RESUMO
We present a massive investigation into the genetic basis of human lifespan. Beginning with a genome-wide association (GWA) study using a de-identified snapshot of the unique AncestryDNA database - more than 300,000 genotyped individuals linked to pedigrees of over 400,000,000 people - we mapped six genome-wide significant loci associated with parental lifespan. We compared these results to a GWA analysis of the traditional lifespan proxy trait, age, and found only one locus, APOE, to be associated with both age and lifespan. By combining the AncestryDNA results with those of an independent UK Biobank dataset, we conducted a meta-analysis of more than 650,000 individuals and identified fifteen parental lifespan-associated loci. Beyond just those significant loci, our genome-wide set of polymorphisms accounts for up to 8% of the variance in human lifespan; this value represents a large fraction of the heritability estimated from phenotypic correlations between relatives.
Assuntos
Estudo de Associação Genômica Ampla/métodos , Longevidade/genética , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Proteínas de Transporte/genética , Bases de Dados Genéticas , Feminino , Humanos , Masculino , Proteínas Nucleares/genética , Linhagem , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Proteínas Proto-Oncogênicas/genéticaRESUMO
Human life span is a phenotype that integrates many aspects of health and environment into a single ultimate quantity: the elapsed time between birth and death. Though it is widely believed that long life runs in families for genetic reasons, estimates of life span "heritability" are consistently low (â¼15-30%). Here, we used pedigree data from Ancestry public trees, including hundreds of millions of historical persons, to estimate the heritability of human longevity. Although "nominal heritability" estimates based on correlations among genetic relatives agreed with prior literature, the majority of that correlation was also captured by correlations among nongenetic (in-law) relatives, suggestive of highly assortative mating around life span-influencing factors (genetic and/or environmental). We used structural equation modeling to account for assortative mating, and concluded that the true heritability of human longevity for birth cohorts across the 1800s and early 1900s was well below 10%, and that it has been generally overestimated due to the effect of assortative mating.