Yu Chenglong, Bakshi Andrew, Agustini Bruno, Walker Alicia, Lin Tian, Lotfaliany Mojtaba, Williams Lana J, McNeil John J, Wray Naomi R, Berk Michael, Lacaze Paul
School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.
Deakin University School of Medicine, The Institute for Mental and Physical Health and Clinical Translation (IMPACT), Geelong, Victoria, Australia.
Mol Psychiatry. 2025 Aug 6. doi: 10.1038/s41380-025-03145-3.
The extent to which genetic predisposition contributes to late-life depression risk, particularly after age 70, remains unclear, despite the high prevalence of depression in this age group and the variability in risk factors by age. This study investigated the association between a polygenic score (PGS) and depression outcomes, including severity, trajectories of depression, and antidepressant medication use, in a longitudinal cohort of 12,029 genotyped older adults of European descent aged ≥70 years, with no history of diagnosed cardiovascular disease events, dementia, or permanent physical disability at baseline. Participants were followed for a median of 4.7 years. The PGS was derived using the latest Psychiatric Genomics Consortium data for major depression. Depression was defined by the CES-D-10 score thresholds of ≥8 (primary outcome), ≥10, and ≥12 (secondary outcomes), alongside antidepressant medication use and four previously established longitudinal trajectories of depressive symptoms: low (non-depressed), moderate (subthreshold), high (persistent), and initially low but increasing (emerging). Multivariable models were used to examine associations between the PGS (per standard deviation, SD) and outcomes, adjusting for covariates. At baseline, mean participant age was 75.1 years, 54.9% were female, and 9.1% had depression (CES-D-10 ≥ 8). The PGS was significantly associated with baseline depression (OR = 1.23 [1.15-1.31]), incident depression (HR = 1.18 [1.14-1.23]) and antidepressant medication use (OR = 1.39 [1.31-1.47]). Compared with non-depressed participants, the PGS was associated with increasing severity of depression trajectory classes (subthreshold depression OR = 1.15 [1.11-1.20], emerging depression OR = 1.22 [1.13-1.31], persistent depression OR = 1.40 [1.31-1.49]). These findings suggest that the PGS may play an important role in risk stratification for late-life depression.
尽管老年抑郁症的患病率很高，且风险因素因年龄而异，但基因易感性在多大程度上导致晚年患抑郁症的风险，尤其是在70岁以后，仍不清楚。本研究在一个纵向队列中调查了多基因评分（PGS）与抑郁结局之间的关联，这些抑郁结局包括严重程度、抑郁轨迹以及抗抑郁药物的使用情况。该队列由12,029名年龄≥70岁、具有欧洲血统且在基线时无心血管疾病事件、痴呆或永久性身体残疾诊断史的基因分型老年人组成。参与者的随访时间中位数为4.7年。PGS是使用最新的精神基因组学联盟关于重度抑郁症的数据得出的。抑郁症由CES-D-10评分阈值≥8（主要结局）、≥10和≥12（次要结局）定义，同时结合抗抑郁药物的使用情况以及之前确定的四种抑郁症状纵向轨迹：低（非抑郁）、中度（亚阈值）、高（持续）和最初低但上升（新发）。多变量模型用于检验PGS（每标准差，SD）与结局之间的关联，并对协变量进行了调整。在基线时，参与者的平均年龄为75.1岁，54.9%为女性，9.1%患有抑郁症（CES-D-10≥8）。PGS与基线抑郁症（OR = 1.23 [1.15 - 1.31]）、新发抑郁症（HR = 1.18 [1.14 - 1.23]）和抗抑郁药物的使用（OR = 1.39 [1.31 - 1.47]）显著相关。与非抑郁参与者相比，PGS与抑郁轨迹类别的严重程度增加相关（亚阈值抑郁症OR = 1.15 [1.11 - 1.20]，新发抑郁症OR = 1.22 [1.13 - 1.31]，持续性抑郁症OR = 1.40 [1.31 - 1.49]）。这些发现表明，PGS可能在晚年抑郁症的风险分层中发挥重要作用。
