Look up the longevity association of rare variants in our Ashkenazi Jewish centenarian cohort:


Studies in model organisms have demonstrated that multiple, conserved genetic pathways influence life span. On the basis of homology, it is widely hypothesized that these conserved signaling pathways are similarly involved in human aging and longevity. Common variants associated with human survival have been extensively searched for in many recent genome-wide association studies (GWAS) using a variety of trait definitions and study designs. Most of longevity-associated common variants have small effect sizes, and currently common variants collectively only explain a very small proportion of heritability for human longevity. As several recent studies suggest, rare variants likely account for at least some of the 'missing' heritability.

We examined rare coding variants in a cohort of 515 Ashkenazi Jewish centenarians by whole-exome sequencing (WES) and tested for enrichment using a case-control design. The exceptional longevity of this cohort and their homogeneous genetic background provided us with increased power to detect causal rare variants. As controls we used 496 Ashkenazi Jewish individuals, mostly from the same households as the centenarians, between age ~70 and 95 without a parental history of extreme longevity (i.e., neither parent survived beyond 95 years of age).

We analyzed rare variants with alternative allele frequencies (AAF) < 1% in Ashkenazi Jewish populations, which were calculated based on the average of the allele frequencies in 731 unrelated (to the first-degree kinship) Ashkenazi Jewish individuals in our centenarian cohort (2,021) (excluding centenarians and other individuals included in our study) and the ones reported in gnomAD. We evaluated the longevity association of each rare coding variant using the firth logistic regression.


Rare coding variants in conserved aging pathways contribute to human longevity and protection against AD and other age-related diseases. Lin JR, Sin-Chan P, Napolioni V, Torres GG, Mitra J, Zhang Q, Jabalameli MR, Wang Z, Nguyen N, Gao T, Regeneron Genetics Center, Laudes M, Gorg S, Franke A, Nebel A, Greicius MD, Atzmon G, Ye K, Gorbunova V, Ladiges WC, Shuldiner A, Niedernhofer LJ, Robbins PD, Milman S, Suh Y, Vijg J, Barzilai N, Zhang ZD (2021) Nat Aging 1(9):783-794.  reprint