Analysis of east Asian Parkinson's disease Genomes Identifies Novel Susceptibility Loci and Functional Regulatory Variation
- 1National Neuroscience Institute of Singapore
Abstract
BackgroundParkinson 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.
MethodsThis 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.
FindingsWe 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 = 2.853x10-10) and HLA-V/HLA-G (lead variant rs11751333, Pmeta_combined = 1.031x10-9). 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 (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).
InterpretationThese 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.
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BibTeX
@misc{sun2026analysis,
title = {{Analysis of east Asian Parkinson's disease Genomes Identifies Novel Susceptibility Loci and Functional Regulatory Variation}},
author = {Q. Sun and E. Y. Ng and T. S. Toh and K. S. Lim and J. J. D. Wang and T. Welton and L. C. S. Tan and K. M. Prakash and L.-L. Chan and J. N. Foo and A. Singleton and L. Screven and H. Leonard and M. A. Nalls and A. Ahmad-Annuar and Y. W. Tay and H.-J. Kim and J. H. Shin and M. Funayama and N. Hattori and T. Hatano and J.-Y. Lee and B. Jeon and C.-H. Li and S.-P. Fan and P.-S. Chen and C.-H. Lin and S.-Y. Lim and A.-H. Tan and E.-K. Tan},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.26362212},
url = {https://www.medrxiv.org/content/10.64898/2026.09.03.26362212v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Analysis of east Asian Parkinson's disease Genomes Identifies Novel Susceptibility Loci and Functional Regulatory Variation
AU - Q. Sun
AU - E. Y. Ng
AU - T. S. Toh
AU - K. S. Lim
AU - J. J. D. Wang
AU - T. Welton
AU - L. C. S. Tan
AU - K. M. Prakash
AU - L.-L. Chan
AU - J. N. Foo
AU - A. Singleton
AU - L. Screven
AU - H. Leonard
AU - M. A. Nalls
AU - A. Ahmad-Annuar
AU - Y. W. Tay
AU - H.-J. Kim
AU - J. H. Shin
AU - M. Funayama
AU - N. Hattori
AU - T. Hatano
AU - J.-Y. Lee
AU - B. Jeon
AU - C.-H. Li
AU - S.-P. Fan
AU - P.-S. Chen
AU - C.-H. Lin
AU - S.-Y. Lim
AU - A.-H. Tan
AU - E.-K. Tan
PY - 2026
DA - 2026/09/03
PB - medRxiv
DO - 10.64898/2026.09.03.26362212
UR - https://www.medrxiv.org/content/10.64898/2026.09.03.26362212v1
AB - BackgroundParkinson 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. MethodsThis 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. FindingsWe 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 = 2.853x10-10) and HLA-V/HLA-G (lead variant rs11751333, Pmeta_combined = 1.031x10-9). 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 (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). InterpretationThese 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.
ER -