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

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 turn...

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Published inGeroScience 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
LanguageEnglish
Published Cham Springer International Publishing 01.04.2022
Springer Nature B.V
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Abstract 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.
AbstractList 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.
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.
Author Gunn, Sophia
O’Connell, Jeffrey R.
Schork, Nicholas J.
Perls, Thomas
Wainberg, Michael
Feitosa, Mary F.
Song, Zeyuan
Montasser, May E.
Price, Nathan
Sebastiani, Paola
Boudreau, Robert
Stitziel, Nathan
Andersen, Stacy
Tan, Qihua
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  surname: Sebastiani
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  organization: Institute for Clinical Research and Health Policy Studies, Tufts Medical Center
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Issue 2
Keywords Long-lived families
polygenic risk scores
Exceptional Longevity
Language English
License 2022. The Author(s), under exclusive licence to American Aging Association.
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Snippet A surprising and well-replicated result in genetic studies of human longevity is that centenarians appear to carry disease-associated variants in numbers...
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SubjectTerms 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
Title Distribution of 54 polygenic risk scores for common diseases in long lived individuals and their offspring
URI https://link.springer.com/article/10.1007/s11357-022-00518-2
https://www.ncbi.nlm.nih.gov/pubmed/35119614
https://www.proquest.com/docview/2670111374
https://pubmed.ncbi.nlm.nih.gov/PMC9135909
Volume 44
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