Genome-wide association study using whole-genome sequencing identifies risk loci for Parkinson's disease in Chinese population

• Main Authors: Pan, Hongxu, Liu, Zhenhua, Ma, Jinghong, Li, Yuanyuan, Zhao, Yuwen, Zhou, Xiaoxia, Xiang, Yaqin, Wang, Yige, Zhou, Xun, He, Runcheng, Xie, Yali, Zhou, Qiao, Yuan, Kai, Xu, Qian, Sun, Qiying, Wang, Junling, Yan, Xinxiang, Zhang, Hainan, Wang, Chunyu, Lei, Lifang, Liu, Weiguo, Wang, Xuejing, Ding, Xuebing, Wang, Tao, Xue, Zheng, Zhang, Zhentao, Chen, Ling, Wang, Qing, Liu, Yonghong, Tang, Jiayu, Zhang, Xuewei, Peng, Shifang, Wang, Chaodong, Ding, Jianqing, Liu, Chunfeng, Wang, Lijuan, Chen, Haibo, Shen, Lu, Jiang, Hong, Wu, Xinyin, Tan, Hongzhuan, Luo, Dan, Xiao, Shuiyuan, Chen, Xiang, Tan, Jieqiong, Hu, Zhengmao, Chen, Chao, Xia, Kun, Zhang, Zhuohua, Foo, Jia Nee, Blauwendraat, Cornelis, Nalls, Mike A., Singleton, Andrew B., Liu, Jun, Chan, Piu, Zheng, Houfeng, Li, Jinchen, Guo, Jifeng, Yang, Jian, Tang, Beisha
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2024
• Subjects: Medicine, Health and Life Sciences; Parkinson disease; Chinese
• Online Access: https://hdl.handle.net/10356/173730
• Institution: Nanyang Technological University

Genome-wide association studies (GWASs) have identified numerous susceptibility loci for Parkinson's disease (PD), but its genetic architecture remains underexplored in populations of non-European ancestry. To identify genetic variants associated with PD in the Chinese population, we performed a GWAS using whole-genome sequencing (WGS) in 1,972 cases and 2,478 controls, and a replication study in a total of 8209 cases and 9454 controls. We identified one new risk variant rs61204179 (Pcombined = 1.47 × 10-9) with low allele frequency, four previously reported risk variants (NUCKS1/RAB29-rs11557080, SNCA-rs356182, FYN-rs997368, and VPS13C-rs2251086), as well as three risk variants in LRRK2 coding region (A419V, R1628P, and G2385R) with genome-wide significance (P < 5 × 10-8) for PD in Chinese population. Moreover, of the reported genome-wide significant risk variants found mostly in European ancestry populations, the correlation coefficient (rb) of effect size accounting for sampling errors was 0.91 between datasets and 63.6% attained P < 0.05 in Chinese population. Accordingly, we estimated a heritability of 0.14-0.18 for PD, and a moderate genetic correlation between European ancestry and Chinese populations (rg = 0.47, se = 0.21). Polygenic risk score (PRS) analysis revealed that individuals with PRS values in the highest quartile had a 3.9-fold higher risk of developing PD than the lowest quartile. In conclusion, the present GWAS identified PD-associated variants in Chinese population, as well as genetic factors shared among distant populations. Our findings shed light on the genetic homogeneity and heterogeneity of PD in different ethnic groups and suggested WGS might continue to improve our understanding of the genetic architecture of PD.