Objective: The present study aims to conduct a meta-analysis in a large, diverse cohort to discover novel Parkinson’s disease (PD) loci and replicate previously reported associations.

Background: PD is a heritable neurodegenerative disease, with a previous largest study reporting 90 variants across 78 associated genomic loci in the Europeans.

Method: We meta-analyzed GWAS datasets from 30 worldwide populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (COURAGE-PD) consortium. We further combined our data with the European ancestry data from the International Parkinson Disease Genomics Consortium (IPDGC).

Results: Our GWAS meta-analyses included 11,545 individuals with PD and 9,810 controls (92.8%: Europeans; 7.1% East-Asians). The genetic variants explained 26.4 % of the genetic liability of PD. We identified a novel chromosomal (Chr) 22 locus with the leading SNP (rs73176685) on the TEF gene (P=7.05×10^-9, I² =0.0%) and replicated previously reported 21 variants across 19 loci (P<6.4×10^-4; Bonferroni corrected P-value for 78 out of 90 variants detected in COURAGE-PD). The IPDGC dataset showed a high correlation with our dataset (r²=0.859), including high predictability of PRS based on IPDGC reported loci in the COURAGE-PD dataset (OR=1.60 per unit increase in PRS, 95% CI=1.55-1.66; r²=0.088). The association of Chr 22 locus was further retained upon the subsequent combination of IPDGC with the COURAGE-PD dataset with the leading SNP (rs5751084) in the 3’ UTR region of the neighboring ZC3H7B gene (P=2.07×10^-8, I² =21.1%, r² with rs73176685=0.69). Functional analyses showed that variant rs5751084 exhibits a high CADD score (15.36), with a most significant association with TEF expression in whole blood. Pleiotropic analysis of the variant further suggested the involvement of the locus in genetic predisposition to depression and sleep disorders in PD, and inflammatory bowel disease and neuroticism, in general population.

Conclusion: The identification of a novel locus on Chr 22 encompassing the TEF gene provides for the first time genome-wide evidence linking non-motor symptoms to PD and thus broadens the understanding of genetic underpinnings of PD in the European population.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genome-wide-meta-analysis-of-parkinsons-disease-identifies-a-novel-chromosomal-22-locus-findings-from-the-courage-pd-consortium/