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Original Investigation
April 20, 2020

Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study

Author Affiliations
  • 1Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
  • 2Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore
  • 3Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
  • 4Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
  • 5Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
  • 6Data Tecnica International LLC, Glen Echo, Maryland
  • 7Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom
  • 8Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
  • 9Department of Neurology, The University of Tokyo Graduate School of Medicine, Bunkyo, Tokyo, Japan
  • 10Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore
  • 11Duke-National University of Singapore Medical School, Singapore, Singapore
  • 12Department of Neurology, National Neuroscience Institute, Singapore, Singapore
  • 13Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 14Margaret K. L. Cheung Research Centre for Management of Parkinsonism, Gerald Choa Neuroscience Centre, Lui Che Woo Institute of Innovative Medicine, Prince of Wales Hospital, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, PR China
  • 15Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
  • 16Department of Neurology, Seoul National University Hospital, Jongno-gu, Seoul, South Korea
  • 17Mah Pooi Soo and Tan Chin Nam Centre for Parkinson's and Related Disorders, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 18Department of Neurology, Chushang Show-Chwan Hospital, Zhushan District, Nantou, Taiwan
  • 19Department of Neurology, Second Affiliated Hospital of Soochow University, Suzhou, PR China
  • 20Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
  • 21Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea
  • 22Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan
  • 23Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang, Jiangxi, PR China
  • 24Second Affiliated Hospital, Department of Neurology, Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, PR China
  • 25Singapore Eye Research Institute, Singapore, Singapore
JAMA Neurol. Published online April 20, 2020. doi:10.1001/jamaneurol.2020.0428
Key Points

Question  What are the genetic risk loci for Parkinson disease in an Asian population?

Findings  In this genetic-association study of 31 575 individuals, 1 novel locus SV2C showed robust replication in European and Japanese samples; 11 genome-wide significant loci were identified in an Asian-only meta–genome-wide association study in 6724 individuals with Parkinson disease and 24 851 controls. Substantial overlap in genetic risk factors appeared to exist between Asian and European individuals, with 63 of 78 polymorphic European risk variants displaying a similar direction of association.

Meaning  Risk prediction models constructed based on Asian and European risk variants appear to be associated with improvements in stratification of Parkinson disease risk in the worldwide population of Asian individuals.

Abstract

Importance  Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian).

Objectives  To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts.

Design Setting, and Participants  Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31 575 individuals passing quality control of 35 994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1 926 361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson’s Disease Society Brain Bank Criteria.

Main Outcomes and Measures  Genotypes of common variants, association with disease status, and polygenic risk scores.

Results  Of 31 575 samples identified, 6724 PD cases (mean [SD] age, 64.3 [10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24 851 controls (age, 59.4 [11.4] years; 11 030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P = 1.17 × 10−10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P = 3.40 × 10−3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P = 6.81 × 10−12).

Conclusions and Relevance  This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta–genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.

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