Gene-based association analysis of depression risk among European ancestry Parkinson’s disease patients

Depression is one of the most common and disabling non-motor symptoms in Parkinson's disease (PD), yet its genetic basis remains poorly understood. Here, we investigate the genetic contributions to depression in PD by estimating the burden from common as well as low-frequency single nucleotide polymorphisms (SNPs) within genes previously implicated in PD or depression risk among European ancestry PD patients from three population-based studies. Using gene-based association analyses (SKAT, Burden, and SKAT-O) in the PASIDA, PEG, and PPMI studies, we evaluated SNP sets in gene regions previously linked to PD or depression. Among PD-related genes, meta-analysis identified a significant association between KRTCAP2 and self-reported depression diagnosis in PD (SKAT-O p = 4.33 × 10⁻⁵), which remained significant after false discovery rate correction. A higher genetic burden in KRTCAP2 was associated with 20% increased odds of depression (OR = 1.20, 95% CI: 1.04-1.38). TRAF5 and LRRK2 showed marginal associations. Among depression-related genes, SPPL3 and ERBB4 were associated with depression diagnosis history, and FNIP2 was associated with current depressive symptoms. The PD polygenic risk score was not associated with depression in PD, while a higher depression polygenic risk score was significantly associated with increased odds of depression diagnosis in both cohorts and the meta-analysis (OR = 1.26, 95% CI: 1.13-1.40). Our findings highlight immune-related genes such as KRTCAP2 and TRAF5 as potential contributors to depression in PD. Additionally, the depression PRS shows statistically significant association with depression diagnosis in PD, suggesting that a general depression-related genetic liability contributes to this non-motor feature in PD. Together, these results suggest that depression in PD may involve both shared and disease-specific genetic mechanisms, offering new insights into its pathogenesis and potential therapeutic targets.