Shared and Sex-Specific Genetic Risk for Parkinson's Disease Risk Across European Populations

IntroductionParkinsons disease (PD) affects females and males differently, with differences in prevalence, clinical phenotypes, and therapeutic response, suggesting that biological sex may influence the underlying molecular mechanisms of PD. The extent to which genetic factors may contribute to these differences remains largely unknown. ObjectiveTo investigate sex-specific autosomal genetic factors associated with PD risk. MethodsWe performed a sex-stratified autosomal GWAS meta-analysis leveraging data from the Global Parkinsons Genetics Program, the International Parkinsons Disease Genomics Consortium, the UK Biobank, and the Fox Insight Genetics Study, including a total of 226,196 individuals from different European populations: 18,145 female PD cases, 95,558 female controls, 28,747 male PD cases, and 83,746 male controls. ResultsWe observed a high genetic correlation between the male and female PD meta-analyses (rg = 0.909, SE = 0.0403; p = 8.03E-113), and the heritability estimates were comparable between sexes ([~]10% in males and [~]11% in females) and similar to estimates from prior sex-combined analyses. Our sex-stratified GWAS identified 57 genome-wide significant association signals, including five novel risk loci, three of which reached genome-wide significance in males only (RBM8A, ANKRD23, and CNTN4) and two in females only (RERE and ARL6IP6). Of the remaining previously identified GWAS loci regions, several showed differences in effect magnitude between sexes, with the GALC, RERE, ARL6IP6, and RBM8A loci demonstrating statistically significant sex-specific effects. ConclusionsOverall, PD genetic architecture appears broadly similar between females and males, but the identification of five novel loci and significant differences at select regions highlights the value of sex-stratified analyses for uncovering additional genetic contributors to PD risk beyond those detected in combined analyses.