Genetic Signatures of Exceptional Longevity in Humans

Abstract

Like most complex phenotypes, exceptional longevity is thought to reflect a combined influence of environmental (e.g., lifestyle choices, where we live) and genetic factors. To explore the genetic contribution, we undertook a genome-wide association study of exceptional longevity in 801 centenarians (median age at death 104 years) and 914 genetically matched healthy controls. Using these data, we built a genetic model that includes 281 single nucleotide polymorphisms (SNPs) and discriminated between cases and controls of the discovery set with 89% sensitivity and specificity, and with 58% specificity and 60% sensitivity in an independent cohort of 341 controls and 253 genetically matched nonagenarians and centenarians (median age 100 years). Consistent with the hypothesis that the genetic contribution is largest with the oldest ages, the sensitivity of the model increased in the independent cohort with older and older ages (71% to classify subjects with an age at death>102 and 85% to classify subjects with an age at death>105). For further validation, we applied the model to an additional, unmatched 60 centenarians (median age 107 years) resulting in 78% sensitivity, and 2863 unmatched controls with 61% specificity. The 281 SNPs include the SNP rs2075650 in TOMM40/APOE that reached irrefutable genome wide significance (posterior probability of association = 1) and replicated in the independent cohort. Removal of this SNP from the model reduced the accuracy by only 1%. Further in-silico analysis suggests that 90% of centenarians can be grouped into clusters characterized by different “genetic signatures” of varying predictive values for exceptional longevity. The correlation between 3 signatures and 3 different life spans was replicated in the combined replication sets. The different signatures may help dissect this complex phenotype into sub-phenotypes of exceptional longevity.

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.…”

Discussion on the paper ‘Statistical contributions to bioinformatics: Design, modelling, structure learning and integration’ by Jeffrey S. Morris and Veerabhadran Baladandayuthapani

“…It is also illustrated by a paper which had to be withdrawn from Science due to inappropriate analysis of an unmatched case control study with regard to Affymetrix and Illumina arrays. This work is later published in Plos One (Sebastiani et al, 2012). Generally, biostatisticians working with clinical data have no or little experience with noisy omics datasets.…”

Integration of ‘omics’ data in aging research: from biomarkers to systems biology

“…Sebastiani et al . (2012) recently published a refined model consisting of 281 SNPs to distinguish between centenarians and younger controls in a cohort of 1715 people. One of these SNPs is located in ApoE, which is so far the only gene that has been reliably associated with longevity at genomewide significance level (Deelen et al ., 2011; Nebel et al ., 2011).…”

“…However, several studies used phenotypes, such as lung function, grip strength or bone mineral density, as proxies to investigate molecular changes in biological aging (Jackson et al ., 2003; Bell et al ., 2012; Levine, 2013). Researchers also investigated reasons of retarded biological aging and longevity by comparing centenarians with younger controls (Biagi et al ., 2012; Sebastiani et al ., 2012). …”