Back to Search
Start Over
Genome-wide survival study identifies a novel synaptic locus and polygenic score for cognitive progression in Parkinson's disease.
- Source :
-
Nature genetics [Nat Genet] 2021 Jun; Vol. 53 (6), pp. 787-793. Date of Electronic Publication: 2021 May 06. - Publication Year :
- 2021
-
Abstract
- A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10 <superscript>-11</superscript> ), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10 <superscript>-8</superscript> ) and WWOX (HR = 2.12, P = 2.37 × 10 <superscript>-8</superscript> ) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.
- Subjects :
- Apolipoprotein E4 genetics
Cognition Disorders genetics
Genetic Predisposition to Disease
Glucosylceramidase genetics
Humans
Longitudinal Studies
Mutation genetics
Parkinson Disease physiopathology
Proportional Hazards Models
Risk Factors
Survival Analysis
Cognition
Disease Progression
Genetic Loci
Genome-Wide Association Study
Multifactorial Inheritance genetics
Parkinson Disease genetics
Parkinson Disease pathology
Synapses genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1718
- Volume :
- 53
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Nature genetics
- Publication Type :
- Academic Journal
- Accession number :
- 33958783
- Full Text :
- https://doi.org/10.1038/s41588-021-00847-6