Identifying the genetic links between Parkinson’s disease and non-motor symptoms: novel insights into disease mechanisms

Abstract Understanding the biological mechanisms that underlie the non-motor symptoms of Parkinson’s disease (PD) requires comprehensive frameworks that unravel the complex interplay of genetic risk factors. Here, we used a disease-agnostic brain cortex gene regulatory network integrated with Mendelian Randomization analyses to identify 19 genes whose changes in expression are causal for PD. We further used the network to identify genes that are regulated by PD-associated genome-wide association study (GWAS) SNPs. Extended protein interaction networks derived from both the causal genes and PD-associated SNPs identified convergent impacts on biological pathways and phenoytpes, connecting PD with established co-occurring traits, including non-motor symptoms. These findings hold promise for therapeutic development. In conclusion, while distinct sets of genes likely influence PD risk and outcomes, the existence of genes in common and intersecting pathways suggests that they may contribute to both increased disease risk and symptom heterogeneity observed in people with Parkinson’s.