Objective: To investigate known pathogenic and risk variants linked to Parkinson’s disease (PD) at a global, multi-ancestry scale.

Background: Genetic forms of PD have been described worldwide; however, about three-quarters of all genetic PD studies were performed in individuals of European ancestry, thereby severely limiting our insight into genotype-phenotype relationships and PD risk on a global scale. The Global Parkinson’s Genetics Program (GP2) is a world-wide initiative aiming to substantially expand our understanding of the role that genetics plays in PD and parkinsonism with a particular focus on populations and ancestries not yet adequately represented in PD research.

Method: We analyzed whole genome sequencing data (WGS) from ~7,700, clinical exome data from ~10,000, and genotyping data from >70,000 individuals from 11 different genetic ancestries from the latest GP2 releases 8 and 9. We screened all individuals, including patients with PD and parkinsonism and healthy controls, for known pathogenic and high-risk single nucleotide variants (SNVs) in genes linked to monogenic forms of PD (including GBA1).

Results: When combining all ancestries, we identified causative or coding risk variants in 11.2% (5,357/47,813) of all clinically affected carriers, including individuals with PD, atypical forms of parkinsonism, and other neurodegenerative diseases. Figure 1 summarizes the percentage of carriers per gene across all identified carriers, by ancestry. GBA1 variant carriers were identified across all ancestries and were most frequent overall (n=3,456; including pathogenic and risk variants), although frequencies significantly differed between populations. The second most frequent gene linked to monogenic PD across ancestries was LRRK2 (n=1,577; including pathogenic and risk variants), whereas SNVs in other genes were rarer and only identified in certain populations. Additionally, 7.2% (2,132/29,792) of all unaffected individuals, including healthy controls, population cohorts, and unaffected family members, and 5.8% (231/3,970) of individuals in prodromal PD stages carried pathogenic or PD risk variants.

Conclusion: This study provides first insights into the monogenic spectrum of PD at a global scale. These findings are critical to uncovering unique genetic contributions to the development of PD and are crucial in the context of clinical trials and personalized medicine.

Figure 1

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MDS Abstracts - https://www.mdsabstracts.org/abstract/investigating-the-global-genetic-spectrum-of-monogenic-parkinsons-disease-and-parkinsonism/