Abstract
We developed a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from large studies of age-related disease in order to narrow the search for SNPs associated with longevity. To gain support for our approach, we first show there is an overlap between loci involved in disease and loci associated with extreme longevity. These results indicate that several disease variants may be depleted in centenarians versus the general population. Next, we used iGWAS to harness information from 14 meta-analyses of disease and trait GWAS to identify longevity loci in two studies of long-lived humans. In a standard GWAS analysis, only one locus in these studies is significant (APOE/TOMM40) when controlling the false discovery rate (FDR) at 10%. With iGWAS, we identify eight genetic loci to associate significantly with exceptional human longevity at FDR < 10%. We followed up the eight lead SNPs in independent cohorts, and found replication evidence of four loci and suggestive evidence for one more with exceptional longevity. The loci that replicated (FDR < 5%) included APOE/TOMM40 (associated with Alzheimer’s disease), CDKN2B/ANRIL (implicated in the regulation of cellular senescence), ABO (tags the O blood group), and SH2B3/ATXN2 (a signaling gene that extends lifespan in Drosophila and a gene involved in neurological disease). Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits, including coronary artery disease and Alzheimer’s disease. iGWAS provides a new analytical strategy for uncovering SNPs that influence extreme longevity, and can be applied more broadly to boost power in other studies of complex phenotypes.
Highlights
Aging and disease are closely related as aging is the largest risk factor for multiple chronic diseases
We show using genome-wide association studies (GWAS) of longevity and disease that there is an overlap between loci involved in longevity and loci involved in several diseases, such as Alzheimer’s disease and coronary artery disease
We develop a new statistical framework to find genetic variants associated with extreme longevity
Summary
Aging and disease are closely related as aging is the largest risk factor for multiple chronic diseases. A great deal is known about the genetic basis of disease risk from genome-wide-association studies. To find specific loci for longevity, genetic association studies have been used to identify polymorphisms that are associated with exceptional longevity. The first studies tested candidate genes suspected to play a role in human longevity. Polymorphisms located near APOE and FOXO3A were found to be consistently associated with extreme longevity[5,6,7]; studies yielded preliminary evidence for dozens of other candidate genes[8]. APOE was initially investigated because its ε4 allele was known to increase the risk of Alzheimer’s disease and coronary artery disease[5,9], while FOXO3 was tested because its homologs influence lifespan in C. elegans, Drosophila and mice[10]
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