Investigating the Shared Genetic Etiology Between Parkinson's Disease and Depression

Abstract

Background: Depression is a common symptom in Parkinson's disease (PD), resulting from underlying neuropathological processes and psychological factors. However, the extent to which shared genetic risk factors contribute to the relationship between depression and PD is poorly understood.

Objective: To examine the effects of common genetic variants influencing the etiology of PD and depression risk at the genome-wide and local genomic regional level.

Methods: We comprehensively investigated the genetic relationship between PD and depression using genome-wide association studies data. First, we estimated the genetic correlation at the genome-wide level using linkage-disequilibrium score regression, followed by local genetic correlation analysis using the GWAS-pairwise method and functional annotation to identify genes that may jointly influence the risk for both traits. Also, we performed Latent Causal Variable, Latent Heritable Confounder Mendelian Randomization, and traditional Mendelian Randomization analyses to investigate the potential causal relationship.

Results: Although the genetic correlation between PD and depression was not statistically significant at the genome-wide level, GWAS-pairwise analyses identified 16 genomic segments associated with PD and depression, implicating nine genes. Further analyses revealed distinct patterns within individual genes, suggesting an intricate pattern. These genes involve various biological processes, including neurotransmitter regulation, senescence, and nucleo-cytoplasmic transport mechanisms. We did not observe genetic evidence of causality between PD and depression.

Conclusions: Our findings did not support a genome-wide genetic correlation or a causal association between both conditions. However, we identified genomic segments but identified genomic segments linked to distinct biological pathways influencing their etiology.Further research is needed to understand their functional consequences.

Keywords: contstartabstract; genome-wide association studies; Parkinson’s disease; depression; genetic correlation; genetics.

Fig. 1

Regional plot for the chr22 : 41452876-41829000 region in GWAS summary statistics showing SNPs associated with Parkinson’s disease (PD) in blue and depression in yellow. Top variants within the region for each dataset are annotated by their rs number, and vertical gray dotted lines highlight their positions within the genes shown in the lower panel, which only includes protein-coding genes. The horizontal red dashed line represents the common genome-wide significance threshold.