Exome sequencing in Asian populations identifies rare deficient SMPD1 alleles that increase risk of Parkinson's disease

Parkinsons disease is an incurable and progressive disease that adversely affects balance, muscle control, and movement. We hypothesized that the landscape of rare, protein-altering genetic variants could provide further mechanistic insights into disease pathogenesis. We performed whole-exome sequencing on 4,298 persons with Parkinsons disease and 5,512 unaffected controls from Singapore, Malaysia, Hong Kong, South Korea, and Taiwan. We tested for association between gene-based burden of rare, predicted damaging variants and risk of Parkinsons disease. Genes surpassing exome-wide significance (P<2.5x10-6) were tested for replication in sequencing data from a further 5,585 Parkinsons disease patients and 5,642 controls of Asian and European ancestry. We observed that carriage of rare, protein-altering variants that were predicted to impair protein function at SMPD1 (a gene encoding for acid sphingomyelinase) were significantly associated with increased risk of Parkinsons disease. Refinement of variant classification using functional acid sphingomyelinase assays suggest that individuals carrying SMPD1 variants with less than 44 percent of normal enzymatic activity show the strongest association with Parkinsons disease risk in both the discovery (odds ratio (OR) = 2.37, 95% CI = 1.68 - 3.35, P = 4.35 x 10-7) and replication collections (OR = 2.18, 95% CI = 1.69 - 2.81, P = 4.80 x 10-10), leading to a significant observation when all data were meta-analyzed (OR = 2.24, 95% CI = 1.83 - 2.76, P = 1.25 x 10-15). Our findings affirm the importance of sphingomyelin metabolism in the pathobiology of neurodegenerative diseases and highlights the utility of functional genomic assays in large-scale exome sequencing studies.