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

PLoS Genetics

Volumn 11, Issue 12, 2015, Pages

  Fortney, Kristen ^a   Dobriban, Edgar ^a   Garagnani, Paolo ^b,c   Pirazzini, Chiara ^b   Monti, Daniela ^d   Mari, Daniela ^e,f   Atzmon, Gil ^g   Barzilai, Nir ^g   Franceschi, Claudio ^b,h   Owen, Art B ^a   Kim, Stuart K ^a  

^a STANFORD UNIVERSITY   (United States)

^b UNIVERSITY OF BOLOGNA   (Italy)

^c UNIVERSITY OF BOLOGNA   (Italy)

^d UNIVERSITY OF FLORENCE   (Italy)

^e UNIVERSITY OF MILAN   (Italy)

^f FONDAZIONE IRCCS CA GRANDA OSPEDALE MAGGIORE POLICLINICO   (Italy)

^g ALBERT EINSTEIN COLLEGE OF MEDICINE   (United States)

^h IRCCS   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

AGING; GENETIC PREDISPOSITION; GENETICS; GENOME-WIDE ASSOCIATION STUDY; HUMAN; LONGEVITY; PATHOLOGY; SINGLE NUCLEOTIDE POLYMORPHISM;

AGING; GENETIC PREDISPOSITION TO DISEASE; GENOME-WIDE ASSOCIATION STUDY; HUMANS; LONGEVITY; POLYMORPHISM, SINGLE NUCLEOTIDE;

EID: 84953289902     PISSN: 15537390     EISSN: 15537404     Source Type: Journal    
DOI: 10.1371/journal.pgen.1005728     Document Type: Article

References (82)

1. Hjelmborg J. V. B., et al. Genetic influence on human lifespan and longevity. Hum. Genet. 119,312–321 (2006). 16463022
2. Schoenmaker M, de Craen AJM, de Meijer PHEM, Beekman M, Blauw GJ, Slagboom PE, et al. Evidence of genetic enrichment for exceptional survival using a family approach: the Leiden Longevity Study. Eur J Hum Genet. 2005;14: 79–84. doi: 10.1038/sj.ejhg.5201508
3. Sebastiani P, Solovieff N, Dewan AT, Walsh KM, Puca A, Hartley SW, et al. Genetic signatures of exceptional longevity in humans. PloS One. 2012;7: e29848. doi: 10.1371/journal.pone.0029848 22279548
4. Tan Q, Zhao JH, Zhang D, Kruse TA, Christensen K, Power for genetic association study of human longevity using the case-control design. Am J Epidemiol. 2008;168: 890–896. doi: 10.1093/aje/kwn205 18756013
5. Schächter F, Faure-Delanef L, Guénot F, Rouger H, Froguel P, Lesueur-Ginot L, et al. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet. 1994;6: 29–32. doi: 10.1038/ng0194-29 8136829
6. Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, et al. FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci. 2008;105: 13987–13992. doi: 10.1073/pnas.0801030105 18765803
7. Christensen K, Johnson TE, Vaupel JW, The quest for genetic determinants of human longevity: challenges and insights. Nat Rev Genet. 2006;7: 436–448. doi: 10.1038/nrg1871 16708071
8. Budovsky A, Craig T, Wang J, Tacutu R, Csordas A, Lourenço J, et al. LongevityMap: a database of human genetic variants associated with longevity. Trends Genet. 2013;29: 559–560. doi: 10.1016/j.tig.2013.08.003 23998809
9. Davignon J, Gregg RE, Sing CF, Apolipoprotein E polymorphism and atherosclerosis. Arterioscler Dallas Tex. 1988;8: 1–21.
10. Murphy CT, The search for DAF-16/FOXO transcriptional targets: approaches and discoveries. Exp Gerontol. 2006;41: 910–921. doi: 10.1016/j.exger.2006.06.040 16934425
11. Deelen J, Beekman M, Uh H-W, Helmer Q, Kuningas M, Christiansen L, et al. Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited. Aging Cell. 2011;10: 686–698. doi: 10.1111/j.1474-9726.2011.00705.x 21418511
12. Nebel A, Kleindorp R, Caliebe A, Nothnagel M, Blanché H, Junge O, et al. A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals. Mech Ageing Dev. 2011;132: 324–330. doi: 10.1016/j.mad.2011.06.008 21740922
13. Deelen J, Beekman M, Uh H-W, Broer L, Ayers KL, Tan Q, et al. Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age. Hum Mol Genet. 2014; ddu139. doi: 10.1093/hmg/ddu139
14. Broer L, Buchman AS, Deelen J, Evans DS, Faul JD, Lunetta KL, et al. GWAS of Longevity in CHARGE Consortium Confirms APOE and FOXO3 Candidacy. J Gerontol A Biol Sci Med Sci. 2014; doi: 10.1093/gerona/glu166
15. US Census Bureau. https://www.census.gov/prod/cen2010/reports/c2010sr-03.pdf. 2010.
16. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE, Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007;39: 17–23. doi: 10.1038/ng1934 17192785
17. Fritsche LG, Chen W, Schu M, Yaspan BL, Yu Y, Thorleifsson G, et al. Seven new loci associated with age-related macular degeneration. Nat Genet. 2013;45: 433–439, 439e1–2. doi: 10.1038/ng.2578 23455636
18. Davies G, Harris SE, Reynolds CA, Payton A, Knight HM, Liewald DC, et al. A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Mol Psychiatry. 2014;19: 76–87. doi: 10.1038/mp.2012.159 23207651
19. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466: 707–713. doi: 10.1038/nature09270 20686565
20. Middelberg RPS, Ferreira MAR, Henders AK, Heath AC, Madden PAF, Montgomery GW, et al. Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits. BMC Med Genet. 2011;12: 123. doi: 10.1186/1471-2350-12-123 21943158
21. Postmus I, Deelen J, Sedaghat S, Trompet S, de Craen AJ, Heijmans BT, et al. LDL cholesterol still a problem in old age? A Mendelian randomization study. Int J Epidemiol. 2015; dyv031. doi: 10.1093/ije/dyv031
22. Freudenberg-Hua Y, Freudenberg J, Vacic V, Abhyankar A, Emde A-K, Ben-Avraham D, et al. Disease variants in genomes of 44 centenarians. Mol Genet Genomic Med. 2014;2: 438–450. doi: 10.1002/mgg3.86 25333069
23. Sebastiani P, Riva A, Montano M, Pham P, Torkamani A, Scherba E, et al. Whole genome sequences of a male and female supercentenarian, ages greater than 114 years. Front Genet. 2011;2: 90. doi: 10.3389/fgene.2011.00090 22303384
24. Beekman M, Nederstigt C, Suchiman HED, Kremer D, van der Breggen R, Lakenberg N, et al. Genome-wide association study (GWAS)-identified disease risk alleles do not compromise human longevity. Proc Natl Acad Sci. 2010;107: 18046–18049. doi: 10.1073/pnas.1003540107 20921414
25. Garagnani P, Giuliani C, Pirazzini C, Olivieri F, Bacalini MG, Ostan R, et al. Centenarians as super-controls to assess the biological relevance of genetic risk factors for common age-related diseases: a proof of principle on type 2 diabetes. Aging. 2013;5: 373–385. 23804578
26. DuGoff EH, Canudas-Romo V, Buttorff C, Leff B, Anderson GF, Multiple Chronic Conditions and Life Expectancy: A Life Table Analysis. Med Care. 2014;52: 688–694. doi: 10.1097/MLR.0000000000000166 25023914
27. Walter S, Mackenbach J, Vokó Z, Lhachimi S, Ikram MA, Uitterlinden AG, et al. Genetic, Physiological, and Lifestyle Predictors of Mortality in the General Population. Am J Public Health. 2012;102: e3–e10. doi: 10.2105/AJPH.2011.300596
28. Martin-Ruiz C, Jagger C, Kingston A, Collerton J, Catt M, Davies K, et al. Assessment of a large panel of candidate biomarkers of ageing in the Newcastle 85+ study. Mech Ageing Dev. 2011;132: 496–502. doi: 10.1016/j.mad.2011.08.001 21864562
29. Naj AC, Jun G, Beecham GW, Wang L-S, Vardarajan BN, Buros J, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet. 2011;43: 436–441. doi: 10.1038/ng.801 21460841
30. Genovese CR, Roeder K, Wasserman L, False discovery control with p-value weighting. Biometrika. 2006;93: 509–524. doi: 10.1093/biomet/93.3.509
31. Roeder K, Bacanu S-A, Wasserman L, Devlin B, Using Linkage Genome Scans to Improve Power of Association in Genome Scans. Am J Hum Genet. 2006;78: 243–252. doi: 10.1086/500026 16400608
32. Li L, Kabesch M, Bouzigon E, Demenais F, Farrall M, Moffatt MF, et al. Using eQTL weights to improve power for genome-wide association studies: a genetic study of childhood asthma. Front Genet. 2013;4: 103. doi: 10.3389/fgene.2013.00103 23755072
33. Roeder K, Wasserman L, Genome-Wide Significance Levels and Weighted Hypothesis Testing. Stat Sci Rev J Inst Math Stat. 2009;24: 398–413. doi: 10.1214/09-STS289
34. Andreassen OA, Thompson WK, Schork AJ, Ripke S, Mattingsdal M, Kelsoe JR, et al. Improved Detection of Common Variants Associated with Schizophrenia and Bipolar Disorder Using Pleiotropy-Informed Conditional False Discovery Rate. PLoS Genet. 2013;9: e1003455. doi: 10.1371/journal.pgen.1003455 23637625
35. Andreassen OA, Djurovic S, Thompson WK, Schork AJ, Kendler KS, O’Donovan MC, et al. Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors. Am J Hum Genet. 2013;92: 197–209. doi: 10.1016/j.ajhg.2013.01.001 23375658
36. Malovini A, Illario M, Iaccarino G, Villa F, Ferrario A, Roncarati R, et al. Association study on long-living individuals from Southern Italy identifies rs10491334 in the CAMKIV gene that regulates survival proteins. Rejuvenation Res. 2011;14: 283–291. doi: 10.1089/rej.2010.1114 21612516
37. Westra H-J, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet. 2013;45: 1238–1243. doi: 10.1038/ng.2756 24013639
38. Welter D, Macarthur J, Morales J, Burdett T, Hall P, Junkins H, et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 2014;42: D1001–1006. doi: 10.1093/nar/gkt1229 24316577
39. Sebastiani P, Bae H, Sun FX, Andersen SL, Daw EW, Malovini A, et al. Meta‐analysis of genetic variants associated with human exceptional longevity. Aging. 2013;5: 653–661. 24244950
40. Emanuele E, Fontana JM, Minoretti P, Geroldi D, Preliminary evidence of a genetic association between chromosome 9p21.3 and human longevity. Rejuvenation Res. 2010;13: 23–26. doi: 10.1089/rej.2009.0970 20230275
41. Pinós T, Fuku N, Cámara Y, Arai Y, Abe Y, Rodríguez-Romo G, et al. The rs1333049 polymorphism on locus 9p21.3 and extreme longevity in Spanish and Japanese cohorts. AGE. 2014;36: 933–943. doi: 10.1007/s11357-013-9593-0 24163049
42. Jeck WR, Siebold AP, Sharpless NE, Review: a meta-analysis of GWAS and age-associated diseases. Aging Cell. 2012;11: 727–731. doi: 10.1111/j.1474-9726.2012.00871.x 22888763
43. Pasmant E, Sabbagh A, Vidaud M, Bièche I, ANRIL, a long, noncoding RNA, is an unexpected major hotspot in GWAS. FASEB J. 2011;25: 444–448. doi: 10.1096/fj.10-172452 20956613
44. Samani NJ, Schunkert H, Chromosome 9p21 and Cardiovascular Disease The Story Unfolds. Circ Cardiovasc Genet. 2008;1: 81–84. doi: 10.1161/CIRCGENETICS.108.832527 20031549
45. Kim WY, Sharpless NE, The Regulation of INK4/ARF in Cancer and Aging. Cell. 2006;127: 265–275. doi: 10.1016/j.cell.2006.10.003 17055429
46. Congrains A, Kamide K, Oguro R, Yasuda O, Miyata K, Yamamoto E, et al. Genetic variants at the 9p21 locus contribute to atherosclerosis through modulation of ANRIL and CDKN2A/B. Atherosclerosis. 2012;220: 449–455. doi: 10.1016/j.atherosclerosis.2011.11.017 22178423
47. He M, Wolpin B, Rexrode K, Manson JE, Rimm E, Hu FB, et al. ABO Blood Group and Risk of Coronary Heart Disease in Two Prospective Cohort Studies. Arterioscler Thromb Vasc Biol. 2012;32: 2314–2320. doi: 10.1161/ATVBAHA.112.248757 22895671
48. Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, Fuchs CS, Petersen GM, Arslan AA, et al. Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009;41: 986–990. doi: 10.1038/ng.429 19648918
49. Chen Y, Chen C, Ke X, Xiong L, Shi Y, Li J, et al. Analysis of Circulating Cholesterol Levels as a Mediator of an Association Between ABO Blood Group and Coronary Heart Disease. Circ Cardiovasc Genet. 2014;7: 43–48. doi: 10.1161/CIRCGENETICS.113.000299 24395926
50. Slack C, Werz C, Wieser D, Alic N, Foley A, Stocker H, et al. Regulation of Lifespan, Metabolism, and Stress Responses by the Drosophila SH2B Protein, Lnk. PLoS Genet. 2010;6: e1000881. doi: 10.1371/journal.pgen.1000881 20333234
51. Ross OA, Rutherford NJ, Baker M, Soto-Ortolaza AI, Carrasquillo MM, DeJesus-Hernandez M, et al. Ataxin-2 repeat-length variation and neurodegeneration. Hum Mol Genet. 2011;20: 3207–3212. doi: 10.1093/hmg/ddr227 21610160
52. Stevenson M, Bae H, Schupf N, Andersen S, Zhang Q, Perls T, et al. Burden of disease variants in participants of the long life family study. Aging. 2015;7: 123–132. 25664523
53. Bergman A, Atzmon G, Ye K, MacCarthy T, Barzilai N, Buffering Mechanisms in Aging: A Systems Approach Toward Uncovering the Genetic Component of Aging. PLoS Comput Biol. 2007;3: e170. doi: 10.1371/journal.pcbi.0030170 17784782
54. Huffman DM, Deelen J, Ye K, Bergman A, Slagboom EP, Barzilai N, et al. Distinguishing between longevity and buffered-deleterious genotypes for exceptional human longevity: the case of the MTP gene. J Gerontol A Biol Sci Med Sci. 2012;67: 1153–1160. doi: 10.1093/gerona/gls103 22496539
55. Schechter CB, Barzilai N, Crandall JP, Atzmon G, Cholesteryl ester transfer protein (CETP) genotype and reduced CETP levels associated with decreased prevalence of hypertension. Mayo Clin Proc. 2010;85: 522–526. doi: 10.4065/mcp.2009.0594 20511482
56. Gierman HJ, Fortney K, Roach JC, Coles NS, Li H, Glusman G, et al. Whole-Genome Sequencing of the World’s Oldest People. PloS One. 2014;9: e112430. doi: 10.1371/journal.pone.0112430 25390934
57. Barzilai N. The Longevity Genes Project. http://www.einstein.yu.edu/centers/aging/longevity-genes-project/. 2014.
58. 1000 Genomes Project ConsortiumAbecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, et al. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491: 56–65. doi: 10.1038/nature11632 23128226
59. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81: 559–575. doi: 10.1086/519795 17701901
60. Kugler KG, Mueller LA, Graber A, MADAM—An open source meta-analysis toolbox for R and Bioconductor. Source Code Biol Med. 2010;5: 3. doi: 10.1186/1751-0473-5-3 20193058
61. Pallejà A, Horn H, Eliasson S, Jensen LJ, DistiLD Database: diseases and traits in linkage disequilibrium blocks. Nucleic Acids Res. 2012;40: D1036–D1040. doi: 10.1093/nar/gkr899 22058129
62. Willer CJ, Li Y, Abecasis GR, METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26: 2190–2191. doi: 10.1093/bioinformatics/btq340 20616382
63. Benjamini Y, Liu W, A step-down multiple hypotheses testing procedure that controls the false discovery rate under independence. J Stat Plan Inference. 1999;82: 163–170. doi: 10.1016/S0378-3758(99)00040-3
64. Johnson AD, Handsaker RE, Pulit SL, Nizzari MM, O’Donnell CJ, de Bakker PIW, SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics. 2008;24: 2938–2939. doi: 10.1093/bioinformatics/btn564 18974171
65. Gibbs RA, Belmont JW, Hardenbol P, Willis TD, Yu F, Yang H, et al. The International HapMap Project. Nature. 2003;426: 789–796. doi: 10.1038/nature02168 14685227
66. Gamazon ER, Zhang W, Konkashbaev A, Duan S, Kistner EO, Nicolae DL, et al. SCAN: SNP and copy number annotation. Bioinforma Oxf Engl. 2010;26: 259–262. doi: 10.1093/bioinformatics/btp644
67. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinforma Oxf Engl. 2010;26: 2336–2337. doi: 10.1093/bioinformatics/btq419
68. Morris AP, Voight BF, Teslovich TM, Ferreira T, Segrè AV, Steinthorsdottir V, et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet. 2012;44: 981–990. doi: 10.1038/ng.2383 22885922
69. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010;42: 508–514. doi: 10.1038/ng.582 20453842
70. Köttgen A, Pattaro C, Böger CA, Fuchsberger C, Olden M, Glazer NL, et al. New loci associated with kidney function and chronic kidney disease. Nat Genet. 2010;42: 376–384. doi: 10.1038/ng.568 20383146
71. Schunkert H, König IR, Kathiresan S, Reilly MP, Assimes TL, Holm H, et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet. 2011;43: 333–338. doi: 10.1038/ng.784 21378990
72. Li D, Duell EJ, Yu K, Risch HA, Olson SH, Kooperberg C, et al. Pathway analysis of genome-wide association study data highlights pancreatic development genes as susceptibility factors for pancreatic cancer. Carcinogenesis. 2012;33: 1384–1390. doi: 10.1093/carcin/bgs151 22523087
73. Timofeeva MN, Hung RJ, Rafnar T, Christiani DC, Field JK, Bickeböller H, et al. Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls. Hum Mol Genet. 2012;21: 4980–4995. doi: 10.1093/hmg/dds334 22899653
74. Estrada K, Styrkarsdottir U, Evangelou E, Hsu Y-H, Duncan EL, Ntzani EE, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012;44: 491–501. doi: 10.1038/ng.2249 22504420
75. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet. 2010;42: 937–948. doi: 10.1038/ng.686 20935630
76. International Consortium for Blood Pressure Genome-Wide Association StudiesEhret GB, Munroe PB, Rice KM, Bochud M, Johnson AD, et al. Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk. Nature. 2011;478: 103–109. doi: 10.1038/nature10405 21909115
77. Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet. 2010;42: 105–116. doi: 10.1038/ng.520 20081858
78. Dastani Z, Hivert M-F, Timpson N, Perry JRB, Yuan X, Scott RA, et al. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. PLoS Genet. 2012;8: e1002607. doi: 10.1371/journal.pgen.1002607 22479202
79. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) ConsortiumGenome-wide association study identifies five new schizophrenia loci. Nat Genet. 2011;43: 969–976. doi: 10.1038/ng.940 21926974
80. Major Depressive Disorder Working Group of the Psychiatric GWAS ConsortiumRipke S, Wray NR, Lewis CM, Hamilton SP, Weissman MM, et al. A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry. 2013;18: 497–511. doi: 10.1038/mp.2012.21 22472876
81. Neale BM, Medland SE, Ripke S, Asherson P, Franke B, Lesch K-P, et al. Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2010;49: 884–897. doi: 10.1016/j.jaac.2010.06.008 20732625
82. Dobriban E., Fortney K., Kim S., Owen A., Optimal Multiple Testing Under a Gaussian Prior on the Effect Sizes. Biometrika. 2015; in press.