Analysis of East Asian Parkinson’s Disease Genomes Identifies Novel Susceptibility Loci and Functional Regulatory Variation

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Abstract
Summary: Background: Parkinson disease (PD) is a genetically complex neurodegenerative disorder, but most genetic discoveries have been derived from populations of European ancestry, limiting the understanding of ancestry-specific genetic risk. Methods: This GWAS included 5,825 East Asian participants (3,043 patients with PD and 2,782 controls). We then combined these results with data from two additional East Asian cohorts through meta-analysis, resulting in a total of 74,716 participants (15,603 patients with PD and 59,113 controls). To our knowledge, this represents the largest genetic study of PD in East Asian populations to date. Findings: We identified two novel loci that were associated with PD in East Asian cohorts and reached genome-wide significance in the cross-ancestry meta-analysis (> 1.9 million subjects): TLE4 (lead variant rs10780320, P meta_combined = 2.853×10 − 10) and HLA-V/HLA-G (lead variant rs11751333, P meta_combined = 1.031×10-9). Integration of brain eQTL data identified an East Asian– specific intergenic variant at the LRRK2 locus (rs1388594) was significantly associated with LRRK2 expression in the basal ganglia. This association was replicated across 3 independent East Asian cohorts (P gp2_EAS = 8.71 × 10 −4 , P sg_EAS = 1.13 × 10 −5 , PTPMI_EAS = 4.86 × 10 −4 ) and reached genome-wide significance in the East Asian meta-analysis (P meta_EAS = 5.85 × 10 −10 ; OR = 1.10, 95% CI: 1.07– 1.13). The variant was not associated with PD in populations of European ancestry (P = 0.08). Interpretation: These findings improve our understanding of the genetics of PD across different ancestry groups and highlight the need to include people from different backgrounds in genetic studies to identify ancestry-specific risk variants.
Funding Information
  • Singapore Ministry of Health’s National Medical Research Council (MOH-OFLCG24may-0004)

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