Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk
Elaine Guo Yan Chew, Zhehao Liu, Zheng Li, Sun Ju Chung, Michelle Mulan Lian, Moses Tandiono, Yue Jing Heng, Ebonne Ng, Louis C.S. Tan, Wee Ling Chng, Tiak Ju Tan, Esther KL Peh, Ying Swan Ho, Xiao Yin Chen, Erin YT Lim, Chu Hua Chang, Jonavan J. Leong, Ting Xuan Peh, Ling Ling Chan, Yinxia Chao, Wing‐Lok Au, Kumar M. Prakash, Jia Lun Lim, Yi Wen Tay, Vincent Mok, Anne Chan, Juei‐Jueng Lin, Beom S. Jeon, Kyuyoung Song, Clement C. Tham, Chi Pui Pang, Jeeyun Ahn, Kyu Hyung Park, Janey L. Wiggs, Tin Aung, Ai Huey Tan, Azlina Ahmad Annuar, Mary B. Makarious, Cornelis Blauwendraat, Mike A. Nalls, Laurie Robak, Roy N. Alcalay, Ziv Gan-Or, Richard Reynolds, Shen‐Yang Lim, Yun Xia, Chiea Chuen Khor, Eng‐King Tan, Zhenxun Wang, Jia Nee Foo
Abstract
Parkinson’s disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10−15) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10−8). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease. Using whole-exome sequencing followed by in vitro enzymatic assays, Chew, Liu, Li, Chung et al. identified rare protein-coding variants in GBA1 and SMPD1 that significantly associate with risk of Parkinson’s disease across cohorts of Asian descent.