Genomic risk prediction for depression in a large prospective study of older adults of European descent

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.