{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T08:22:04Z","timestamp":1781857324976,"version":"3.54.5"},"reference-count":86,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T00:00:00Z","timestamp":1733702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100007801","name":"Science and Technology Agency, S\u00e9neca Foundation","doi-asserted-by":"publisher","award":["20762\/FPI\/18"],"award-info":[{"award-number":["20762\/FPI\/18"]}],"id":[{"id":"10.13039\/100007801","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01NS112499"],"award-info":[{"award-number":["1R01NS112499"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013301","name":"Parkinson\u2019s Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013301","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012264","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100012264","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["ZO1 AG000534"],"award-info":[{"award-number":["ZO1 AG000534"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Genome-wide association studies have increased our understanding of Parkinson\u2019s disease genetics by identifying common disease-associated variants. However, much of the heritability remains unaccounted for, and we hypothesized that this could be explained, in part, by epistasis, the statistical interaction between two or more genetic variants.<\/jats:p>\n               <jats:p>Here, we developed a genome-wide non-exhaustive epistasis screening pipeline called variant\u2013variant interaction through variable thresholds (VARI3) and applied it to diverse Parkinson\u2019s disease genome-wide association study cohorts. We used 14 cohorts of European ancestry (14 671 cases and 17 667 controls) as a discovery stage, identifying 14 significant candidate variant\u2013variant interactions. We then used four independent cohorts (13 377 cases and 413 789 controls) as the replication stage, successfully replicating three epistasis signals located near to SNCA and within MAPT and WNT3. Admixture analysis showed that the epistatic effect on Parkinson\u2019s disease of those variants at these loci was observed in individuals with both European ancestry and Native American ancestry. We assessed the functional impact of the epistasis signals across a range of functional\/-omics datasets, identifying significant single-variant expression quantitative trait loci across brain tissues, epistasis expression quantitative trait locus signals in whole blood, Parkinson\u2019s disease-relevant pathways and ontologies, and chromatin interactions between the regions of the interacting single nucleotide polymorphisms.<\/jats:p>\n               <jats:p>In conclusion, we identified and replicated novel epistatic signals associated with Parkinson\u2019s disease risk across multiple cohorts with diverse genetic ancestry, highlighting their enrichment in pathways relevant to Parkinson\u2019s disease.<\/jats:p>","DOI":"10.1093\/brain\/awae398","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T23:40:58Z","timestamp":1733874058000},"page":"2060-2074","source":"Crossref","is-referenced-by-count":5,"title":["Genome-wide epistasis analysis reveals significant epistatic signals associated with Parkinson\u2019s disease risk"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9927-7178","authenticated-orcid":false,"given":"Alejandro","family":"Cisterna-Garcia","sequence":"first","affiliation":[{"name":"Departamento de Ingenier\u00eda de la Informaci\u00f3n y las Comunicaciones, Universidad de Murcia , Murcia 30100 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2679-9503","authenticated-orcid":false,"given":"Bernabe I","family":"Bustos","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine , Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bandres-Ciga","sequence":"additional","affiliation":[{"name":"Molecular Genetics Section, Laboratory of Neurogenetics, and Center for Alzheimers and Related Dementias (CARD) National Institute on Aging, National Institutes of Health , Bethesda, MD 20892 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago P","family":"Leal","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute , Cleveland, OH 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif I","family":"Sarihan","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute , Cleveland, OH 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christie","family":"Jok","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine , Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4716-1886","authenticated-orcid":false,"given":"Dimitri","family":"Krainc","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine , Chicago, IL 60611 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio F","family":"Mata","sequence":"additional","affiliation":[{"name":"Genomic Medicine Institute, Lerner Research Institute , Cleveland, OH 44106 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J","family":"Lubbe","sequence":"additional","affiliation":[{"name":"Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine , Chicago, IL 60611 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