Novel loci and pathways significantly associated with longevity

Abstract

Only two genome-wide significant loci associated with longevity have been identified so far, probably because of insufficient sample sizes of centenarians, whose genomes may harbor genetic variants associated with health and longevity. Here we report a genome-wide association study (GWAS) of Han Chinese with a sample size 2.7 times the largest previously published GWAS on centenarians. We identified 11 independent loci associated with longevity replicated in Southern-Northern regions of China, including two novel loci (rs2069837-IL6; rs2440012-ANKRD20A9P) with genome-wide significance and the rest with suggestive significance (P < 3.65 × 10−5). Eight independent SNPs overlapped across Han Chinese, European and U.S. populations, and APOE and 5q33.3 were replicated as longevity loci. Integrated analysis indicates four pathways (starch, sucrose and xenobiotic metabolism; immune response and inflammation; MAPK; calcium signaling) highly associated with longevity (P ≤ 0.006) in Han Chinese. The association with longevity of three of these four pathways (MAPK; immunity; calcium signaling) is supported by findings in other human cohorts. Our novel finding on the association of starch, sucrose and xenobiotic metabolism pathway with longevity is consistent with the previous results from Drosophilia. This study suggests protective mechanisms including immunity and nutrient metabolism and their interactions with environmental stress play key roles in human longevity.

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

“…Carriers of the−174G > C mutation have an increased risk of developing various major diseases, including Alzheimer disease 30 , CVD 31 , non-insulin-dependent diabetes mellitus 32 , bone fragility 33 , and systemic-onset juvenile chronic arthritis 34 . A genome-wide association study comparing >2,000 Chinese centenarians to middle-aged controls found that the SNP rs2069837 in IL6 was significantly associated with extreme longevity, confirming the role of IL-6 in conditioning morbidity and mortality, especially in old age 35 . Confirming the role of IL-6 in health, in a large Mendelian randomization analysis, the IL6R SNP rs7529229, marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala), was associated with increased circulating IL-6 levels 24 .…”

Role of lncRNAs in Cellular Aging

“…Many SNPs are not associated with coding genes but with non-coding region where lncRNAs may be transcribed (118). For example, a recent study on Asian centurions revealed a novel SNP rs2440012 associated with longevity (119). Given the growing evidence of the functional role lncRNAs in physiological and pathological processes, we believe it is just a matter of time to illustrate role of lncRNAs in aging.…”

The genetic component of human longevity: New insights from the analysis of pathway‐based SNP‐SNP interactions

“…GWAS of human longevity in worldwide samples (North America, Europe and very recently China) generally failed to give new insights into genetic determinants of human longevity: only the TOMM40/APOE/APOC1 locus, associated with longevity, was replicated in different populations (Deelen et al., 2014; Lin et al., 2016; Newman et al., 2010; Sebastiani et al., 2012), while rs2149954 on 5q33.3 (Deelen et al., 2014; Zeng et al., 2016) and the FOXO3A locus (Broer et al., 2015 and references therein) are the other signals showing population‐specific associations. Some authors attempted to analyse epistatic intragenic (Tan, Soerensen, Kruse, Christensen & Christiansen, 2013; Zeng et al., 2010) or intergenic effects (Napolioni, Giannì, Carpi, Predazzi & Lucarini, 2011a; Napolioni et al., 2011b), however comprising a limited number of genetic variants.…”