Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances

Abstract

We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, and 13q21.31, and identify and replicate novel findings near ABO, ZC3HC1, and IGF2R. We also validate previous findings near 5q33.3/EBF1 and FOXO3, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer – but not other cancers – explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Trans-biobank analysis with 676,000 individuals elucidates the association of polygenic risk scores of complex traits with human lifespan

“…We finally performed a fixed-effect meta-analysis of the PRS-lifespan association studies from BioBank Japan, UK Biobank, and FinnGen, by inverse variance method. To estimate the years of life gained or lost from PRS-lifespan associations, we converted the effect size from the Cox proportional hazard models into the years gained based on the following equation as described preciously 39, 47 ; …”

Developments in molecular epidemiology of aging

“…In humans, studies of relatives estimate the heritability of lifespan, or the fraction of variation related to genetics, to range from 10 to 30% [12]. Molecular genetic studies suggest that there may be differences between the genetics influencing the normal range of lifespan variation and genetics influencing extreme longevity [13], although there is also evidence for some commonality [14]. The role of the inherited genome in determining variation in human lifespan remains a subject of active study.…”

“…But, discovery in aging research remains in the early stages. Recent GWAS have changed approaches from comparisons of extremely long-lived persons with controls in the normal age range [57,58] to studies of parental lifespan [14,59,60], which allow much larger samples. And new methods are being applied to conduct GWAS of longevity processes in samples of still-living individuals [61].…”

Long-Term Exposure to Elevated Lipoprotein(a) Levels, Parental Lifespan and Risk of Mortality

“…In a 2017 genetic association study that sought to identify variants associated with parental lifespan, Joshi et al 11 identified four loci including the LPA locus to be associated with parental lifespan at the genome-wide significance level. In a follow-up study of over a million parental lifespans, Timmers et al 10 confirmed the association between variants in LPA and parental lifespan. Interesting results were also recently reported by Zenin et al 23 who have shown that variants in LPA may be associated with disease-free survival (also known as healthspan) in the UK Biobank, thereby suggesting that lower Lp(a) might not only be associated with longer lifespan, but also with healthy living into old age.…”

“…Two recent genome-wide association studies identified variants at the LPA locus to be associated with shorter lifespan (as estimated by parental lifespan). 10,11 The association between measured and genetically-determined Lp(a) levels and human longevity is controversial and despite evidence suggesting that LPA might be a locus influencing longevity, it is unknown if a concentration-dependent effect of Lp(a) levels on human longevity exists. In this study, we used a 2-sample Mendelian randomization (2SMR) study design to determine whether genetic variants associated with elevated Lp(a) levels are causally associated with human longevity, as estimated by parental lifespan, in the UK Biobank.…”