Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity

摘要

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. Author Summary Longevity is a complex phenotype, and few genetic variants that affect lifespan have been identified. However, aging and disease are closely related, and a great deal is known about the genetic basis of disease risk. Here, 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 then develop a new statistical framework to find genetic variants associated with extreme longevity. The method, informed GWAS (iGWAS), takes advantage of knowledge from 14 large studies of disease and disease-related traits in order to narrow the search for SNPs associated with longevity. Using iGWAS, we found eight SNPs that are significant in our discovery cohorts, and we were able to validate four of these in replication studies of long-lived subjects. Our results implicate new loci in longevity and reveal a genetic overlap between longevity and age-related diseases and traits. Beyond the study of human longevity, iGWAS can be applied to boost statistical power in any GWAS of a target phenotype by using larger GWAS of genetically-related conditions.