Genome‐wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited

Abstract

Summary By studying the loci that contribute to human longevity, we aim to identify mechanisms that contribute to healthy aging. To identify such loci, we performed a genome‐wide association study (GWAS) comparing 403 unrelated nonagenarians from long‐living families included in the Leiden Longevity Study (LLS) and 1670 younger population controls. The strongest candidate SNPs from this GWAS have been analyzed in a meta‐analysis of nonagenarian cases from the Rotterdam Study, Leiden 85‐plus study, and Danish 1905 cohort. Only one of the 62 prioritized SNPs from the GWAS analysis ( P < 1 × 10 −4 ) showed genome‐wide significance with survival into old age in the meta‐analysis of 4149 nonagenarian cases and 7582 younger controls [OR = 0.71 (95% CI 0.65–0.77), P = 3.39 × 10 −17 ]. This SNP, rs2075650, is located in TOMM40 at chromosome 19q13.32 close to the apolipoprotein E ( APOE ) gene. Although there was only moderate linkage disequilibrium between rs2075650 and the ApoE ε4 defining SNP rs429358, we could not find an APOE ‐independent effect of rs2075650 on longevity, either in cross‐sectional or in longitudinal analyses. As expected, rs429358 associated with metabolic phenotypes in the offspring of the nonagenarian cases from the LLS and their partners. In addition, we observed a novel association between this locus and serum levels of IGF‐1 in women ( P = 0.005). In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE ε4 allele. No other major longevity locus was found.

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67. 67.

    Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD. FOXO3A genotype is strongly associated with human longevity. Proc. Natl. Acad. Sci. U.S.A. 2008;105:13987-13992.

    Not in our library10.1073/pnas.0801030105

Cited by papers we hold 17

• Cancer and Aging: Two Tightly Interconnected Biological Processes · 2021
  No notice
• APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease · 2020
  No notice
• Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances · 2019
  No notice
• Determinants of cognitive performance and decline in 20 diverse ethno-regional groups: A COSMIC collaboration cohort study · 2019
  No notice
• A meta-analysis of genome-wide association studies identifies multiple longevity genes · 2019
  Corrected
• Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines · 2018
  No notice
• Aging and Alzheimer’s disease: Comparison and associations from molecular to system level · 2018
  No notice
• Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity · 2017
  No notice
• New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk · 2016
  No notice
• Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring · 2015
  No notice
• Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity · 2015
  No notice
• Age and sun exposure-related widespread genomic blocks of hypomethylation in nonmalignant skin · 2015
  No notice
• Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age · 2014
  No notice
• Genetics of healthy aging and longevity · 2013
  No notice
• Human serum metabolic profiles are age dependent · 2012
  No notice
• Genetic Signatures of Exceptional Longevity in Humans · 2012
  No notice
• The Genetics of Extreme Longevity: Lessons from the New England Centenarian Study · 2012
  No notice

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