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

Parkinson’s 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 Parkinson’s 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 Parkinson’s disease. Genes surpassing exome-wide significance ( P <2.5×10-6) were tested for replication in sequencing data from a further 5,585 Parkinson’s 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 Parkinson’s 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 Parkinson’s disease risk in both the discovery (odds ratio (OR) = 2.37, 95% CI = 1.68 - 3.35, P = 4.35 × 10-7) and replication collections (OR = 2.18, 95% CI = 1.69 - 2.81, P = 4.80 × 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 × 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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work is supported by the Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant (MOH-000207; to E.-K.T.) Open Fund Individual Research Grant (MOH-000559; to J.N.F.; MOH-001110; to Z.W.), Singapore Translational Research Investigator Award (STaR) (MOH-000435; to. T.A. and Z.W.), as well as the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE-T2EP30220-0005; to J.N.F.) and Tier 3 (MOE-MOET32020-0004; to J.N.F.). C.C.K is supported by the Singapore National Research Foundation Investigatorship (NRF-NRFI2018-01). S.-Y.L. and A.-H.T. are supported by the University of Malaya Parkinson's Disease and Movement Disorders Research Program (PV035-2017). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the ethics committees or institutional review boards of the respective institutions (SingHealth Centralized Institutional Review Board CIRB 2002/008/A and 2019/2334 and Nanyang Technological University Institutional Review Board IRB-2016-08-011). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes