5.1]岁），包括660名有FHR - BD的参与者和404名无任何情绪障碍FHR的参与者，接受了精神障碍反复评估。在平均（标准差）为6.3（5.7）年的可变随访间隔期间，共发生了399次情绪障碍发病。在校正FHR - BD和早期精神病理学症状后，多个PGS与发病相关，包括ADHD的PGS（风险比[HR]，1.19；95%置信区间，1.06 - 1.34）、自我调节的PGS（HR，1.19；95%置信区间，1.06 - 1.34）、神经质的PGS（HR，1.18；95%置信区间，1.06 - 1.32）、MDD的PGS（HR，1.17；95%置信区间，1.04 - 1.31）、成瘾风险因素的PGS（HR，1.16；95%置信区间，1.04 - 1.30）、焦虑的PGS（HR，1.15；95%置信区间，1.02 - 1.28）、BD的PGS（HR，1.14；95%置信区间，1.02 - 1.28）和主观幸福感的PGS（HR，0.89；95%置信区间，0.79 - 0.99）。成瘾风险因素、焦虑、BD和MDD的高PGS与对照组发病概率增加相关。ADHD和自我调节的高PGS增加了FHR - BD参与者的发病率。自我调节、ADHD和成瘾风险因素的PGS与BD发病的关联比与MDD发病的关联更强。
在这项队列研究中，多个PGS与情绪障碍发病相关，独立于BD家族史以及ADHD或焦虑症的病前诊断。PGS与情绪障碍风险之间的关联因家族史状态而异。
