Polygenic risk score for disability and insights into disability-related molecular mechanisms
Late life disability is a highly devastating condition affecting 20% or more of persons aged 65 years and older in the USA; it is an important determinant of acute medical and long-term care costs which represent a growing burden on national economies. Disability is a multifactorial trait that contributes substantially to decline of health/wellbeing. Accordingly, gaining insights into the genetics of disability could help in identifying molecular mechanisms of this devastating condition and age-related processes contributing to a large fraction of specific geriatric conditions, concordantly with geroscience. We performed a genome-wide association study of disability in a sample of 24,068 subjects from five studies with 12,550 disabled individuals. We identified 30 promising disability-associated polymorphisms in 19 loci at p < 10−4; four of them attained suggestive significance, p < 10−5. In contrast, polygenic risk scores aggregating effects of minor alleles of independent SNPs that were adversely or beneficially associated with disability showed highly significant associations in meta-analysis, p = 3.13 × 10−45 and p = 5.60 × 10−23, respectively, and were replicated in each study. The analysis of genetic pathways, related diseases, and biological functions supported the connections of genes for the identified SNPs with disabling and age-related conditions primarily through oxidative/nitrosative stress, inflammatory response, and ciliary signaling. We identified musculoskeletal system development, maintenance, and regeneration as important components of gene functions. The beneficial and adverse gene sets may be differently implicated in the development of musculoskeletal-related disability with the beneficial set characterized, e.g., by regulation of chondrocyte proliferation and bone formation, and the adverse set by inflammation and bone loss.
KeywordsDisability Polygenic risk score Genetic architecture Biological function
A.M.K. conceived and designed the experiment and wrote the paper; C.K., S.A.K., and Y.L. performed statistical analyses; C.K., A.I.Y., and E.S. contributed to drafting of the paper. C.K., A.N., and I.C. prepared data. I.C. performed biological analysis
This research was supported by the National Institute on Aging (grant numbers P01 AG043352, R01 AG047310, and R01 AG061853). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This manuscript was prepared using limited access datasets obtained though the dbGaP (accession numbers phs000315.v7.p3, phs000675.v3.p3, phs000287.v3.p1, phs000007.v29.p10, and phs000428.v1.p1) and the University of Michigan. See also Supporting Acknowledgment Text in Online Resource 1.
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Conflict of interest
The authors declare that they have no conflict of interest.
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