Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk

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<sup>-15</sup>) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10<sup>-8</sup>). 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.

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Publication Details

Journal
Nature Aging
Published
2024-11-21
DOI
https://doi.org/10.1038/s43587-024-00760-7
Citations
13
Primary Topic
Parkinson's Disease Mechanisms and Treatments
Type
article
Field-Weighted Citation Impact
4.80

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article

Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk

Laurie Robak, Sun Ju Chung, Xiao Yin Chen, Juei‐Jueng Lin et al.
13 citations
Nature Aging
Parkinson's Disease Mechanisms and Treatments
4.80
article

Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk

Laurie Robak, Sun Ju Chung, Xiao Yin Chen, Juei‐Jueng Lin, Vincent Mok, Tin Aung, Ling Ling Chan, Clement Chee Yung Tham, Roy N. Alcalay, Jia Nee Foo, Kyu Hyung Park, Tiak Ju Tan, Chu Hua Chang, Elaine Guo Yan Chew, Mike A. Nalls, Yinxia Chao, Mary B. Makarious, Eng‐King Tan, Shen‐Yang Lim, Wing‐Lok Au, Moses Tandiono, Ying Swan Ho, Louis C.S. Tan, Yi Wen Tay, Richard Reynolds, Jia Lun Lim, Michelle Mulan Lian, Ai Huey Tan, Jeeyun Ahn, Cornelis Blauwendraat, Chiea Chuen Khor, Janey L. Wiggs, Yun Xia, Ting Xuan Peh, Zheng Li, Zhehao Liu, Zhenxun Wang, Esther KL Peh, Wee Ling Chng, Beom S. Jeon, Chi Pui Pang, Erin YT Lim, Azlina Ahmad Annuar, Kyuyoung Song, Anne Chan, Ziv Gan-Or, Jonavan J. Leong, Yue Jing Heng, Ebonne Ng, Kumar Manharlal Prakash
article en
13 citations

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<sup>-15</sup>) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10<sup>-8</sup>). 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.

Nature AgingVol. 5(2)
Agency for Science, Technology and Research (SG), Ulsan College (KR), Massachusetts Eye and Ear Infirmary (US), Montreal Neurological Institute and Hospital (CA), National Institutes of Health (US), Department of Health (CN), Harvard University (US), Seoul National University (KR), National University of Singapore (SG), Nanyang Technological University (SG), Chinese University of Hong Kong (HK), Baylor College of Medicine (US), Singapore General Hospital (SG), Columbia University Irving Medical Center (US), Tel Aviv Sourasky Medical Center (IL), Seoul Metropolitan Government (KR), Asan Medical Center (KR), Seoul National University Hospital (KR), University of Malaya (MY), University of Ulsan (KR), Data Tecnica International (United States) (US), SNUH SMG-SNU Boramae Medical Center (KR), Singapore Institute for Clinical Sciences (SG), Chu Shang Show Chwan Hospital (TW), National Institute of Neurological Disorders and Stroke (US), Prince of Wales Hospital (CN), Singapore Eye Research Institute (SG), Neurological Research Institute (US), Duke-NUS Medical School (SG), National Neuroscience Institute (SG), National Institute on Aging (US), Bioprocessing Technology Institute (SG), National Hospital for Neurology and Neurosurgery (GB), University College London (GB), Imperial College London (GB), McGill University (CA), Genome Institute of Singapore (SG)
U.S. Department of Health and Human Services, Amazon Web Services, Parkinson's Foundation, National Research Foundation, Agency for Science, Technology and Research, National Research Foundation Singapore, Nanyang Technological University, Universiti Malaya, Ministry of Education, India, Genome Institute of Singapore, Bộ Giáo dục và Ðào tạo, National Institutes of Health, Medical Research Council, National Medical Research Council, NIH Office of the Director
Openalex Percentile: Top 4%
Parkinson's Disease Mechanisms and Treatments
4.80
DOIOpen Access PDFOpenAlex
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