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Med."],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Genetic factors contribute to neurodegenerative diseases, with high heritability estimates across diagnoses; however, a large portion of the genetic influence remains poorly understood. Many previous studies have attempted to fill the gaps by performing linkage analyses and association studies in individual disease cohorts, but have failed to consider the clinical and pathological overlap observed across neurodegenerative diseases and the potential for genetic overlap between the phenotypes. Here, we leveraged rare variant association analyses (RVAAs) to elucidate the genetic overlap among multiple neurodegenerative diagnoses, including Alzheimer\u2019s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson\u2019s disease (PD), as well as cerebrovascular disease, using the data generated with a custom-designed neurodegenerative disease gene panel in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). As expected, only ~3% of ONDRI participants harboured a monogenic variant likely driving their disease presentation. Yet, when genes were binned based on previous disease associations, we observed an enrichment of putative loss of function variants in PD genes across all ONDRI cohorts. Further, individual gene-based RVAA identified significant enrichment of rare, nonsynonymous variants in <jats:italic>PARK2<\/jats:italic> in the FTD cohort, and in <jats:italic>NOTCH3<\/jats:italic> in the PD cohort. The results indicate that there may be greater heterogeneity in the genetic factors contributing to neurodegeneration than previously appreciated. Although the mechanisms by which these genes contribute to disease presentation must be further explored, we hypothesize they may be a result of rare variants of moderate phenotypic effect contributing to overlapping pathology and clinical features observed across neurodegenerative diagnoses.<\/jats:p>","DOI":"10.1038\/s41525-021-00243-3","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T10:03:06Z","timestamp":1632823386000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Contribution of rare variant associations to neurodegenerative disease presentation"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3863-9304","authenticated-orcid":false,"given":"Allison A.","family":"Dilliott","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9820-3110","authenticated-orcid":false,"given":"Abdalla","family":"Abdelhady","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5003-1935","authenticated-orcid":false,"given":"Kelly M.","family":"Sunderland","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sali M. 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M.F. is listed on a patent related to methods and kits for differential diagnosis of Alzheimer disease vs frontotemporal dementia using blood biomarkers. D.G. reports honorariums from Sunovion and Paladin Labs Inc. as well as clinical trials with CIHR, Genzyme Corporation\/Sanofi Canada, and Eli Lilly and Company. A.E.L. reports consultancy support from Abbvie, Acorda, AFFiRis, Biogen, Denali, Janssen, Intracellular, Kallyope, Lundbeck, Paladin, Retrophin, Roche, Sun Pharma, Theravance, and Corticobasal Degeneration Solutions; advisory board support form Jazz Pharma, PhotoPharmics, Sunovion; other honoraria from Sun Pharma, AbbVie, Sunovion, American Academy of Neurology and the International Parkinson and Movement Disorder Society; grants from Brain Canada, Canadian Institutes of Health Research, Corticobasal Degeneration Solutions, Edmond J Safra Philanthropic Foundation, Michael J. Fox Foundation, the Ontario Brain Institute, Parkinson Foundation, Parkinson Canada, and W. Garfield Weston Foundation and royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press. M.M. receives salary support from the Department of Medicine at Sunnybrook Health Sciences Centre, the University of Toronto, and the Sunnybrook Research Institute, as well as advisory board support from Arkuda Therapeutics, Ionis Pharmaceuticals, Alector and Wave Life Sciences; royalties from Henry Stewart Talks Ltd; grants paid to institution from Weston Brain Institute, Ontario Brain Institute, Washington University and Canadian Institutes of Health Research outside the submitted work; and clinical trials support from Roche and Alector. G.S. is the Editor-in-Chief of the World Stroke Academy for the World Stroke Organization and receives CME honorarium from Servier and Roche, as well as grants from Roche. M.C.T. receives consultancy support from Biogen and Hoffman-La Roche and is a board member of Alzheimer\u2019s Society of Toronto. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"80"}}