Analysis of east Asian Parkinson's disease Genomes Identifies Novel Susceptibility Loci and Functional Regulatory Variation

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, Pmeta_combined = 2.853 x 10^-10) and HLA-V/HLA-G (lead variant rs11751333, Pmeta_combined = 1.031 x 10^-9). Integration of brain eQTL data identified an East Asian-specific intergenic variant at the LRRK2 locus (rs1388594) that was significantly associated with LRRK2 expression in the basal ganglia. This association was replicated across three independent East Asian cohorts (Pgp2_EAS = 8.71 x 10^-4, Psg_EAS = 1.13 x 10^-5, PTPMI_EAS = 4.86 x 10^-4) and reached genome-wide significance in the East Asian meta-analysis (Pmeta_EAS = 5.85 x 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 ancestry groups and highlight the importance of including diverse populations in genetic studies to identify ancestry-specific risk variants.