Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity
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{"title"=>"Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity", "type"=>"journal", "authors"=>[{"first_name"=>"Kristen", "last_name"=>"Fortney", "scopus_author_id"=>"36099931500"}, {"first_name"=>"Edgar", "last_name"=>"Dobriban", "scopus_author_id"=>"55711190100"}, {"first_name"=>"Paolo", "last_name"=>"Garagnani", "scopus_author_id"=>"16052588800"}, {"first_name"=>"Chiara", "last_name"=>"Pirazzini", "scopus_author_id"=>"23668427700"}, {"first_name"=>"Daniela", "last_name"=>"Monti", "scopus_author_id"=>"7102189734"}, {"first_name"=>"Daniela", "last_name"=>"Mari", "scopus_author_id"=>"36836829000"}, {"first_name"=>"Gil", "last_name"=>"Atzmon", "scopus_author_id"=>"6603255277"}, {"first_name"=>"Nir", "last_name"=>"Barzilai", "scopus_author_id"=>"7005711408"}, {"first_name"=>"Claudio", "last_name"=>"Franceschi", "scopus_author_id"=>"56236886700"}, {"first_name"=>"Art B.", "last_name"=>"Owen", "scopus_author_id"=>"7202050285"}, {"first_name"=>"Stuart K.", "last_name"=>"Kim", "scopus_author_id"=>"8073488900"}], "year"=>2015, "source"=>"PLoS Genetics", "identifiers"=>{"pui"=>"607579449", "sgr"=>"84953289902", "issn"=>"15537404", "pmid"=>"26677855", "scopus"=>"2-s2.0-84953289902", "doi"=>"10.1371/journal.pgen.1005728", "isbn"=>"1553-7390"}, "id"=>"f420babb-ac5a-3a7d-a715-d28b8310cd36", "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.", "link"=>"http://www.mendeley.com/research/genomewide-scan-informed-agerelated-disease-identifies-loci-exceptional-human-longevity", "reader_count"=>114, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Librarian"=>1, "Researcher"=>31, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>18, "Student > Postgraduate"=>6, "Student > Master"=>16, "Other"=>11, "Student > Bachelor"=>9, "Professor"=>12}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>5, "Librarian"=>1, "Researcher"=>31, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>18, "Student > Postgraduate"=>6, "Student > Master"=>16, "Other"=>11, "Student > Bachelor"=>9, "Professor"=>12}, "reader_count_by_subject_area"=>{"Unspecified"=>6, "Agricultural and Biological Sciences"=>50, "Veterinary Science and Veterinary Medicine"=>1, "Business, Management and Accounting"=>1, "Chemistry"=>1, "Computer Science"=>4, "Engineering"=>2, "Biochemistry, Genetics and Molecular Biology"=>24, "Nursing and Health Professions"=>1, "Mathematics"=>3, "Medicine and Dentistry"=>14, "Neuroscience"=>3, "Physics and Astronomy"=>1, "Psychology"=>2, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>14}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>2}, "Mathematics"=>{"Mathematics"=>3}, "Unspecified"=>{"Unspecified"=>6}, "Engineering"=>{"Engineering"=>2}, "Chemistry"=>{"Chemistry"=>1}, "Neuroscience"=>{"Neuroscience"=>3}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>50}, "Computer Science"=>{"Computer Science"=>4}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>24}, "Veterinary Science and Veterinary Medicine"=>{"Veterinary Science and Veterinary Medicine"=>1}}, "reader_count_by_country"=>{"United States"=>3, "Qatar"=>1, "Japan"=>1, "Brazil"=>2, "United Kingdom"=>3, "Italy"=>1, "Germany"=>2, "India"=>1}, "group_count"=>5}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2611099"], "description"=>"<p>The y axis shows weighted P values and the x axis indicates position of the SNPs. Color of the SNP indicates linkage to the lead SNP (purple). Green boxes indicate genes harboring missense SNPs in LD with candidate longevity SNPs, and magenta boxes indicate genes whose expression is associated with a candidate longevity SNP (eQTL). A. Data for rs4420638 in APE/TOMM40. B. Data for rs497756 in CDKN2B. C. Data for rs514659 in ABO. D. Data for rs3184504 in SH2B3.</p>", "links"=>[], "tags"=>["discovery rate", "longevity loci", "disease variants", "fdr", "apoe", "Exceptional Human Longevity", "iGWAS", "snp", "harness information", "CDKN", "trait GWAS", "artery disease", "GWAS analysis", "replication evidence", "SH 2B", "abo", "gain support"], "article_id"=>1626520, "categories"=>["Biological Sciences"], "users"=>["Kristen Fortney", "Edgar Dobriban", "Paolo Garagnani", "Chiara Pirazzini", "Daniela Monti", "Daniela Mari", "Gil Atzmon", "Nir Barzilai", "Claudio Franceschi", "Art B. Owen", "Stuart K. Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005728.g004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Regional_plots_for_four_longevity_associated_SNPs_/1626520", "title"=>"Regional plots for four longevity-associated SNPs.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-12-18 11:22:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/2611101", "https://ndownloader.figshare.com/files/2611102", "https://ndownloader.figshare.com/files/2611103", "https://ndownloader.figshare.com/files/2611104", "https://ndownloader.figshare.com/files/2611105", "https://ndownloader.figshare.com/files/2611106", "https://ndownloader.figshare.com/files/2611107", "https://ndownloader.figshare.com/files/2611108", "https://ndownloader.figshare.com/files/2611109", "https://ndownloader.figshare.com/files/2611110"], "description"=>"<div><p>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 (<i>APOE/TOMM40</i>) 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 <i>APOE/TOMM40</i> (associated with Alzheimer’s disease), <i>CDKN2B/ANRIL</i> (implicated in the regulation of cellular senescence), <i>ABO</i> (tags the O blood group), and <i>SH2B3/ATXN2</i> (a signaling gene that extends lifespan in <i>Drosophila</i> 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.</p></div>", "links"=>[], "tags"=>["discovery rate", "longevity loci", "disease variants", "fdr", "apoe", "Exceptional Human Longevity", "iGWAS", "snp", "harness information", "CDKN", "trait GWAS", "artery disease", "GWAS analysis", "replication evidence", "SH 2B", "abo", "gain support"], "article_id"=>1626522, "categories"=>["Biological Sciences"], "users"=>["Kristen Fortney", "Edgar Dobriban", "Paolo Garagnani", "Chiara Pirazzini", "Daniela Monti", "Daniela Mari", "Gil Atzmon", "Nir Barzilai", "Claudio Franceschi", "Art B. Owen", "Stuart K. Kim"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1005728.s001", "https://dx.doi.org/10.1371/journal.pgen.1005728.s002", "https://dx.doi.org/10.1371/journal.pgen.1005728.s003", "https://dx.doi.org/10.1371/journal.pgen.1005728.s004", "https://dx.doi.org/10.1371/journal.pgen.1005728.s005", "https://dx.doi.org/10.1371/journal.pgen.1005728.s006", "https://dx.doi.org/10.1371/journal.pgen.1005728.s007", "https://dx.doi.org/10.1371/journal.pgen.1005728.s008", "https://dx.doi.org/10.1371/journal.pgen.1005728.s009", "https://dx.doi.org/10.1371/journal.pgen.1005728.s010"], "stats"=>{"downloads"=>19, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genome_Wide_Scan_Informed_by_Age_Related_Disease_Identifies_Loci_for_Exceptional_Human_Longevity_/1626522", "title"=>"Genome-Wide Scan Informed by Age-Related Disease Identifies Loci for Exceptional Human Longevity", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-12-18 11:22:20"}
  • {"files"=>["https://ndownloader.figshare.com/files/2611095"], "description"=>"<p>Shown are results for coronary artery disease and Alzheimer’s disease. The y axis is the observed P values for longevity[<a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005728#pgen.1005728.ref003\" target=\"_blank\">3</a>], and the x axis is the expected P values under the null hypothesis that the disease is independent of longevity. The cyan, blue and purple lines show the P values for longevity of the top 100, 250, and 500 disease SNPs from independent genetic loci, respectively. Red lines show the background distribution of longevity P values for all independent genetic loci tested in both the longevity and disease GWAS. The grey horizontal line corresponds to the threshold for nominal significance (P< = 0.05) for longevity. Significance of enrichment was determined with the hypergeometric test. (*) P < 0.05, (**) P < 0.005. Q-Q plots for other diseases and traits are shown in <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005728#pgen.1005728.s002\" target=\"_blank\">S1</a> and <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005728#pgen.1005728.s003\" target=\"_blank\">S2</a> Figs.</p>", "links"=>[], "tags"=>["discovery rate", "longevity loci", "disease variants", "fdr", "apoe", "Exceptional Human Longevity", "iGWAS", "snp", "harness information", "CDKN", "trait GWAS", "artery disease", "GWAS analysis", "replication evidence", "SH 2B", "abo", "gain support"], "article_id"=>1626516, "categories"=>["Biological Sciences"], "users"=>["Kristen Fortney", "Edgar Dobriban", "Paolo Garagnani", "Chiara Pirazzini", "Daniela Monti", "Daniela Mari", "Gil Atzmon", "Nir Barzilai", "Claudio Franceschi", "Art B. Owen", "Stuart K. Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005728.g001", "stats"=>{"downloads"=>2, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Disease_GWAS_show_substantial_genetic_overlap_with_longevity_/1626516", "title"=>"Disease GWAS show substantial genetic overlap with longevity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-12-18 11:22:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/2611096"], "description"=>"<p><b>A.</b> Shown is a basic schematic of our method for deriving weights. First, we perform a cross-disease analysis across all meta-analyses of disease GWA studies. Next, we use the results of the cross-disease analysis to derive weights for the longevity GWAS. Finally, we weight the P values from the longevity studies, and identify significant SNPs. <b>B</b>. Weighting boosts new loci to significance. Shown are Manhattan plots of all SNPs before (in black) and after (green) adjusting their P values with disease-informed weights. The black and green lines show the FDR < 10% cutoff in the unweighted and weighted GWAS, respectively. Without weights, only the <i>APOE</i> locus is significant in NECS and 90PLUS; after weighting, 7 more loci become statistically significant at FDR < 10%. The x axis shows SNPs according to their chromosomal positions.</p>", "links"=>[], "tags"=>["discovery rate", "longevity loci", "disease variants", "fdr", "apoe", "Exceptional Human Longevity", "iGWAS", "snp", "harness information", "CDKN", "trait GWAS", "artery disease", "GWAS analysis", "replication evidence", "SH 2B", "abo", "gain support"], "article_id"=>1626517, "categories"=>["Biological Sciences"], "users"=>["Kristen Fortney", "Edgar Dobriban", "Paolo Garagnani", "Chiara Pirazzini", "Daniela Monti", "Daniela Mari", "Gil Atzmon", "Nir Barzilai", "Claudio Franceschi", "Art B. Owen", "Stuart K. Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005728.g002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Informed_GWAS_implicates_8_loci_in_longevity_/1626517", "title"=>"Informed GWAS implicates 8 loci in longevity.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-12-18 11:22:18"}
  • {"files"=>["https://ndownloader.figshare.com/files/2611097"], "description"=>"<p>Shown are raw P values for each lead longevity SNP in each of the 14 meta-analyses of disease GWA studies that contributed to the cross-disease analysis used by iGWAS. Colors of blue indicate P values in the disease GWAS. The darkest blue corresponds to genome-wide significance. ADIP, adiponectin levels; LOAD, late-onset Alzheimer's disease; AMD, age-related macular degeneration; ART, rheumatoid arthritis; BMD, bone mineral density; BMI, body mass index; DBP, diastolic blood pressure; DIA, type 2 diabetes; CAD, coronary artery disease; INS, fasting insulin levels; CKD, chronic kidney disease; CAN_LUNG, lung cancer; CAN_PANC, pancreatic cancer; TCHO, total cholesterol.</p>", "links"=>[], "tags"=>["discovery rate", "longevity loci", "disease variants", "fdr", "apoe", "Exceptional Human Longevity", "iGWAS", "snp", "harness information", "CDKN", "trait GWAS", "artery disease", "GWAS analysis", "replication evidence", "SH 2B", "abo", "gain support"], "article_id"=>1626518, "categories"=>["Biological Sciences"], "users"=>["Kristen Fortney", "Edgar Dobriban", "Paolo Garagnani", "Chiara Pirazzini", "Daniela Monti", "Daniela Mari", "Gil Atzmon", "Nir Barzilai", "Claudio Franceschi", "Art B. Owen", "Stuart K. Kim"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1005728.g003", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nominal_associations_with_multiple_diseases_for_longevity_loci_/1626518", "title"=>"Nominal associations with multiple diseases for longevity loci.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-12-18 11:22:18"}

PMC Usage Stats | Further Information

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  • {"unique-ip"=>"23", "full-text"=>"30", "pdf"=>"12", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2017", "month"=>"11"}
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  • {"unique-ip"=>"31", "full-text"=>"27", "pdf"=>"9", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"1"}
  • {"unique-ip"=>"20", "full-text"=>"20", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"5"}
  • {"unique-ip"=>"27", "full-text"=>"22", "pdf"=>"15", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"8", "cited-by"=>"0", "year"=>"2018", "month"=>"4"}
  • {"unique-ip"=>"15", "full-text"=>"15", "pdf"=>"11", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"11", "cited-by"=>"0", "year"=>"2018", "month"=>"6"}
  • {"unique-ip"=>"30", "full-text"=>"26", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"4", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"20", "full-text"=>"21", "pdf"=>"10", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"14", "full-text"=>"11", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"6", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"19", "full-text"=>"19", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"24", "full-text"=>"24", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"15", "full-text"=>"13", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"26", "full-text"=>"22", "pdf"=>"8", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"33", "full-text"=>"29", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"26", "full-text"=>"22", "pdf"=>"10", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"20", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"26", "full-text"=>"24", "pdf"=>"12", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"15", "full-text"=>"13", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"1", "year"=>"2019", "month"=>"8"}

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}

F1000Prime | Further Information

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