Back to Search Start Over

Exome-wide association studies in general and long-lived populations identify genetic variants related to human age

Authors :
Marylyn D. Ritchie
Colm O'Dushlaine
Aris Baras
Jeffrey D. Reid
Sofiya Milman
Alan R. Shuldiner
Patrick Sin-Chan
Dadong Li
Scott M. Damrauer
David J. Carey
David H. Ledbetter
Nir Barzilai
Cristopher V. Van Hout
David J. Glass
Anthony Marcketta
Nehal Gosalia
Aris N. Economides
Daniel J. Rader
Alexander H. Li
Bin Ye
John D. Overton
Chuan Gao
Publication Year :
2020
Publisher :
Cold Spring Harbor Laboratory, 2020.

Abstract

SUMMARYAging is characterized by degeneration in cellular and organismal functions leading to increased disease susceptibility and death. Although our understanding of aging biology in model systems has increased dramatically, large-scale sequencing studies to understand human aging are now just beginning. We applied exome sequencing and association analyses (ExWAS) to identify age-related variants on 58,470 participants of the DiscovEHR cohort. Linear Mixed Model regression analyses of age at last encounter revealed variants in genes known to be linked with clonal hematopoiesis of indeterminate potential, which are associated with myelodysplastic syndromes, as top signals in our analysis, suggestive of age-related somatic mutation accumulation in hematopoietic cells despite patients lacking clinical diagnoses. In addition to APOE, we identified rare DISP2 rs183775254 (p = 7.40×10−10) and ZYG11A rs74227999 (p = 2.50×10−08) variants that were negatively associated with age in either both sexes combined and females, respectively, which were replicated with directional consistency in two independent cohorts. Epigenetic mapping showed these variants are located within cell-type-specific enhancers, suggestive of important transcriptional regulatory functions. To discover variants associated with extreme age, we performed exome-sequencing on persons of Ashkenazi Jewish descent ascertained for extensive lifespans. Case-Control analyses in 525 Ashkenazi Jews cases (Males ≥ 92 years, Females ≥ 95years) were compared to 482 controls. Our results showed variants in APOE (rs429358, rs6857), and TMTC2 (rs7976168) passed Bonferroni-adjusted p-value, as well as several nominally-associated population-specific variants. Collectively, our Age-ExWAS, the largest performed to date, confirmed and identified previously unreported candidate variants associated with human age.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........e0b9122e0fec6a5f78b11396b9011569
Full Text :
https://doi.org/10.1101/2020.07.19.188789