Genetic overlap between Parkinson disease and inflammatory bowel disease

Abstract

ImportanceParkinson disease (PD) and inflammatory bowel disease (IBD) have been associated, implying shared pathophysiology. Characterizing genetic pleiotropy between the two conditions aids the exploration of common etiology. ObjectiveTo estimate the genetic correlation between PD and IBD and to identify specific loci influencing both conditions. DesignGenetic study with applications of high definition likelihood and conditional false discovery rate (FDR) framework. SettingThe study was based on summary statistics of genome-wide association studies (GWAS). ParticipantsThe PD GWAS comprised 37,688 cases and 981,372 controls, and the IBD GWAS included 25,042 cases and 34,915 controls. Participants were of mixed ethnicity. ExposuresNone. Main Outcomes and MeasuresThe main outcomes were a set of single nucleotide polymorphisms (SNPs) identified by conditional FDR analysis as jointly associated with PD and IBD. ResultsWeak but statistically significant genetic correlations were detected for PD with both Crohns disease (CD) and ulcerative colitis (UC), the two main subtypes of IBD. A total of 1333 SNPs in 28 genomic loci and 1915 SNPs in 22 loci were jointly associated with PD-CD and PD-UC, respectively, at conjunctional FDR under 0.01. The pleiotropic loci appeared distinctive for PD-CD and PD-UC, are mostly novel and comprise loci with either same or opposing genetic effects on the two phenotypes. Positional and eQTL mapping prioritized 316 PD-CD and 303 PD-UC genes, among which only <10% are differentially expressed in both colon and substantia nigra. The KEGG pathways enriched by all prioritized genes were highly concordant between PD-CD and PD-UC, with the majority being related to immune and/or autoimmune dysfunction. Conclusions and RelevanceOverall, we found robust evidence for a genetic link between PD and each subtype of IBD. The identified genetic overlap is complex at the locus and gene levels, indicating the presence of both common etiology and antagonistic pleiotropy. At the functional level, our results highlighted a central role of host immunity and/or autoimmunity in the PD-IBD relationship.