Contribution of rare variant associations to neurodegenerative disease presentation
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Published:2021-09-28
Issue:1
Volume:6
Page:
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ISSN:2056-7944
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Container-title:npj Genomic Medicine
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language:en
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Short-container-title:npj Genom. Med.
Author:
Dilliott Allison A.ORCID, Abdelhady AbdallaORCID, Sunderland Kelly M.ORCID, Farhan Sali M. K., Abrahao Agessandro, Binns Malcolm A., Black Sandra E., Borrie Michael, Casaubon Leanne K., Dowlatshahi Dar, Finger Elizabeth, Fischer Corinne E., Frank Andrew, Freedman Morris, Grimes David, Hassan Ayman, Jog Mandar, Kumar Sanjeev, Kwan Donna, Lang Anthony E.ORCID, Mandzia Jennifer, Masellis Mario, McIntyre Adam D., Pasternak Stephen H.ORCID, Pollock Bruce G.ORCID, Rajji Tarek K., Rogaeva Ekaterina, Sahlas Demetrios J., Saposnik Gustavo, Sato Christine, Seitz Dallas, Shoesmith Christen, Steeves Thomas D. L., Swartz Richard H., Tan BrianORCID, Tang-Wai David F., Tartaglia Maria C., Turnbull John, Zinman Lorne, Hegele Robert A.ORCID,
Abstract
AbstractGenetic 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’s disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), mild cognitive impairment, and Parkinson’s 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 PARK2 in the FTD cohort, and in NOTCH3 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.
Funder
Ontario Brain Institute
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics,Molecular Biology
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