TY - JOUR
T1 - Similar burden of pathogenic coding variants in exceptionally long-lived individuals and individuals without exceptional longevity
AU - Regeneron Genetics Center
AU - Gutman, Danielle
AU - Lidzbarsky, Gabriel
AU - Milman, Sofiya
AU - Gao, Tina
AU - Sin-Chan, Patrick
AU - Gonzaga-Jauregui, Claudia
AU - Deelen, Joris
AU - Shuldiner, Alan R.
AU - Barzilai, Nir
AU - Atzmon, Gil
N1 - Funding Information:
This work was supported by The Nathan Shock Center of Excellence for the basic Biology of Aging (P30AG038072) (N.B.), the Einstein-Paul Glenn Foundation for Medical Research Center for the Biology of Human Aging (N.B.), NIH/NIA1 R01 AG 042188-01 (G.A/N.B), NIH-1 R01 AG 046949 - 01, R01 AG057909(N.B.), U19 AG056278, ISF 193/16 (G.A.), NIH K23AG051148 (S.M.), and the Regeneron Genetics Center, LLC, a subsidiary of Regeneron Pharmaceuticals, Inc. We thank Mr. Ilia Burgsdorf for his contributions to this study. We thank Andrew Blumenfeld for bioinformatics support.
Funding Information:
This work was supported by The Nathan Shock Center of Excellence for the basic Biology of Aging (P30AG038072) (N.B.), the Einstein‐Paul Glenn Foundation for Medical Research Center for the Biology of Human Aging (N.B.), NIH/NIA1 R01 AG 042188‐01 (G.A/N.B), NIH‐1 R01 AG 046949 ‐ 01, R01 AG057909(N.B.), U19 AG056278, ISF 193/16 (G.A.), NIH K23AG051148 (S.M.), and the Regeneron Genetics Center, LLC, a subsidiary of Regeneron Pharmaceuticals, Inc. We thank Mr. Ilia Burgsdorf for his contributions to this study. We thank Andrew Blumenfeld for bioinformatics support.
Publisher Copyright:
© 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd
PY - 2020/10/1
Y1 - 2020/10/1
N2 - 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.
AB - 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.
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U2 - 10.1111/acel.13216
DO - 10.1111/acel.13216
M3 - Article
AN - SCOPUS:85089960936
VL - 19
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
IS - 10
M1 - e13216
ER -