期刊
NPJ GENOMIC MEDICINE
卷 6, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41525-021-00243-3
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资金
- Ontario Brain Institute
- Ontario government
- Canadian Institute of Health Research
- Heart & Stroke Foundation Clinician Scientist Award
- CIHR
- Weston Foundation
- Alzheimer Society of Canada
- Physicians and Services Incorporated Foundation
- Ministry of Research and Innovation of Ontario
- Alector
- Biogen
- TauRx
- Vielight Inc.
- Hoffman-La Roche
- St. Michaels Hospital Foundation
- Brain Canada
- Patient-Centered Outcomes Research Institute
- Saul A. Silverman Family Foundation
- Parkinson Canada
- PSI Foundation
- Parkinson Research Consortium
- EU Joint Programme-Neurodegenerative Disease Research
- uOBMRI
- Brain and Behaviour Foundation
- National Institute on Aging
- BrightFocus Foundation
- Centre for Ageing and Brain Health Innovation
- Centre for Addiction and Mental Health
- University of Toronto
- Peter & Shelagh Godsoe Endowed Chair in Late-Life Mental Health
- Brain and Behavior Research Foundation
- Canada Foundation for Innovation
- Canada Research Chair
- Canadian Institutes of Health Research
- Centre for Aging and Brain Health Innovation
- National Institutes of Health
- Ontario Ministry of Health and Long-Term Care
- Ontario Ministry of Research and Innovation
- Weston Brain Institute
- Heart and Stroke Foundation Mid Career Scientist Award
- National Institute of Health
- Baycrest Foundation
- Bruyere Research Institute
- Centre for Addiction and Mental Health Foundation
- London Health Sciences Foundation
- LC Campbell Foundation
- McMaster University Faculty of Health Sciences
- Ottawa Brain and Mind Research Institute
- Queen's University Faculty of Health Sciences
- Providence Care (Kingston)
- Sunnybrook Health Sciences Foundation
- St. Michael's Hospital
- Thunder Bay Regional Health Sciences Centre
- University of Ottawa Faculty of Medicine
- Windsor/Essex County ALS Association
- Temerty Family Foundation
Rare variant association analyses were used to uncover genetic overlap among various neurodegenerative diseases, revealing enrichment of specific genes in different disease cohorts. The findings suggest a greater heterogeneity in the genetic factors contributing to neurodegeneration than previously thought.
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 similar to 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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