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

被引：105

作者：

Fortney, Kristen ^{[1
,2
]}

Dobriban, Edgar ^{[3
]}

Garagnani, Paolo ^{[4
,5
]}

Pirazzini, Chiara ^{[4
,6
]}

Monti, Daniela ^{[7
]}

Mari, Daniela ^{[8
,9
]}

Atzmon, Gil ^{[10
]}

Barzilai, Nir ^{[10
]}

Franceschi, Claudio ^{[4
,11
]}

Owen, Art B. ^{[3
]}

Kim, Stuart K. ^{[1
,2
]}

机构：

[1] Stanford Univ, Dept Dev Biol, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[3] Stanford Univ, Dept Stat, Stanford, CA 94305 USA

[4] Univ Bologna, Dept Expt Diagnost & Specialty Med Expt Pathol, Bologna, Italy

[5] St Orsola Malpighi Univ Hosp, Ctr Appl Biomed Res, Bologna, Italy

[6] Univ Bologna, Interdept Ctr L Galvani CIG, Bologna, Italy

[7] Univ Florence, Dept Clin Expt & Biomed Sci, Florence, Italy

[8] Univ Milan, Dept Med Sci, Milan, Italy

[9] Maggiore Policlin Hosp, IRCCS Ca Grande Fdn, Geriatr Unit, Milan, Italy

[10] Albert Einstein Coll Med, Dept Genet, Bronx, NY 10467 USA

[11] IRCCS, Inst Neurol Sci Bologna, Bologna, Italy

来源：

PLOS GENETICS | 2015年 / 11卷 / 12期

基金：

美国国家卫生研究院;

关键词：

ABO BLOOD-GROUP; GENETIC-VARIANTS; CARDIOVASCULAR-DISEASE; COMMON VARIANTS; IMPROVE POWER; APOE LOCUS; OLD-AGE; ASSOCIATION; METAANALYSIS; RISK;

D O I：

10.1371/journal.pgen.1005728

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

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.

引用

页数：23

共 80 条

[1] An integrated map of genetic variation from 1,092 human genomes [J].

Altshuler, David M. ;

Durbin, Richard M. ;

Abecasis, Goncalo R. ;

Bentley, David R. ;

Chakravarti, Aravinda ;

Clark, Andrew G. ;

Donnelly, Peter ;

Eichler, Evan E. ;

Flicek, Paul ;

Gabriel, Stacey B. ;

Gibbs, Richard A. ;

Green, Eric D. ;

Hurles, Matthew E. ;

Knoppers, Bartha M. ;

Korbel, Jan O. ;

Lander, Eric S. ;

Lee, Charles ;

Lehrach, Hans ;

Mardis, Elaine R. ;

Marth, Gabor T. ;

McVean, Gil A. ;

Nickerson, Deborah A. ;

Schmidt, Jeanette P. ;

Sherry, Stephen T. ;

Wang, Jun ;

Wilson, Richard K. ;

Gibbs, Richard A. ;

Dinh, Huyen ;

Kovar, Christie ;

Lee, Sandra ;

Lewis, Lora ;

Muzny, Donna ;

Reid, Jeff ;

Wang, Min ;

Wang, Jun ;

Fang, Xiaodong ;

Guo, Xiaosen ;

Jian, Min ;

Jiang, Hui ;

Jin, Xin ;

Li, Guoqing ;

Li, Jingxiang ;

Li, Yingrui ;

Li, Zhuo ;

Liu, Xiao ;

Lu, Yao ;

Ma, Xuedi ;

Su, Zhe ;

Tai, Shuaishuai ;

Tang, Meifang .

NATURE, 2012, 491 (7422) :56-65

[2] Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer [J].

Amundadottir, Laufey ;

Kraft, Peter ;

Stolzenberg-Solomon, Rachael Z. ;

Fuchs, Charles S. ;

Petersen, Gloria M. ;

Arslan, Alan A. ;

Bueno-de-Mesquita, H. Bas ;

Gross, Myron ;

Helzlsouer, Kathy ;

Jacobs, Eric J. ;

LaCroix, Andrea ;

Zheng, Wei ;

Albanes, Demetrius ;

Bamlet, William ;

Berg, Christine D. ;

Berrino, Franco ;

Bingham, Sheila ;

Buring, Julie E. ;

Bracci, Paige M. ;

Canzian, Federico ;

Clavel-Chapelon, Francoise ;

Clipp, Sandra ;

Cotterchio, Michelle ;

de Andrade, Mariza ;

Duell, Eric J. ;

Fox, John W., Jr. ;

Gallinger, Steven ;

Gaziano, J. Michael ;

Giovannucci, Edward L. ;

Goggins, Michael ;

Gonzalez, Carlos A. ;

Hallmans, Goran ;

Hankinson, Susan E. ;

Hassan, Manal ;

Holly, Elizabeth A. ;

Hunter, David J. ;

Hutchinson, Amy ;

Jackson, Rebecca ;

Jacobs, Kevin B. ;

Jenab, Mazda ;

Kaaks, Rudolf ;

Klein, Alison P. ;

Kooperberg, Charles ;

Kurtz, Robert C. ;

Li, Donghui ;

Lynch, Shannon M. ;

Mandelson, Margaret ;

McWilliams, Robert R. ;

Mendelsohn, Julie B. ;

Michaud, Dominique S. .

NATURE GENETICS, 2009, 41 (09) :986-U47

[3] Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate [J].

Andreassen, Ole A. ;

Thompson, Wesley K. ;

Schork, Andrew J. ;

Ripke, Stephan ;

Mattingsdal, Morten ;

Kelsoe, John R. ;

Kendler, Kenneth S. ;

O'Donovan, Michael C. ;

Rujescu, Dan ;

Werge, Thomas ;

Sklar, Pamela ;

Roddey, J. Cooper ;

Chen, Chi-Hua ;

McEvoy, Linda ;

Desikan, Rahul S. ;

Djurovic, Srdjan ;

Dale, Anders M. .

PLOS GENETICS, 2013, 9 (04)

[4] Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors [J].

Andreassen, Ole A. ;

Djurovic, Srdjan ;

Thompson, Wesley K. ;

Schork, Andrew J. ;

Kendler, Kenneth S. ;

O'Donovan, Michael C. ;

Rujescu, Dan ;

Werge, Thomas ;

van de Bunt, Martijn ;

Morris, Andrew P. ;

McCarthy, Mark I. ;

Roddey, J. Cooper ;

McEvoy, Linda K. ;

Desikan, Rahul S. ;

Dale, Anders M. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2013, 92 (02) :197-209

[5] Genome-wide association study (GWAS)-identified disease risk alleles do not compromise human longevity [J].

Beekman, Marian ;

Nederstigt, Christa ;

Suchiman, H. Eka D. ;

Kremer, Dennis ;

van der Breggen, Ruud ;

Lakenberg, Nico ;

Alemayehu, Wendimagegn Ghidey ;

de Craen, Anton J. M. ;

Westendorp, Rudi G. J. ;

Boomsma, Dorret I. ;

de Geus, Eco J. C. ;

Houwing-Duistermaat, Jeanine J. ;

Heijmans, Bastiaan T. ;

Slagboom, P. Eline .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (42) :18046-18049

[6] A step-down multiple hypotheses testing procedure that controls the false discovery rate under independence [J].

Benjamini, Y ;

Liu, W .

JOURNAL OF STATISTICAL PLANNING AND INFERENCE, 1999, 82 (1-2) :163-170

[7] Buffering mechanisms in aging: A systems approach toward uncovering the genetic component of aging [J].

Bergman, Aviv ;

Atzmon, Gil ;

Ye, Kenny ;

MacCarthy, Thomas ;

Barzilai, Nir .

PLOS COMPUTATIONAL BIOLOGY, 2007, 3 (08) :1648-1656

[8] Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database [J].

Bertram, Lars ;

McQueen, Matthew B. ;

Mullin, Kristina ;

Blacker, Deborah ;

Tanzi, Rudolph E. .

NATURE GENETICS, 2007, 39 (01) :17-23

[9] GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy [J].

Broer, Linda ;

Buchman, Aron S. ;

Deelen, Joris ;

Evans, Daniel S. ;

Faul, Jessica D. ;

Lunetta, Kathryn L. ;

Sebastiani, Paola ;

Smith, Jennifer A. ;

Smith, Albert V. ;

Tanaka, Toshiko ;

Yu, Lei ;

Arnold, Alice M. ;

Aspelund, Thor ;

Benjamin, Emelia J. ;

De Jager, Philip L. ;

Eirkisdottir, Gudny ;

Evans, Denis A. ;

Garcia, Melissa E. ;

Hofman, Albert ;

Kaplan, Robert C. ;

Kardia, Sharon L. R. ;

Kiel, Douglas P. ;

Oostra, Ben A. ;

Orwoll, Eric S. ;

Parimi, Neeta ;

Psaty, Bruce M. ;

Rivadeneira, Fernando ;

Rotter, Jerome I. ;

Seshadri, Sudha ;

Singleton, Andrew ;

Tiemeier, Henning ;

Uitterlinden, Andre G. ;

Zhao, Wei ;

Bandinelli, Stefania ;

Bennett, David A. ;

Ferrucci, Luigi ;

Gudnason, Vilmundur ;

Harris, Tamara B. ;

Karasik, David ;

Launer, Lenore J. ;

Perls, Thomas T. ;

Slagboom, P. Eline ;

Tranah, Gregory J. ;

Weir, David R. ;

Newman, Anne B. ;

van Duijn, Cornelia M. ;

Murabito, Joanne M. .

JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES, 2015, 70 (01) :110-118

[10] LongevityMap: a database of human genetic variants associated with longevity [J].

Budovsky, Arie ;

Craig, Thomas ;

Wang, Jingwei ;

Tacutu, Robi ;

Csordas, Attila ;

Lourenco, Joana ;

Fraifeld, Vadim E. ;

de Magalhaes, Joao Pedro .

TRENDS IN GENETICS, 2013, 29 (10) :559-560

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