Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans
Authors: Jia Nee Foo, Elaine Guo Yan Chew, Sun Ju Chung, Rong Peng, Cornelis Blauwendraat, Mike A. Nalls, Kin Y. Mok, Wataru Satake, Tatsushi Toda, Yinxia Chao, Louis C. S. Tan, Moses Tandiono, Michelle M. Lian, Ebonne Y. Ng, Kumar-M. Prakash, Wing-Lok Au, Wee-Yang Meah, Shi Qi Mok, Azlina Ahmad Annuar, Anne Y. Y. Chan, Ling Chen, Yongping Chen, Beom S. Jeon, Lulu Jiang, Jia Lun Lim, Juei-Jueng Lin, Chunfeng Liu, Chengjie Mao, Vincent Mok, Zhong Pei, Hui-Fang Shang, Chang-He Shi, Kyuyoung Song, Ai Huey Tan, Yih-Ru Wu, Yu-ming Xu, Renshi Xu, Yaping Yan, Jing Yang, BaoRong Zhang, Woon-Puay Koh, Shen-Yang Lim, Chiea Chuen Khor, Jianjun Liu, Eng-King Tan
Journal: JAMA Neurology (2020)

<h3>Importance</h3> 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). <h3>Objectives</h3> To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts. <h3>Design Setting, and Participants</h3> 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. <h3>Main Outcomes and Measures</h3> Genotypes of common variants, association with disease status, and polygenic risk scores. <h3>Results</h3> 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 (<i>SV2C</i>and<i>WBSCR17</i>) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for<i>SV2C</i>(rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21;<i>P</i> = 1.17 × 10<sup>−10</sup>in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at<i>WBSCR17</i>(rs9638616;<i>I</i><sup>2</sup>=67.1%;<i>P</i> = 3.40 × 10<sup>−3</sup>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%;<i>P</i> = 6.81 × 10<sup>−12</sup>). <h3>Conclusions and Relevance</h3> 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.