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

Chew EG 1 , Liu Z 2 , Li Z 3 , Chung SJ 4 , Lian MM 1 , Tandiono M 1 Show all authors , Heng YJ 1 , Ng EY 5 , Tan LC 6 , Chng WL 2 , Tan TJ 3 , Peh EK 7 , Ho YS 7 , Chen XY 3 , Lim EY 3 , Chang CH 1 , Leong JJ 1 , Peh TX 3 , Chan LL 2 , Chao Y 2 , Au WL 6 , Prakash KM 2 , Lim JL 8 , Tay YW 8 , Mok V 9 , Chan AY 9 , Lin JJ 10 , Jeon BS 11 , Song K 12 , Tham CC 13 , Pang CP 13 , Ahn J 14 , Park KH 15 , Wiggs JL 16 , Aung T 2 , Tan AH 17 , Ahmad Annuar A 8 , Makarious MB 18 , Blauwendraat C 18 , Nalls MA 19 , Robak LA 20 , Alcalay RN 21 , Gan-Or Z 22 , Reynolds R 1 , Lim SY 17 , Xia Y 1 , Khor CC 23 , Tan EK 24 , Wang Z 25 , Foo JN 26

Affiliations 

  • 1 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
  • 2 Duke-National University of Singapore Medical School, Singapore, Singapore
  • 3 Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
  • 4 Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
  • 5 Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore
  • 6 Department of Neurology, National Neuroscience Institute, Singapore, Singapore
  • 7 Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore, Singapore
  • 8 Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 9 Department of Medicine and Therapeutics, Division of Neurology, Margaret K.L. Cheung Research Centre for Management of Parkinsonism, Lui Che Woo Institute of Innovative Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
  • 10 Department of Neurology, Chushang Show-Chwan Hospital, Nantou, Taiwan
  • 11 Department of Neurology, Seoul National University Hospital, Seoul, South Korea
  • 12 Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea
  • 13 Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
  • 14 Department of Ophthalmology, Seoul Metropolitan Government, Seoul National University Boramae Medical Center, Seoul, South Korea
  • 15 Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea
  • 16 Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
  • 17 Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 18 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
  • 19 Center for Alzheimer's and Related Dementias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
  • 20 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
  • 21 Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
  • 22 The Neuro (Montréal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada
  • 23 Duke-National University of Singapore Medical School, Singapore, Singapore. [email protected]
  • 24 Duke-National University of Singapore Medical School, Singapore, Singapore. [email protected]
  • 25 Duke-National University of Singapore Medical School, Singapore, Singapore. [email protected]
  • 26 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore. [email protected]
Nat Aging, 2024 Nov 21.
PMID: 39572736 DOI: 10.1038/s43587-024-00760-7

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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