Genome-wide epistasis analysis in Parkinson’s disease between populations with different genetic ancestry reveals significant variant-variant interactions

Genome-wide association studies (GWAS) have increased our understanding of Parkinson’s disease (PD) genetics through the identification of common disease-associated variants. However, much of the heritability remains unaccounted for and we hypothesized that this could be partly explained by epistasis. Here, we developed a genome-wide non-exhaustive epistasis screening pipeline called Variant-variant interaction through variable thresholds ( VARI3 ) and applied it to diverse PD GWAS cohorts. First, as a discovery cohort, we used 14 cohorts of European ancestry (14,671 cases and 17,667 controls) to identify candidate variant-variant interactions. Next, we replicated significant results in a cohort with a predominately Latino genetic ancestry (807 cases and 690 controls). We identified 14 significant epistatic signals in the discovery stage, with genes showing enrichment in PD-relevant ontologies and pathways. Next, we successfully replicated two of the 14 interactions, where the signals were located nearby SNCA and within MAPT and WNT3 . Finally, we determined that the epistatic effect on PD of those variants was similar between populations. In brief, we identified several epistatic signals associated with PD and replicated associations despite differences in the genetic ancestry between cohorts. We also observed their biological relevance and effect on the phenotype using in silico analysis. ### Competing Interest Statement D.K. is the Founder and Scientific Advisory Board Chair of Lysosomal Therapeutics Inc. and Vanqua Bio. D.K. serves on the scientific advisory boards of The Silverstein Foundation, Intellia Therapeutics, AcureX and Prevail Therapeutics and is a Venture Partner at OrbiMed. M.A.N. is the founder and CEO/Consultant of Data Tecnica International LLC, and serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc. A.C-G., B.I.B, S.B-C., T.P.L, E.I.S, C.J, C.B, A.B.S, I.F.M, S.J.L and J.A.B declare that they have no competing interests. ### Funding Statement A.C-G. was supported by the Science and Technology Agency, Seneca Foundation, Comunidad Autonoma Region de Murcia, Spain through the grant 20762/FPI/18. D.K. is supported by the Simpson Querrey Center for Neurogenetics. ### 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: Data used in preparation of this article were obtained from controlled access data from the IPDGC, including the Baylor College of Medicine / University of Maryland cohort, Finnish PD GWAS, McGill Parkinson's cohort, Oslo PD Study, Spanish Parkinson's cohort, UK PD GWAS, Vance PD cohort, Dutch PD GWAS, German PD GWAS, NIA PD GWAS, PROPARK study, PROBAND study, TUBI (Tubingen) cohort, Myers-Faroud cohort, and LARGE-PD cohort. As the analyses in this manuscript utilize secondary analyses of suitably anonymized datasets, they do not require ethics committee review. The respective ethical committees for medical research approved involvement in genetic studies and all participants gave written informed consent in the original publications for the datasets used. The details of these studies can be obtained upon contacting the IPDGC (ipdgc.contact{at}gmail.com). 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 and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The code generated during this study is available at Data used in preparation of this article were obtained from controlled access data from the IPDGC, including the Baylor College of Medicine / University of Maryland cohort, Finnish PD GWAS, McGill Parkinson's cohort, Oslo PD Study, Spanish Parkinson's cohort, UK PD GWAS, Vance PD cohort, Dutch PD GWAS, German PD GWAS, NIA PD GWAS, PROPARK study, PROBAND study, TUBI (Tubingen) cohort, Myers-Faroud cohort, and LARGE-PD cohort. As the analyses in this manuscript utilize secondary analyses of suitably anonymized datasets, they do not require ethics committee review. The respective ethical committees for medical research approved involvement in genetic studies and all participants gave written informed consent in the original publications for the datasets used. The details of these studies can be obtained upon contacting the IPDGC (ipdgc.contact{at}gmail.com).