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Meta-Analysis
. 2020 Jun 1;77(6):746-754.
doi: 10.1001/jamaneurol.2020.0428.

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

Jia Nee Foo  1   2 , Elaine Guo Yan Chew  1   2 , Sun Ju Chung  3 , Rong Peng  4 , Cornelis Blauwendraat  5 , Mike A Nalls  5   6 , Kin Y Mok  7 , Wataru Satake  8   9 , Tatsushi Toda  9 , Yinxia Chao  10   11 , Louis C S Tan  11   12 , Moses Tandiono  1   2 , Michelle M Lian  1   2 , Ebonne Y Ng  10 , Kumar-M Prakash  10 , Wing-Lok Au  12 , Wee-Yang Meah  2 , Shi Qi Mok  2 , Azlina Ahmad Annuar  13 , Anne Y Y Chan  14 , Ling Chen  15 , Yongping Chen  4 , Beom S Jeon  16 , Lulu Jiang  15 , Jia Lun Lim  13   17 , Juei-Jueng Lin  18 , Chunfeng Liu  19 , Chengjie Mao  19 , Vincent Mok  14 , Zhong Pei  15 , Hui-Fang Shang  4 , Chang-He Shi  20 , Kyuyoung Song  21 , Ai Huey Tan  17 , Yih-Ru Wu  22 , Yu-Ming Xu  20 , Renshi Xu  23 , Yaping Yan  24 , Jing Yang  20 , BaoRong Zhang  24 , Woon-Puay Koh  11 , Shen-Yang Lim  17 , Chiea Chuen Khor  2   25 , Jianjun Liu  2 , Eng-King Tan  10   11
Affiliations
Meta-Analysis

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

Jia Nee Foo et al. JAMA Neurol. .

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Foo reported receiving grants from the National Research Foundation of Singapore during the conduct of the study; in addition, Dr Foo had a patent to Biomarkers for risk prediction of Parkinson disease pending. Dr Nalls reported receiving personal fees from the National Institutes of Health during the conduct of the study. Dr K. Mok reported receiving grants from the Medical Research Council and Wellcome Trust during the conduct of the study; grants from Weston Medical Trustees, Wellcome Trust, the Medical Research Council, the Innovation Commission of the Government of Hong Kong, Chow Tai Fook Charity, and the Michael J Fox Foundation outside the submitted work; and having an honorary appointment, with no financial compensation, in Hong Kong University of Science and technology. Dr Satake reported receiving grants from the Japan Agency for Medical Research and Development during the conduct of the study. Dr A. H. Tan reported receiving lecturing honoraria from Novartis, Boehringer Ingelheim, and the International Parkinson & Movement Disorder Society. Dr S. Lim reported receiving lecturing honoraria from the Asian Oceanian Association of Neurology, Chinese Neuroscience Society, Chinese University of Hong Kong, Head Foundation Singapore, International Association of Parkinsonism and Related Disorders, International Parkinson and Movement Disorder Society, Ipsen, Japan International Parkinson Disease and Movement Disorder Symposium, Korean Movement Disorders Society, Lundbeck, Medtronic, Novartis, Taiwan Movement Disorder Society, and UCB; and consultation fees from Lundbeck. Dr J. Liu reported having a patent to Biomarkers for risk prediction of Parkinson disease. Dr E. K. Tan reported having a patent to Biomarkers for risk prediction of Parkinson disease. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Genome-Wide Association Study of Parkinson Disease in East Asian Individuals
Meta–genome-wide association studies of 5 East Asian sample collections, with novel loci labeled in red, previously reported loci in black, and genome-wide significant loci in bold font. Horizontal lines indicate the thresholds for genome-wide significant association (5 × 10−8) (red) and suggestive association (1 × 10−4) (blue).
Figure 2.
Figure 2.. Two Novel Parkinson Disease Risk Loci
Associations at SV2C (A) and WBSCR17 (B) in the Asian meta–genome-wide association studies. chr Indicates chromosome; cM/Mb, centimorgan/megabase (genomic location in reference build 37 [Hg19]); OR, odds ratio; and SNV, single-nucleotide variant (formerly SNP).
Figure 3.
Figure 3.. Polygenic Risk Score (PRS) Analysis in Asian Samples
Polygenic risk score distribution using 11 genome-wide significant Asian single-nucleotide variant (SNVs) (formerly, SNP) (A) and 90 known Parkinson disease SNVs (78 polymorphic) (B) identified in European samples and receiver operator curve based on polygenic risk prediction of Parkinson disease with previously reported SNVs (black) (area under the curve [AUC], 60.2%) vs combined European and Asian SNVs (orange) (AUC, 63.1%) (C).
See this image and copyright information in PMC

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