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

Kristen Fortney, Edgar Dobriban, Paolo Garagnani, Chiara Pirazzini, Daniela Monti, Daniela Mari, Gil Atzmon, Nir Barzilai, Claudio Franceschi, Art B. Owen, Stuart K. Kim

Research output: Contribution to journalArticle

53 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1005728
JournalPLoS Genetics
Volume11
Issue number12
DOIs
StatePublished - 2015

Fingerprint

genome
Genome-Wide Association Study
Genome
loci
Single Nucleotide Polymorphism
Alzheimer disease
Alzheimer Disease
Genetic Loci
gene
Cell Aging
harness
senescence
Blood Group Antigens
blood groups
Genes
Drosophila
Meta-Analysis
phenotype
Coronary Artery Disease
blood

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Fortney, K., Dobriban, E., Garagnani, P., Pirazzini, C., Monti, D., Mari, D., ... Kim, S. K. (2015). Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity. PLoS Genetics, 11(12), [e1005728]. https://doi.org/10.1371/journal.pgen.1005728

Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity. / Fortney, Kristen; Dobriban, Edgar; Garagnani, Paolo; Pirazzini, Chiara; Monti, Daniela; Mari, Daniela; Atzmon, Gil; Barzilai, Nir; Franceschi, Claudio; Owen, Art B.; Kim, Stuart K.

In: PLoS Genetics, Vol. 11, No. 12, e1005728, 2015.

Research output: Contribution to journalArticle

Fortney, K, Dobriban, E, Garagnani, P, Pirazzini, C, Monti, D, Mari, D, Atzmon, G, Barzilai, N, Franceschi, C, Owen, AB & Kim, SK 2015, 'Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity', PLoS Genetics, vol. 11, no. 12, e1005728. https://doi.org/10.1371/journal.pgen.1005728
Fortney, Kristen ; Dobriban, Edgar ; Garagnani, Paolo ; Pirazzini, Chiara ; Monti, Daniela ; Mari, Daniela ; Atzmon, Gil ; Barzilai, Nir ; Franceschi, Claudio ; Owen, Art B. ; Kim, Stuart K. / Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity. In: PLoS Genetics. 2015 ; Vol. 11, No. 12.
@article{21f51946932f468dae15a09a466d1f47,
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.",
author = "Kristen Fortney and Edgar Dobriban and Paolo Garagnani and Chiara Pirazzini and Daniela Monti and Daniela Mari and Gil Atzmon and Nir Barzilai and Claudio Franceschi and Owen, {Art B.} and Kim, {Stuart K.}",
year = "2015",
doi = "10.1371/journal.pgen.1005728",
language = "English (US)",
volume = "11",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "12",

}

TY - JOUR

T1 - Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity

AU - Fortney, Kristen

AU - Dobriban, Edgar

AU - Garagnani, Paolo

AU - Pirazzini, Chiara

AU - Monti, Daniela

AU - Mari, Daniela

AU - Atzmon, Gil

AU - Barzilai, Nir

AU - Franceschi, Claudio

AU - Owen, Art B.

AU - Kim, Stuart K.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84953289902&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84953289902&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1005728

DO - 10.1371/journal.pgen.1005728

M3 - Article

C2 - 26677855

AN - SCOPUS:84953289902

VL - 11

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 12

M1 - e1005728

ER -