Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson's...

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.