The View of Mortality as Not Easily Explainable By Common Genetic Variants
It is likely the case that natural variations in longevity emerge from the interaction of many, many minor genetic differences with lifestyle and other environmental factors. The majority of these contributions to longevity will be tiny, and their presence will vary widely across a population:
Twin studies have estimated the heritability of longevity to be approximately 20-30%. Genome-wide association studies (GWAS) have revealed a large number of determinants of morbidity, but so far, no new polymorphisms have been discovered to be associated with longevity per se in GWAS.We aim to determine whether the genetic architecture of mortality can be explained by single nucleotide polymorphisms (SNPs) associated with common traits and diseases related to mortality. By extensive quality control of published GWAS we created a genetic score from 707 common SNPs associated with 125 diseases or risk factors related with overall mortality. We prospectively studied the association of the genetic score with: (1) time-to-death; (2) incidence of the first of nine major diseases (coronary heart disease, stroke, heart failure, diabetes, dementia, lung, breast, colon and prostate cancers) in two population-based cohorts of Dutch and Swedish individuals (N = 15,039; age range 47-99 years).
During a median follow-up of 6.3 years (max 22.2 years), we observed 4,318 deaths and 2,132 incident disease events. The genetic score was significantly associated with time-to-death. The association between the genetic score and incidence of major diseases was stronger. Associations were stronger for individuals dying at older ages. Our findings are compatible with the view of mortality as a complex and highly polygenetic trait, not easily explainable by common genetic variants related to diseases and physiological traits.