Similar burden of pathogenic coding variants in exceptionally long‐lived individuals and individuals without exceptional longevity
Aging Cell, vol. 19, pp. e13216
Abstract
Centenarians (exceptionally long-lived individuals-ELLI) are a unique segment of the population, exhibiting long human lifespan and healthspan, despite generally practicing similar lifestyle habits as their peers. We tested disease-associated mutation burden in ELLI genomes by determining the burden of pathogenic variants reported in the ClinVar and HGMD databases using data from whole exome sequencing (WES) conducted in a cohort of ELLI, their offspring, and control individuals without antecedents of familial longevity (n = 1879), all descendent from the founder population of Ashkenazi Jews. The burden of pathogenic variants did not differ between the three groups. Additional analyses of variants subtypes and variant effect predictor (VEP) biotype frequencies did not reveal a decrease of pathogenic or loss-of-function (LoF) variants in ELLI and offspring compared to the control group. Case-control pathogenic variants enrichment analyses conducted in ELLI and controls also did not identify significant differences in any of the variants between the groups and polygenic risk scores failed to provide a predictive model. Interestingly, cancer and Alzheimer's disease-associated variants were significantly depleted in ELLI compared to controls, suggesting slower accumulation of mutation. That said, polygenic risk score analysis failed to find any predictive variants among the functional variants tested. The high similarity in the burden of pathogenic variation between ELLI and individuals without familial longevity supports the notion that extension of lifespan and healthspan in ELLI is not a consequence of pathogenic variant depletion but rather a result of other genomic, epigenomic, or potentially nongenomic properties.
Authors 10
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Affiliation as printed
Faculty of Natural Sciences University of Haifa Haifa Israel
Faculty of Natural Sciences, University of Haifa, Haifa, Israel
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Affiliation as printed
Faculty of Natural Sciences University of Haifa Haifa Israel
Faculty of Natural Sciences, University of Haifa, Haifa, Israel
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Albert Einstein College of Medicine
Affiliation as printed
Department of Medicine Albert Einstein College of Medicine Bronx New York USA
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
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Albert Einstein College of Medicine
Affiliation as printed
Department of Medicine Albert Einstein College of Medicine Bronx New York USA
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
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Affiliation as printed
Regeneron Genetics Center Tarrytown New York USA
Regeneron Genetics Center, Tarrytown, New York, USA
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Affiliation as printed
Regeneron Genetics Center Tarrytown New York USA
Regeneron Genetics Center, Tarrytown, New York, USA
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Leiden University Medical Center · Max Planck Institute for Biology of Ageing
Affiliation as printed
Max Planck Institute for Biology of Ageing Cologne Germany
Molecular Epidemiology Department of Biochemical Data Sciences Leiden University Medical Center Leiden The Netherlands
Max Planck Institute for Biology of Ageing, Cologne, Germany
Molecular Epidemiology, Department of Biochemical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
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Affiliation as printed
Regeneron Genetics Center Tarrytown New York USA
Regeneron Genetics Center, Tarrytown, New York, USA
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Albert Einstein College of Medicine
Affiliation as printed
Department of Medicine Albert Einstein College of Medicine Bronx New York USA
Genetic, Institute for Aging Research and the Diabetes Research Center Albert Einstein College of Medicine Bronx New York USA
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
Genetic, Institute for Aging Research and the Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA
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Gil Atzmon corresponding
Albert Einstein College of Medicine · University of Haifa
Affiliation as printed
Department of Medicine Albert Einstein College of Medicine Bronx New York USA
Faculty of Natural Sciences University of Haifa Haifa Israel
Genetic, Institute for Aging Research and the Diabetes Research Center Albert Einstein College of Medicine Bronx New York USA
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA
Faculty of Natural Sciences, University of Haifa, Haifa, Israel
Genetic, Institute for Aging Research and the Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA
Cited by 12 stored of 13
12 results
Cited by patents worldwide 1 (Lens.org)
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DEVICE AND METHOD FOR DETECTING TUMOR MUTATION BURDEN (TMB) BASED ON CAPTURE SEQUENCINGUS20220072553A1 2022-03-10 Discontinued