Contribution of rare variant associations to neurodegenerative disease presentation
Abstract 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 stud...
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Nature Portfolio
2021
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oai:doaj.org-article:c14898e55b0f4ab5b45663002d3057662021-12-02T18:51:09ZContribution of rare variant associations to neurodegenerative disease presentation10.1038/s41525-021-00243-32056-7944https://doaj.org/article/c14898e55b0f4ab5b45663002d3057662021-09-01T00:00:00Zhttps://doi.org/10.1038/s41525-021-00243-3https://doaj.org/toc/2056-7944Abstract 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’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.Allison A. DilliottAbdalla AbdelhadyKelly M. SunderlandSali M. K. FarhanAgessandro AbrahaoMalcolm A. BinnsSandra E. BlackMichael BorrieLeanne K. CasaubonDar DowlatshahiElizabeth FingerCorinne E. FischerAndrew FrankMorris FreedmanDavid GrimesAyman HassanMandar JogSanjeev KumarDonna KwanAnthony E. LangJennifer MandziaMario MasellisAdam D. McIntyreStephen H. PasternakBruce G. PollockTarek K. RajjiEkaterina RogaevaDemetrios J. SahlasGustavo SaposnikChristine SatoDallas SeitzChristen ShoesmithThomas D. L. SteevesRichard H. SwartzBrian TanDavid F. Tang-WaiMaria C. TartagliaJohn TurnbullLorne ZinmanONDRI InvestigatorsRobert A. HegeleNature PortfolioarticleMedicineRGeneticsQH426-470ENnpj Genomic Medicine, Vol 6, Iss 1, Pp 1-9 (2021) |
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Medicine R Genetics QH426-470 |
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Medicine R Genetics QH426-470 Allison A. Dilliott Abdalla Abdelhady Kelly M. Sunderland Sali M. K. Farhan Agessandro Abrahao Malcolm A. Binns Sandra E. Black Michael Borrie Leanne K. Casaubon Dar Dowlatshahi Elizabeth Finger Corinne E. Fischer Andrew Frank Morris Freedman David Grimes Ayman Hassan Mandar Jog Sanjeev Kumar Donna Kwan Anthony E. Lang Jennifer Mandzia Mario Masellis Adam D. McIntyre Stephen H. Pasternak Bruce G. Pollock Tarek K. Rajji Ekaterina Rogaeva Demetrios J. Sahlas Gustavo Saposnik Christine Sato Dallas Seitz Christen Shoesmith Thomas D. L. Steeves Richard H. Swartz Brian Tan David F. Tang-Wai Maria C. Tartaglia John Turnbull Lorne Zinman ONDRI Investigators Robert A. Hegele Contribution of rare variant associations to neurodegenerative disease presentation |
| description |
Abstract 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’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. |
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| author |
Allison A. Dilliott Abdalla Abdelhady Kelly M. Sunderland Sali M. K. Farhan Agessandro Abrahao Malcolm A. Binns Sandra E. Black Michael Borrie Leanne K. Casaubon Dar Dowlatshahi Elizabeth Finger Corinne E. Fischer Andrew Frank Morris Freedman David Grimes Ayman Hassan Mandar Jog Sanjeev Kumar Donna Kwan Anthony E. Lang Jennifer Mandzia Mario Masellis Adam D. McIntyre Stephen H. Pasternak Bruce G. Pollock Tarek K. Rajji Ekaterina Rogaeva Demetrios J. Sahlas Gustavo Saposnik Christine Sato Dallas Seitz Christen Shoesmith Thomas D. L. Steeves Richard H. Swartz Brian Tan David F. Tang-Wai Maria C. Tartaglia John Turnbull Lorne Zinman ONDRI Investigators Robert A. Hegele |
| author_facet |
Allison A. Dilliott Abdalla Abdelhady Kelly M. Sunderland Sali M. K. Farhan Agessandro Abrahao Malcolm A. Binns Sandra E. Black Michael Borrie Leanne K. Casaubon Dar Dowlatshahi Elizabeth Finger Corinne E. Fischer Andrew Frank Morris Freedman David Grimes Ayman Hassan Mandar Jog Sanjeev Kumar Donna Kwan Anthony E. Lang Jennifer Mandzia Mario Masellis Adam D. McIntyre Stephen H. Pasternak Bruce G. Pollock Tarek K. Rajji Ekaterina Rogaeva Demetrios J. Sahlas Gustavo Saposnik Christine Sato Dallas Seitz Christen Shoesmith Thomas D. L. Steeves Richard H. Swartz Brian Tan David F. Tang-Wai Maria C. Tartaglia John Turnbull Lorne Zinman ONDRI Investigators Robert A. Hegele |
| author_sort |
Allison A. Dilliott |
| title |
Contribution of rare variant associations to neurodegenerative disease presentation |
| title_short |
Contribution of rare variant associations to neurodegenerative disease presentation |
| title_full |
Contribution of rare variant associations to neurodegenerative disease presentation |
| title_fullStr |
Contribution of rare variant associations to neurodegenerative disease presentation |
| title_full_unstemmed |
Contribution of rare variant associations to neurodegenerative disease presentation |
| title_sort |
contribution of rare variant associations to neurodegenerative disease presentation |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/c14898e55b0f4ab5b45663002d305766 |
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