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

Foo JN 1 , Chew EGY 1 , Chung SJ 2 , Peng R 3 , Blauwendraat C 4 , Nalls MA 4 Show all authors , Mok KY 5 , Satake W 6 , Toda T 7 , Chao Y 8 , Tan LCS 9 , Tandiono M 1 , Lian MM 1 , Ng EY 8 , Prakash KM 8 , Au WL 10 , Meah WY 11 , Mok SQ 11 , Annuar AA 12 , Chan AYY 13 , Chen L 14 , Chen Y 3 , Jeon BS 15 , Jiang L 14 , Lim JL 12 , Lin JJ 16 , Liu C 17 , Mao C 17 , Mok V 13 , Pei Z 14 , Shang HF 3 , Shi CH 18 , Song K 19 , Tan AH 20 , Wu YR 21 , Xu YM 18 , Xu R 22 , Yan Y 23 , Yang J 18 , Zhang B 23 , Koh WP 9 , Lim SY 20 , Khor CC 11 , Liu J 11 , Tan EK 8

Affiliations 

  • 1 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
  • 2 Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
  • 3 Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China
  • 4 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland
  • 5 Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, United Kingdom
  • 6 Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
  • 7 Department of Neurology, The University of Tokyo Graduate School of Medicine, Bunkyo, Tokyo, Japan
  • 8 Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore, Singapore
  • 9 Duke-National University of Singapore Medical School, Singapore, Singapore
  • 10 Department of Neurology, National Neuroscience Institute, Singapore, Singapore
  • 11 Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore
  • 12 Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 13 Margaret 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
  • 14 Department of Neurology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
  • 15 Department of Neurology, Seoul National University Hospital, Jongno-gu, Seoul, South Korea
  • 16 Department of Neurology, Chushang Show-Chwan Hospital, Zhushan District, Nantou, Taiwan
  • 17 Department of Neurology, Second Affiliated Hospital of Soochow University, Suzhou, PR China
  • 18 Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, PR China
  • 19 Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, South Korea
  • 20 Mah 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
  • 21 Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University, Taipei, Taiwan
  • 22 Department of Neurology, Jiangxi Provincial People's Hospital, Affiliated People's Hospital of Nanchang University, Nanchang, Jiangxi, PR China
  • 23 Second Affiliated Hospital, Department of Neurology, Zhejiang University College of Medicine, Hangzhou, Zhejiang Province, PR China
JAMA Neurol, 2020 06 01;77(6):746-754.
PMID: 32310270 DOI: 10.1001/jamaneurol.2020.0428

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.

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

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