Distribution of 54 polygenic risk scores for common diseases in long lived individuals and their offspring

• Published in: GeroScience Vol. 44; no. 2; pp. 719 - 729
• Main Authors: Gunn, Sophia, Wainberg, Michael, Song, Zeyuan, Andersen, Stacy, Boudreau, Robert, Feitosa, Mary F., Tan, Qihua, Montasser, May E., O’Connell, Jeffrey R., Stitziel, Nathan, Price, Nathan, Perls, Thomas, Schork, Nicholas J., Sebastiani, Paola
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.04.2022; Springer Nature B.V
• Subjects: Aged, 80 and over; Aging; Alzheimer Disease - genetics; Alzheimer's disease; Biomedical and Life Sciences; Cardiovascular disease; Cell Biology; Cognitive ability; Coronary artery; Dementia; Dementia disorders; Environmental factors; Genetic disorders; Genetic Predisposition to Disease - genetics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Geriatrics; Geriatrics/Gerontology; Health risk assessment; Heart diseases; Humans; Life Sciences; Longevity; Molecular Medicine; Multifactorial Inheritance - genetics; Neurodegenerative diseases; Original; Original Article; Polygenic inheritance; Regression analysis; Risk assessment; Risk Factors; Long-lived families; polygenic risk scores; Exceptional Longevity
• DOI: 10.1007/s11357-022-00518-2
• ISSN: 2509-2715

A surprising and well-replicated result in genetic studies of human longevity is that centenarians appear to carry disease-associated variants in numbers similar to the general population. With the proliferation of large genome-wide association studies (GWAS) in recent years, investigators have turned to polygenic scores to leverage GWAS results into a measure of genetic risk that can better predict the risk of disease than individual significant variants alone. We selected 54 polygenic risk scores (PRSs) developed for a variety of outcomes, and we calculated their values in individuals from the New England Centenarian Study (NECS, N  = 4886) and the Long Life Family Study (LLFS, N  = 4577). We compared the distribution of these PRSs among exceptionally long-lived individuals (ELLI), their offspring, and controls, and we also examined their predictive values, using t -tests and regression models adjusting for sex and principal components reflecting the ancestral background of the individuals (PCs). In our analyses, we controlled for multiple testing using a Bonferroni-adjusted threshold for 54 traits. We found that only 4 of the 54 PRSs differed between ELLIs and controls in both cohorts. ELLIs had significantly lower mean PRSs for Alzheimer’s disease (AD) and coronary artery disease (CAD) than controls, suggesting a genetic predisposition to extreme longevity may be mediated by reduced susceptibility to these traits. ELLIs also had significantly higher mean PRSs for improved cognitive function and parental extreme longevity. In addition, the PRS for AD was associated with a higher risk of dementia among controls but not ELLIs ( p  = 0.003, 0.3 in NECS, p  = 0.03, 0.9 in LLFS, respectively). ELLIs have a similar burden of genetic disease risk as the general population for most traits but have a significantly lower genetic risk of AD and CAD. The lack of association between AD PRS and dementia among ELLIs suggests that the genetic risk for AD that they do have is somehow counteracted by protective genetic or environmental factors.