Objective: To assess genome-wide genetic risk for Parkinson’s disease (PD) within and across genetically determined European ancestries (European, Ashkenazi Jewish, Finnish, and Icelandic). We conducted meta-analyses of PD genome-wide association study (GWAS) summary statistics, stratified by source (clinically-recruited cohorts versus population biobanks) and by ancestry. The combined cross-European meta-analysis meta-analysis included 63,555 cases, 17,700 proxy cases with a family history of PD, and 1,746,386 controls, making it the largest investigation of PD genetic risk to date.

Background: GWAS have been instrumental in advancing our understanding of PD, nominating up to 90 genetic risk variants1. As GWAS continue to grow in sample size and improve in genotyping and sequencing quality, they will continue to identify additional variants that will provide additional insight into PD genetic risk. Additionally, genetic risk for PD may vary across European sub-populations due to differences in allele frequencies and linkage disequilibrium (LD) patterns2. Using advanced genetic ancestry estimates allows for a more detailed investigation into population-specific risk factors, offering deeper insight into the genetic architecture of PD.

Method: Meta-analyses were performed using standard fixed and random effect models for the European sub-populations, the case-control studies, and the population biobanks separately. Finally, all of the European ancestries for all study types as well as proxy cases were combined in our final cross-European meta-analysis. We estimated heritable risk across ancestry groups, investigated tissue and cell-type enrichment, and prioritized risk genes using public data to facilitate functional follow-up efforts.

Results: The final combined cross-European meta-analysis identified 134 risk loci (59 novel), with a total of 157 independent signals, significantly expanding our understanding of PD risk.

Conclusion: By integrating diverse European populations and leveraging harmonized data from the Global Parkinson’s Genetics Program (GP2), we reveal new insight into the genetic architecture of Parkinson’s disease. We identified a total of 134 risk loci, expanding the number of known loci associated with PD by approximately 24%, and performed follow-up analyses in an effort to facilitate follow-up studies and precision medicine efforts with the goal of advancing PD research.

Manhattan plot of meta-analysis

References: 1. Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol. 18, 1091–1102 (2019).
2. Rivas, M. A. et al. Insights into the genetic epidemiology of Crohn’s and rare diseases in the Ashkenazi Jewish population. PLoS Genet. 14, e1007329 (2018).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/novel-parkinsons-disease-genetic-risk-factors-within-and-across-european-populations/