Abstract

Genome-wide association studies (GWAS) have increased our understanding of Parkinson's disease (PD) genetics by identifying common disease-associated variants. However, much of the heritability remains unaccounted for and we hypothesized that this could be partly explained by epistasis, the statistical interaction between two or more genetic variants. Here, we developed a genome-wide non-exhaustive epistasis screening pipeline called Variant-variant interaction through variable thresholds (VARI3) and applied it to diverse PD GWAS cohorts. We used 14 cohorts of European ancestry (14,671 cases and 17,667 controls) as a discovery stage, identifying 14 significant candidate variant-variant interactions. We then used four independent cohorts (13,377 cases and 413,789 controls) as replication stage, successfully replicating three epistasis signals located nearby SNCA and within MAPT and WNT3. Admixture analysis showed that the epistatic effect on PD of those variants at these loci was observed in both European ancestry and Native American ancestry individuals. We assessed the functional impact of the epistasis signals across a range of functional/-omics datasets identifying significant single-variant eQTLs across brain tissues, epistasis eQTL signals in whole-blood, PD-relevant pathways and ontologies, and chromatin interactions between the regions of the interacting SNPs. In conclusion, we identified and replicated novel epistatic signals associated with PD risk across multiple diverse genetic ancestry cohorts, highlighting their enrichment in pathways relevant to Parkinson's disease.