Similar burden of pathogenic coding variants in exceptionally long‐lived individuals and individuals without exceptional longevity

Gutman, Danielle; Lidzbarsky, Gabriel; Milman, Sofiya; Gao, Ting; Sin‐Chan, Patrick; Gonzaga‐Jauregui, Claudia; Deelen, Joris; Shuldiner, Alan R.; Barzilai, Nir; Atzmon, Gil

doi:10.1111/acel.13216

Cited by 10 publications

(10 citation statements)

References 56 publications

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“…In contrast to previous literature that could not identify a significant difference in the overall burden of disease variants in ELLIs [7,25], we showed here that, on average, ELLIs carry a lower burden of variants associated with AD, CAD, and lupus. In addition, we showed that ELLIs have higher PRS for cognitive function.…”

Section: Discussioncontrasting

confidence: 99%

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

Gunn

Wainberg

Song

et al. 2021

Preprint

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Background: 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 risk of disease than individual significant variants alone. Methods: 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 ancestral background of the individuals (PCs). In our analyses we controlled for multiple testing using a Bonferroni-adjusted threshold for 54 traits. Results: 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), coronary artery disease (CAD) and systemic lupus than controls, suggesting 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. In addition, the PRS for AD was associated with higher risk of dementia among controls but not ELLIs (p = 0.0004, 0.3 in NECS, p = 0.03, 0.93 in LLFS respectively). Interestingly, ELLIs did not have a larger number of homozygous risk genotypes for AD (TNECS = -1.72, TLLFs = 0.83) and CAD (TNECS = -5.08, TLLFs = -0.31) in both cohorts, but did have significantly larger number of homozygous protective genotypes than controls for the two traits (AD: TNECS =3.10, TLLFs = 2.2, CAD: TNECS = 6.57, TLLFs =2.36, respectively). Conclusions: ELLIs have a similar burden of genetic disease risk as the general population for most traits, but have significantly lower genetic risk of AD, CAD, and lupus. The lack of association between AD PRS and dementia among ELLIs suggests that their genetic risk for AD is somehow buffered by protective genetic or environmental factors.

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Section: Discussioncontrasting

confidence: 99%

“…In addition, our results agree with the recent discovery of lower polygenic risk for AD in centenarians and their offspring of Ashkenazi Jewish descent [25]. Our findings regarding AD, CAD and cognitive function are consistent with this previous work, as well as the resilience to AD and CAD seen in ELLIs.…”

Section: Discussionsupporting

confidence: 93%

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

Gunn

Wainberg

Song

et al. 2021

Preprint

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“…Our findings also complement those of Timmers et al, [26] finding associations between a lifespan PRS and common diseases in the UKBB. Importantly, our results also agree with the recent discovery of a lower burden of heterozygous variants for AD in centenarians and their offspring of Ashkenazi Jewish descent [27]. Overall, our findings regarding AD, CAD, and cognitive function are consistent with previous work, which considers polygenic risk beyond genome-wide significant variants and is sufficiently powered.…”

Section: Discussionsupporting

confidence: 92%

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

et al. 2022

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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 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

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“…This low prevalence is all the more counterintuitive given that these oldest-old are indistinguishable from the general population by (a) their number of risk alleles for NCD [42], as well as (b) by their lifestyles [43]. This observation has been confirmed in American Ashkenazi Jews, a population whose strong founder effect (loss of genetic variation that may occur when a few individuals from a large population establish a new population that subsequently may present with distinctively different genotypical and phenotypical profiles) suggests larger statistical power in finding gene-longevity associations [44]. The effect of genes on longevity has recently been estimated to be below 10% [45].…”

Section: Observation 2: Healthy Centenarians Are Indistinguishable By Genes and Lifestylementioning

confidence: 81%

Dismantling Anti-Ageing Medicine: Why Age-Relatedness of Cardiovascular Disease is Proof of Robustness Rather Than of Ageing-Associated Vulnerability

Kraushaar¹,

Bauer

2021

Heart, Lung and Circulation

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Ageing is perceived to be the common culprit behind the most prevalent noncommunicable chronic diseases (NCD) such as cardiovascular disease (CVD). Treating ageing as a means to prevent its downstream pathologies has become the logical extension of this idea, and the defining criterion of anti-ageing medicine (evidence-based early detection, prevention, and treatment of age-related diseases). Challenging the underlying rationale, we here argue that the disease's late-in-life occurrence is proof of a genetically conserved robustness that helps us resist disease long enough for it to masquerade as a consequence of living long rather than of living wrong. Robustness is an acknowledged hallmark phenomenon of all complex systems (while there exists no universally adopted definition, a hallmark of complex systems is that they consist of many networked components whose interactions may give rise to system behaviours which cannot be derived or predicted from a reductionist knowledge of the interacting parts, even if this knowledge is complete) and a key concept in the complexity sciences (a relatively new branch of science that attempts to find and understand the common mechanisms and patterns shared by all complex systems). To reconceptualise the age-relatedness of chronic diseases in this sense has important implications for medical research and practice. The goal of our essay is to open a discussion that may enhance the overall understanding of robustness and prevent a misguided redirection of funding away from established disease specific research and towards anti-ageing medicine. This essay is timely, as the forthcoming 11 th version of the International Classification of Diseases (ICD) will be the first to recognise ageing as a condition, thereby legitimising anti-ageing medical research. On a more pragmatic note, and for the benefit of people alive today, we propose a practical strategy to remedy the mismatch between heritable robustness and the lifestyle challenges that gradually overwhelm it.

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Similar burden of pathogenic coding variants in exceptionally long‐lived individuals and individuals without exceptional longevity

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 10 publications

References 56 publications

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

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

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

Dismantling Anti-Ageing Medicine: Why Age-Relatedness of Cardiovascular Disease is Proof of Robustness Rather Than of Ageing-Associated Vulnerability

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