title: Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity.
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.
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, California, United States of America.|Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Kristen
authors.initials: K
authors.lastname: Fortney
authors.affiliation: Department of Statistics, Stanford University, Stanford, California, United States of America.
authors.forename: Edgar
authors.initials: E
authors.lastname: Dobriban
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine Experimental Pathology, University of Bologna, Bologna, Italy.|Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Garagnani
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine Experimental Pathology, University of Bologna, Bologna, Italy.|Interdepartmental Centre "L. Galvani" CIG, University of Bologna, Bologna, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Pirazzini
authors.affiliation: Department of Clinical, Experimental and Biomedical Sciences, University of Florence, Florence, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Monti
authors.affiliation: Department of Medical Sciences, University of Milan, Milan, Italy.|Geriatric Unit, IRCCS Ca' Grande Foundation, Maggiore Policlinico Hospital, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Mari
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
authors.affiliation: Department of Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine Experimental Pathology, University of Bologna, Bologna, Italy.|IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
authors.affiliation: Department of Statistics, Stanford University, Stanford, California, United States of America.
authors.forename: Art B
authors.initials: AB
authors.lastname: Owen
authors.affiliation: Department of Developmental Biology, Stanford University, Stanford, California, United States of America.|Department of Genetics, Stanford University, Stanford, California, United States of America.
authors.forename: Stuart K
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000375:Aging / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008136:Longevity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide