Gene set analysis of GWAS data for human longevity highlights the relevance of the insulin/IGF-1 signaling and telomere maintenance pathways
Tóm tắt
In genome-wide association studies (GWAS) of complex traits, single SNP analysis is still the most applied approach. However, the identified SNPs have small effects and provide limited biological insight. A more appropriate approach to interpret GWAS data of complex traits is to analyze the combined effect of a SNP set grouped per pathway or gene region. We used this approach to study the joint effect on human longevity of genetic variation in two candidate pathways, the insulin/insulin-like growth factor (IGF-1) signaling (IIS) pathway and the telomere maintenance (TM) pathway. For the analyses, we used genotyped GWAS data of 403 unrelated nonagenarians from long-lived sibships collected in the Leiden Longevity Study and 1,670 younger population controls. We analyzed 1,021 SNPs in 68 IIS pathway genes and 88 SNPs in 13 TM pathway genes using four self-contained pathway tests (PLINK set-based test, Global test, GRASS and SNP ratio test). Although we observed small differences between the results of the different pathway tests, they showed consistent significant association of the IIS and TM pathway SNP sets with longevity. Analysis of gene SNP sets from these pathways indicates that the association of the IIS pathway is scattered over several genes (AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2, and YWHAG), while the association of the TM pathway seems to be mainly determined by one gene (POT1). In conclusion, this study shows that genetic variation in genes involved in the IIS and TM pathways is associated with human longevity.
Tài liệu tham khảo
Allsopp RC (1996) Models of initiation of replicative senescence by loss of telomeric DNA. Exp Gerontol 31:235–243
Anselmi CV, Malovini A, Roncarati R, Novelli V, Villa F, Condorelli G, Bellazzi R, Puca AA (2009) Association of the FOXO3A locus with extreme longevity in a southern Italian centenarian study. Rejuv Res 12:95–104
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, Harris MA, Hill DP, Issel-Tarver L, Kasarskis A, Lewis S, Matese JC, Richardson JE, Ringwald M, Rubin GM, Sherlock G (2000) Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat Genet 25:25–29
Atzmon G, Cho M, Cawthon RM, Budagov T, Katz M, Yang X, Siegel G, Bergman A, Huffman DM, Schechter CB, Wright WE, Shay JW, Barzilai N, Govindaraju DR, Suh Y (2010) Evolution in health and medicine Sackler colloquium: genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci USA 107(Suppl 1):1710–1717
Bakaysa SL, Mucci LA, Slagboom PE, Boomsma DI, McClearn GE, Johansson B, Pedersen NL (2007) Telomere length predicts survival independent of genetic influences. Aging Cell 6:769–774
Beekman M, Blauw GJ, Houwing-Duistermaat JJ, Brandt BW, Westendorp RG, Slagboom PE (2006) Chromosome 4q25, microsomal transfer protein gene, and human longevity: novel data and a meta-analysis of association studies. J Gerontol A-Biol 61:355–362
Bischoff C, Petersen HC, Graakjaer J, ndersen-Ranberg K, Vaupel JW, Bohr VA, Kolvraa S, Christensen K (2006) No association between telomere length and survival among the elderly and oldest old. Epidemiology 17:190–194
Blackburn EH (1991) Structure and function of telomeres. Nature 350:569–573
Blake JA, Bult CJ, Kadin JA, Richardson JE, Eppig JT (2011) The Mouse Genome Database (MGD): premier model organism resource for mammalian genomics and genetics. Nucleic Acids Res 39:D842–D848
Bluher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299:572–574
Cawthon RM, Smith KR, O'Brien E, Sivatchenko A, Kerber RA (2003) Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361:393–395
Chapman J, Whittaker J (2008) Analysis of multiple SNPs in a candidate gene or region. Genet Epidemiol 32:560–566
Chen LS, Hutter CM, Potter JD, Liu Y, Prentice RL, Peters U, Hsu L (2010) Insights into colon cancer etiology via a regularized approach to gene set analysis of GWAS data. Am J Hum Genet 86:860–871
Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L (2001) Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science 292:104–106
Codd V, Mangino M, van der Harst P, Braund PS, Kaiser M, Beveridge AJ, Rafelt S, Moore J, Nelson C, Soranzo N, Zhai G, Valdes AM, Blackburn H, Mateo Leach I, de Boer RA, Goodall AH, Ouwehand W, van Veldhuisen DJ, van Gilst WH, Navis G, Burton PR, Tobin MD, Hall AS, Thompson JR, Spector T, Samani NJ (2010) Common variants near TERC are associated with mean telomere length. Nat Genet 42:197–199
Collins K, Mitchell JR (2002) Telomerase in the human organism. Oncogene 21:564–579
de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–2110
Deelen J, Beekman M, Uh HW, Helmer Q, Kuningas M, Christiansen L, Kremer D, van der Breggen R, Suchiman HE, Lakenberg N, van den Akker EB, Passtoors WM, Tiemeier H, van Heemst D, de Craen AJ, Rivadeneira F, de Geus EJ, Perola M, van der Ouderaa FJ, Gunn DA, Boomsma DI, Uitterlinden AG, Christensen K, van Duijn CM, Heijmans BT, Houwing-Duistermaat JJ, Westendorp RG, Slagboom PE (2011) Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited. Aging Cell 10:686–698
Eriksson N, Macpherson JM, Tung JY, Hon LS, Naughton B, Saxonov S, Avey L, Wojcicki A, Pe'er I, Mountain J (2010) Web-based, participant-driven studies yield novel genetic associations for common traits. PLoS Genet 6:e1000993
Flachsbart F, Caliebe A, Kleindorp R, Blanche H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci USA 106:2700–2705
Fridley BL, Biernacka JM (2011) Gene set analysis of SNP data: benefits, challenges, and future directions. Eur J Hum Genet 19:837–843
Friedman DB, Johnson TE (1988) A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118:75–86
Giannakou ME, Goss M, Junger MA, Hafen E, Leevers SJ, Partridge L (2004) Long-lived Drosophila with overexpressed dFOXO in adult fat body. Science 305:361
Goeman JJ, Buhlmann P (2007) Analyzing gene expression data in terms of gene sets: methodological issues. Bioinformatics 23:980–987
Goeman JJ, van de Geer SA, de Kort F, van Houwelingen HC (2004) A global test for groups of genes: testing association with a clinical outcome. Bioinformatics 20:93–99
Gudmundsson H, Gudbjartsson DF, Frigge M, Gulcher JR, Stefansson K (2000) Inheritance of human longevity in Iceland. Eur J Hum Genet 8:743–749
Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460
Harrington L, McPhail T, Mar V, Zhou W, Oulton R, Bass MB, Arruda I, Robinson MO (1997) A mammalian telomerase-associated protein. Science 275:973–977
He H, Wang Y, Guo X, Ramchandani S, Ma J, Shen MF, Garcia DA, Deng Y, Multani AS, You MJ, Chang S (2009) Pot1b deletion and telomerase haploinsufficiency in mice initiate an ATR-dependent DNA damage response and elicit phenotypes resembling dyskeratosis congenita. Mol Cell Biol 29:229–240
Hjelmborg JV, Iachine I, Skytthe A, Vaupel JW, McGue M, Koskenvuo M, Kaprio J, Pedersen NL, Christensen K (2006) Genetic influence on human lifespan and longevity. Hum Genet 119:312–321
Hockemeyer D, Palm W, Wang RC, Couto SS, de Lange T (2008) Engineered telomere degradation models dyskeratosis congenita. Genes Dev 22:1773–1785
Holmans P (2010) Statistical methods for pathway analysis of genome-wide data for association with complex genetic traits. Adv Genet 72:141–179
Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le BY (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421:182–187
Hwangbo DS, Gershman B, Tu MP, Palmer M, Tatar M (2004) Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature 429:562–566
Kanehisa M, Goto S (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28:27–30
Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366:461–464
Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) Daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277:942–946
Kimura M, Hjelmborg JV, Gardner JP, Bathum L, Brimacombe M, Lu X, Christiansen L, Vaupel JW, Aviv A, Christensen K (2008) Telomere length and mortality: a study of leukocytes in elderly Danish twins. Am J Epidemiol 167:799–806
Levy D, Neuhausen SL, Hunt SC, Kimura M, Hwang SJ, Chen W, Bis JC, Fitzpatrick AL, Smith E, Johnson AD, Gardner JP, Srinivasan SR, Schork N, Rotter JI, Herbig U, Psaty BM, Sastrasinh M, Murray SS, Vasan RS, Province MA, Glazer NL, Lu X, Cao X, Kronmal R, Mangino M, Soranzo N, Spector TD, Berenson GS, Aviv A (2010) Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. Proc Natl Acad Sci USA 107:9293–9298
Li Y, Wang WJ, Cao H, Lu J, Wu C, Hu FY, Guo J, Zhao L, Yang F, Zhang YX, Li W, Zheng GY, Cui H, Chen X, Zhu Z, He H, Dong B, Mo X, Zeng Y, Tian XL (2009) Genetic association of FOXO1A and FOXO3A with longevity trait in Han Chinese populations. Hum Mol Genet 18:4897–4904
Lin K, Dorman JB, Rodan A, Kenyon C (1997) Daf-16: An HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278:1319–1322
Luo L, Peng G, Zhu Y, Dong H, Amos CI, Xiong M (2010) Genome-wide gene and pathway analysis. Eur J Hum Genet 18:1045–1053
Manolio TA, Brooks LD, Collins FS (2008) A HapMap harvest of insights into the genetics of common disease. J Clin Invest 118:1590–1605
Martin-Ruiz CM, Gussekloo J, van Heemst D, von Zglinicki T, Westendorp RG (2005) Telomere length in white blood cells is not associated with morbidity or mortality in the oldest old: a population-based study. Aging Cell 4:287–290
Mirabello L, Yu K, Kraft P, De Vivo I, Hunter DJ, Prescott J, Wong JY, Chatterjee N, Hayes RB, Savage SA (2010) The association of telomere length and genetic variation in telomere biology genes. Hum Mutat 31:1050–1058
Morris JZ, Tissenbaum HA, Ruvkun G (1996) A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382:536–539
Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, Meyne J, Ratliff RL, Wu JR (1988) A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA 85:6622–6626
Newman AB, Walter S, Lunetta KL, Garcia ME, Slagboom PE, Christensen K, Arnold AM, Aspelund T, Aulchenko YS, Benjamin EJ, Christiansen L, D'Agostino RB Sr, Fitzpatrick AL, Franceschini N, Glazer NL, Gudnason V, Hofman A, Kaplan R, Karasik D, Kelly-Hayes M, Kiel DP, Launer LJ, Marciante KD, Massaro JM, Miljkovic I, Nalls MA, Hernandez D, Psaty BM, Rivadeneira F, Rotter J, Seshadri S, Smith AV, Taylor KD, Tiemeier H, Uh HW, Uitterlinden AG, Vaupel JW, Walston J, Westendorp RG, Harris TB, Lumley T, van Duijn CM, Murabito JM (2010) A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the cohorts for heart and aging research in genomic epidemiology consortium. J Gerontol A-Biol 65:478–487
O'Dushlaine C, Kenny E, Heron EA, Segurado R, Gill M, Morris DW, Corvin A (2009) The SNP ratio test: pathway analysis of genome-wide association datasets. Bioinformatics 25:2762–2763
Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389:994–999
Pan W (2009) Asymptotic tests of association with multiple SNPs in linkage disequilibrium. Genet Epidemiol 33:497–507
Pawlikowska L, Hu D, Huntsman S, Sung A, Chu C, Chen J, Joyner AH, Schork NJ, Hsueh WC, Reiner AP, Psaty BM, Atzmon G, Barzilai N, Cummings SR, Browner WS, Kwok PY, Ziv E (2009) Association of common genetic variation in the insulin/IGF1 signaling pathway with human longevity. Aging Cell 8:460–472
Perls T, Kunkel LM, Puca AA (2002) The genetics of exceptional human longevity. J Mol Neurosci 19:233–238
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575
Rafnar T, Sulem P, Stacey SN, Geller F, Gudmundsson J, Sigurdsson A, Jakobsdottir M, Helgadottir H, Thorlacius S, Aben KK, Blondal T, Thorgeirsson TE, Thorleifsson G, Kristjansson K, Thorisdottir K, Ragnarsson R, Sigurgeirsson B, Skuladottir H, Gudbjartsson T, Isaksson HJ, Einarsson GV, Benediktsdottir KR, Agnarsson BA, Olafsson K, Salvarsdottir A, Bjarnason H, Asgeirsdottir M, Kristinsson KT, Matthiasdottir S, Sveinsdottir SG, Polidoro S, Hoiom V, Botella-Estrada R, Hemminki K, Rudnai P, Bishop DT, Campagna M, Kellen E, Zeegers MP, de Verdier P, Ferrer A, Isla D, Vidal MJ, Andres R, Saez B, Juberias P, Banzo J, Navarrete S, Tres A, Kan D, Lindblom A, Gurzau E, Koppova K, de Vegt F, Schalken JA, van der Heijden HF, Smit HJ, Termeer RA, Oosterwijk E, van Hooij O, Nagore E, Porru S, Steineck G, Hansson J, Buntinx F, Catalona WJ, Matullo G, Vineis P, Kiltie AE, Mayordomo JI, Kumar R, Kiemeney LA, Frigge ML, Jonsson T, Saemundsson H, Barkardottir RB, Jonsson E, Jonsson S, Olafsson JH, Gulcher JR, Masson G, Gudbjartsson DF, Kong A, Thorsteinsdottir U, Stefansson K (2009) Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat Genet 41:221–227
Schoenmaker M, de Craen AJ, de Meijer PH, Beekman M, Blauw GJ, Slagboom PE, Westendorp RG (2006) Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden longevity study. Eur J Hum Genet 14:79–84
Selman C, Partridge L, Withers DJ (2011) Replication of extended lifespan phenotype in mice with deletion of insulin receptor substrate 1. PLoS One 6:e16144
Skytthe A, Pedersen NL, Kaprio J, Stazi MA, Hjelmborg JV, Iachine I, Vaupel JW, Christensen K (2003) Longevity studies in GenomEUtwin. Twin Res 6:448–454
Soerensen M, Dato S, Christensen K, McGue M, Stevnsner T, Bohr VA, Christiansen L (2010) Replication of an association of variation in the FOXO3A gene with human longevity using both case-control and longitudinal data. Aging Cell 9:1010–1017
Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96
Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS (2001) A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292:107–110
Tatar M, Bartke A, Antebi A (2003) The endocrine regulation of aging by insulin-like signals. Science 299:1346–1351
Teichert M, Eijgelsheim M, Rivadeneira F, Uitterlinden AG, van Schaik RH, Hofman A, De Smet PA, van Gelder T, Visser LE, Stricker BH (2009) A genome-wide association study of acenocoumarol maintenance dosage. Hum Mol Genet 18:3758–3768
Torkamani A, Topol EJ, Schork NJ (2008) Pathway analysis of seven common diseases assessed by genome-wide association. Genomics 92:265–272
van der Horst A, Burgering BM (2007) Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 8:440–450
Vulliamy T, Beswick R, Kirwan M, Marrone A, Digweed M, Walne A, Dokal I (2008) Mutations in the telomerase component NHP2 cause the premature ageing syndrome dyskeratosis congenita. Proc Natl Acad Sci USA 105:8073–8078
Wang K, Li M, Hakonarson H (2010) Analysing biological pathways in genome-wide association studies. Nat Rev Genet 11:843–854
Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (2008) FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci USA 105:13987–13992
Yang Q, Zheng YL, Harris CC (2005) POT1 and TRF2 cooperate to maintain telomeric integrity. Mol Cell Biol 25:1070–1080