Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

Abstract

The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10−8). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10−36), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

“…In the DKLS, DNA was isolated from whole blood using standard methods (Miller et al ., 1988) and genotyping was carried out according to the manufacturer's protocol using the Illumina HumanOmniExpress BeadChips (Illumina Inc.) (Deelen et al ., 2014), which contains 730 525 SNP markers with a median spacing of 2.1 kb and a mean spacing of 4.0 kb.…”

“…So far, only a limited number of loci have been consistently associated with length of life (Murabito et al ., 2012; Deelen et al ., 2014), and hence much of the heritability is still unaccounted for. This missing heritability might in part be explained by copy number variants (CNVs) (Manolio et al ., 2009).…”

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.…”

Immunochip analysis identifies association of the RAD 50/ IL 13 region with human longevity

“…APOE and FOXO3 were initially detected in candidate‐driven case–control investigations, but APOE has since then been confirmed in a number of genome‐wide association studies (GWAS). In addition, a single nucleotide polymorphism (SNP) on chromosome 5q33.3 was recently identified in a GWAS meta‐analysis on long‐lived individuals (LLI) aged ≥ 90 years (Deelen et al ., 2014). Besides the detection of APOE and the 5q33.3 locus, longevity GWAS have been relatively unsuccessful and have failed to reveal novel associations with genome‐wide significance or sufficient reproducibility (Deelen et al ., 2011, 2014; Nebel et al ., 2011).…”

“…In addition, a single nucleotide polymorphism (SNP) on chromosome 5q33.3 was recently identified in a GWAS meta‐analysis on long‐lived individuals (LLI) aged ≥ 90 years (Deelen et al ., 2014). Besides the detection of APOE and the 5q33.3 locus, longevity GWAS have been relatively unsuccessful and have failed to reveal novel associations with genome‐wide significance or sufficient reproducibility (Deelen et al ., 2011, 2014; Nebel et al ., 2011). Here, we performed a large‐scale candidate gene study by targeting established immune‐associated loci present on the Immunochip (Trynka et al ., 2011).…”