Language
English
Publication Date
2-1-2025
Journal
Nature Aging
DOI
10.1038/s43587-024-00760-7
PMID
39572736
PMCID
PMC11839463
PubMedCentral® Posted Date
11-21-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Parkinson’s disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (< 44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10−15) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10−8). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease.
Keywords
Humans, Parkinson Disease, Exome Sequencing, Genetic Predisposition to Disease, Asian People, Male, Female, Aged, Middle Aged, Glucosylceramidase, Case-Control Studies, Genetic Variation, Neuroscience, Genetics, Ageing
Published Open-Access
yes
Recommended Citation
Chew, Elaine Gy; Liu, Zhehao; Li, Zheng; et al., "Exome Sequencing in Asian Populations Identifies Low-Frequency and Rare Coding Variation Influencing Parkinson’s Disease Risk" (2025). Faculty and Staff Publications. 5156.
https://digitalcommons.library.tmc.edu/baylor_docs/5156
Included in
Genetic Phenomena Commons, Genetic Processes Commons, Genetic Structures Commons, Medical Genetics Commons, Medical Molecular Biology Commons, Medical Specialties Commons