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). The parents were used, as the participants themselves are predominantly young and healthy, and we were seeking the heritable aspect of lifespan. We found that a nicotine receptor gene (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=5.7x10^-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.
Associations between parental attained ages and health status
Children of centenarians have lower prevalence of cardiovascular disease and live longer. Our recent work in the US Health and Retirement study (n=6500) showed large reductions in overall mortality in middle aged offspring for each decade their mothers or fathers lived beyond 65yrs. Estimates were little changed adjusting for classical risk factors. There was no effect of the parent's attained age on spouse's mortality. We showed parental survival associations with lower cancer incidence for the first time, but found no association with arthritis in offspring. We also found evidence of substantially lower rates of cognitive decline in offspring of long lived parents. These analyses suggest a strong intrinsic (probably genetic) influence explaining parent and offspring health advantage during ageing, and might provide a phenotype for understanding why some people suffer from age related disorders in their sixties while others remain disease free into their nineties and beyond. We aim to estimate the associations between the full range of parental attained ages and health status (especially ageing traits) in UK Biobank respondents aged 55yrs and over. Given intergenerational gaps, the 55+ yr olds (estimated 308,000 participants) are more likely to have parents who have lived to very advanced ages. We aim to study parental longevity associations with common diseases in offspring, including diabetes, heart disease, stroke, common age related cancers and arthritis. We also want to estimate associations with common genetic variants (SNPs). At present we plan to analyse the baseline (cross-sectional data) plus the data on all cause mortality already collected. We also request later access to data on incidence of our diseases of interest, deaths by cause, plus genetic variant (SNP) data, as these become available. Our aim is to find new ways of delaying or treating age related disease and disability, to help people age well.
|Lead investigator:||David Melzer|
|Lead institution:||University of Exeter|