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

Autor: Chew EG; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore., Liu Z; Duke-National University of Singapore Medical School, Singapore, Singapore.; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore., Li Z; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore., Chung SJ; Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea., Lian MM; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore., Tandiono M; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore., Heng YJ; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore., Ng EY; Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore., Tan LC; Department of Neurology, National Neuroscience Institute, Singapore, Singapore., Chng WL; Duke-National University of Singapore Medical School, Singapore, Singapore., Tan TJ; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore., Peh EK; Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore, Singapore., Ho YS; Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore, Singapore., Chen XY; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore., Lim EY; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore., Chang CH; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore., Leong JJ; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore., Peh TX; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore., Chan LL; Duke-National University of Singapore Medical School, Singapore, Singapore.; Department of Neuroradiology, Singapore General Hospital, Singapore, Singapore., Chao Y; Duke-National University of Singapore Medical School, Singapore, Singapore.; Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore., Au WL; Department of Neurology, National Neuroscience Institute, Singapore, Singapore., Prakash KM; Duke-National University of Singapore Medical School, Singapore, Singapore.; Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore., Lim JL; Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia., Tay YW; Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia., Mok V; 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.; Gerald Choa Neuroscience Institute, Li Ka Shing Institute of Health Sciences, Hong Kong, China., Chan AY; 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., Lin JJ; Department of Neurology, Chushang Show-Chwan Hospital, Nantou, Taiwan., Jeon BS; Department of Neurology, Seoul National University Hospital, Seoul, South Korea., Song K; Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea., Tham CC; Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China., Pang CP; Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China., Ahn J; Department of Ophthalmology, Seoul Metropolitan Government, Seoul National University Boramae Medical Center, Seoul, South Korea.; Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea., Park KH; Department of Ophthalmology, Seoul National University Hospital, Seoul, Korea., Wiggs JL; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA., Aung T; Duke-National University of Singapore Medical School, Singapore, Singapore.; Singapore Eye Research Institute, Singapore, Singapore., Tan AH; Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia., Ahmad Annuar A; Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia., Makarious MB; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.; UCL Movement Disorders Centre, University College London, London, UK., Blauwendraat C; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; 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., Nalls MA; 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.; Data Tecnica International, LLC, Bethesda, MD, USA., Robak LA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Jan and Dan Duncan Neurologic Research Institute, Texas Children's Hospital, Houston, TX, USA., Alcalay RN; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.; Columbia University Irving Medical Center, New York, NY, USA., Gan-Or Z; The Neuro (Montréal Neurological Institute-Hospital), McGill University, Montréal, QC, Canada.; Department of Human Genetics, McGill University, Montréal, QC, Canada.; Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada., Reynolds R; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore.; Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK., Lim SY; Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia., Xia Y; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore., Khor CC; Duke-National University of Singapore Medical School, Singapore, Singapore. khorcc@gis.a-star.edu.sg.; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore. khorcc@gis.a-star.edu.sg.; Singapore Eye Research Institute, Singapore, Singapore. khorcc@gis.a-star.edu.sg., Tan EK; Duke-National University of Singapore Medical School, Singapore, Singapore. gnrtek@sgh.com.sg.; Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore. gnrtek@sgh.com.sg., Wang Z; Duke-National University of Singapore Medical School, Singapore, Singapore. zhenxun.wang@duke-nus.edu.sg.; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore. zhenxun.wang@duke-nus.edu.sg., Foo JN; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore. jianee.foo@ntu.edu.sg.; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore. jianee.foo@ntu.edu.sg.
Jazyk: angličtina
Zdroj: Nature aging [Nat Aging] 2024 Nov 21. Date of Electronic Publication: 2024 Nov 21.
DOI: 10.1038/s43587-024-00760-7
Abstrakt: 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.
Competing Interests: Competing interests: Z.G.-O. received consultancy fees from Lysosomal Therapeutics, Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanqua Bio, Congruence Therapeutics, Takeda, Jazz Pharmaceuticals, Guidepoint, Lighthouse and Deerfield. R.N.A. received consultation fees from Biogen, Biohaven, Capsida, Gain Therapeutics, Genzyme/Sanofi, Janssen, Servier, SK Biopharmaceuticals, Takeda and Vanqua Bio. Y.X. holds a stock option in NeoCytogen Therapeutics where she is scientific co-founder and Chief Scientific Officer. M.A.N.’s participation in this project was part of a competitive contract awarded to DataTecnica, LLC by the National Institutes of Health to support open science research. M.A.N. also owns stock in Character Bio, Inc. and Neuron23, Inc. The other authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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