Abstract
Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus (CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7×10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.
Highlights
Over the last several decades, genetic studies conducted in-vitro and using model organisms have produced a stream of exciting findings linking specific pathways to major effects on aging [1], including, for example, gene knockouts in nutrient sensing pathways that cause dramatic life extension in C. elegans
We had 90.4% power to detect an allele of 5% minor allele frequency in the sample of
We report the largest analysis far of common genetic variants and normal aging related human longevity, based on the indirect approach of testing variant associations in offspring
Summary
Over the last several decades, genetic studies conducted in-vitro and using model organisms have produced a stream of exciting findings linking specific pathways to major effects on aging [1], including, for example, gene knockouts in nutrient sensing pathways that cause dramatic life extension in C. elegans. It is uncertain to what extent the laboratory findings and the ‘single pathway major effect’ model is relevant to human aging and longevity [3]. In addition to environmental exposures, genetic variation is important: for example, studies conducted on heterozygotic and homozygotic twins consistently report heritability of longer human lifespans of 20-30% [5,6], with negligible heritability before age 60 years but increasing estimates at advanced ages [7]; the low early heritability is hypothesized to be due to more “accidental” or exposure-related deaths at younger ages. Well-powered genome wide association studies (GWAS) provide robust evidence on which common single nucleotide polymorphisms (SNP) are associated with traits including longevity (selected references: [8,9,10,11,12,13,14])
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