2015 Dec 17;11(12):e1005728. doi: 10.1371/journal.pgen.1005728. eCollection 2015.

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

Fortney K, Dobriban E, Garagnani P, Pirazzini C, Monti D, Mari D, Atzmon G, Barzilai N, Franceschi C, Owen A, Kim SK.

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.

Summary Statistics for ankle injury.

iGWAS Summary statistics for SNPs from the NEC and 90PLUS cohorts (zipped text file, 5.7 Mb). The column headings are SNP and iGWAS P for each cohort. The iGWAS p-values for a SNP combine the information from: 1) meta-analysis for association with diverse diseases and 2) association with longevity.

NEC: 801 centenarians and 914 controls.

90PLUS: 5406 elderly over age 90 and 15112 controls.