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

Abstract

SummaryBy 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 genomewide 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 e4 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 e4 allele. No other major longevity locus was found.

Apolipoprotein E region molecular signatures of Alzheimer's disease

“…Consistent with previous studies (Deelen et al., 2011; Fortney et al., 2015), our association analyses showed that minor alleles of rs2075650 and rs157580 ( TOMM40 ) were associated with higher and lower risk of AD development, respectively (Table S2). The effect directions were consistent in all studies; the effect sizes varied markedly, ranging from 0.380 ( p  = 0.014) in the FHS cohort to 1.45 ( p  = 1.65 × 10 −78 ) in the LOADFS cohort for rs2075650 and from −0.052 ( p  = 0.612) in the FHS cohort to −0.705 ( p =  5.98 × 10 −23 ) in the LOADFS cohort for rs157580 (Figure S1 and Table S2).…”

Intranasal insulin alleviates cognitive deficits and amyloid pathology in young adult APP swe/ PS 1dE9 mice

“…People who carry APOE ε4 allele have an increased risk of developing AD, while APOE ε2 carriers are protected from the disease (Deelen et al ., 2011). The level of soluble ApoE protein increases both in patients with AD and in APP/PS1 rat model of AD (Arold et al ., 2012).…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…However, two loci that are repeatedly found by GWAS of aging are APOE (Deelen et al, 2011; Ewbank, 2007; Gerdes, Jeune, Ranberg, Nybo, & Vaupel, 2000) and FOXO3A (Anselmi et al, 2009; Flachsbart et al, 2009; Li et al, 2009; Pawlikowska et al, 2009; Willcox et al, 2008). Similar to AD, APOE ε2 is found to be enriched in elderly and centenarians compared to younger individuals (Seripa et al, 2006).…”