Human Longevity is Influenced by Many Genetic Variants: Evidence from 75,000 UK Biobank Participants

Abstract

Variation in human lifespan is 20 to 30% heritable 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). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested.Genotyped variants (n=845,997) explained 10.2% (SD=1.3%) of combined parental longevity. In GWAS, a locus in the nicotine receptor CHRNA3 -previously associated with increased smoking and lung cancer -was associated with paternal age at death, with each protective allele (rs1051730[G]) being associated with 0.03 years later age at father's death (p=3x10 -8 ). Offspring of longer lived parents had more protective alleles (lower genetic risk scores) 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 gene analyses, variants in the TOMM40/APOE locus were associated with longevity (including rs429358, p=3x10 -5 ), but FOXO variants were not associated.These results support a multiple protective factors model for achieving longer lifespans in humans, with a prominent role for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.

Genetic variants linked to education predict longevity

“…Thus, the score composed of genetic variants weighted toward their relation to educational attainment made similar-sized predictions of longevity risk to genetic scores weighted toward alleles linked to other well-established risk factors for mortality. Note that a number of other polygenic associations with mortality were addressed in the UK Biobank sample in a previous study, using somewhat different methods (33).…”

“…32 for a similar analysis of epigenetic markers). Moreover, higher genetic risk for conditions, such as cardiovascular disease, diabetes, and Alzheimer's disease, has been related to earlier parental mortality (33). Because the expected allelic effect of one allele in parents is 0.5 alleles in offspring (31), precise predictions can be made of the effect of alleles and polygenic scores on traits in the offspring themselves.…”

Leveraging DNA methylation quantitative trait loci to characterize the relationship between methylomic variation, gene expression and complex traits

“…As the power of the SMR approach to detect pleiotropic associations reflects, in part, the power of the initial complex trait GWAS, it is unsurprising that the highest number of SMR associations were found for traits characterized by the largest number of GWAS signals such as height (423 significant GWAS loci, 506 SMR pleiotropic associations) (Wood et al 2014) and inflammatory bowel disease (168 significant GWAS variants, 127 SMR pleiotropic associations) (Liu et al 2015). In contrast, no SMR associations were found for traits with few or no genome-wide significant SNPs including parental age at death (0-1 significant GWAS variants) (Pilling et al 2016), insulin secretion rate (no significant GWAS variants) (Wood et al 2017) and whether a person has ever smoked (no significant GWAS variants) (Tobacco and Genetics Consortium 2010). We compared our SMR results to those obtained using our previous mQTL dataset -generated using a smaller number of samplesobserving high rates of replication for loci that were tested in both analyses.…”

Investigating the Genetic Architecture of Non-Cognitive Skills Using GWAS-by-Subtraction

“…In genetic correlation analysis, NonCog was as stronglyor more stronglyassociated with socioeconomic attainment outcomes, as compared to Cog (for income 33 Longevity. We estimated rg with longevity as proxied by parental lifespan 34 . Genetic correlations were similar for NonCog and Cog (NonCog rg=.32 (SE=.07); Cog rg=.36 (SE=.07); pdiff_fdr=.71).…”