Genome-wide association studies (GWAS) have pinpointed the chromosomal locus 9p21.3 as a genetic hotspot for various age-related disorders. Common genetic variants in this locus are linked to multiple traits, including coronary artery diseases, cancers, and diabetes. Centenarians are known for their reduced risk and delayed onset of these conditions. To investigate whether this evasion of disease risks involves diminished genetic risks in the 9p21.3 locus, we sequenced this region in an Ashkenazi Jewish centenarian cohort (centenarians: n = 450, healthy controls: n = 500). Risk alleles associated with cancers, glaucoma, CAD, and T2D showed a significant depletion in centenarians. Furthermore, the risk and non-risk genotypes are linked to two distinct low-frequency variant profiles, enriched in controls and centenarians, respectively. Our findings provide evidence that the extreme longevity cohort is associated with collectively lower risks of multiple age-related diseases in the 9p21.3 locus.
Bibliographical noteFunding Information:
Research in the Suh lab was supported by the National Institute of Health (AG017242, DK127778, AG076040, AG069750, AG061521, GM104459, AG056278, AG057341, AG057433, AG057706), a grant GCRLE‐1320 from the Global Consortium for Reproductive Longevity and Equality at the Buck Institute, made possible by the Bia‐Echo Foundation, and a grant from The Simons Foundation.
© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
- age-related disease
- population genomics
ASJC Scopus subject areas
- Cell Biology