Mendelian Randomization Study Using Dopaminergic Neuron-Specific eQTL Nominates Potential Causal Genes for Parkinson's Disease.

Abstract

Large-scale genome-wide association studies (GWASs) have reported multiple risk variants for Parkinson's disease (PD). However, little is known about how these reported risk variants confer risk of PD. To nominate genes whose genetically regulated expression in dopaminergic neurons may have a causal role in PD. We conducted a two-sample Mendelian randomization (MR) study by integrating large-scale genome-wide associations and expression quantitative trait loci (eQTL) data from dopaminergic neurons. MR analysis nominated 10 risk genes whose genetically regulated expression in dopaminergic neurons may have a causal role in PD. These MR significant genes include FAM200B, NDUFAF2, NUP42, SH3GL2, STX1B, CCDC189, KAT8, PRSS36, VAMP4, and ZSWIM7. We report the first MR study of PD by using dopaminergic neuron-specific eQTL and nominate novel risk genes for PD. Further functional characterization of the nominated risk genes will provide mechanistic insights into PD pathogenesis and potential therapeutic targets. © 2022 International Parkinson and Movement Disorder Society.