Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population

English version České info

Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype–phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.

Vyšlo v časopise: Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population. PLoS Genet 8(4): e32767. doi:10.1371/journal.pgen.1002629
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002629

Souhrn

Zdroje

1. BellJTPaiAAPickrellJKGaffneyDJPique-RegiR 2011 DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. Genome Biol 12 R10

2. GervinKHammeroMAkselsenHEMoeRNygardH 2011 Extensive variation and low heritability of DNA methylation identified in a twin study. Genome Res 21 1813 21

3. GibbsJRvan der BrugMPHernandezDGTraynorBJNallsMA 2010 Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet 6 e1000952 doi:10.1371/journal.pgen.1000952

4. KaminskyZATangTWangSCPtakCOhGH 2009 DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41 240 245

5. SchalkwykLCMeaburnELSmithRDempsterELJeffriesAR 2010 Allelic skewing of DNA methylation is widespread across the genome. Am J Hum Genet 86 196 212

6. BreitlingLPYangRKornBBurwinkelBBrennerH 2011 Tobacco-smoking-related differential DNA methylation: 27K discovery and replication. Am J Hum Genet 88 450 457

7. Kaminen-AholaNAholaAMagaMMallittKAFaheyP 2010 Maternal ethanol consumption alters the epigenotype and the phenotype of offspring in a mouse model. PLoS Genet 6 e1000811 doi:10.1371/journal.pgen.1000811

8. WolffGLKodellRLMooreSRCooneyCA 1998 Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. FASEB J 12 949 957

9. TalensRPBoomsmaDITobiEWKremerDJukemaJW 2010 Variation, patterns, and temporal stability of DNA methylation: considerations for epigenetic epidemiology. FASEB J 24 3135 3144

10. WongCCCaspiAWilliamsBCraigIWHoutsR 2010 A longitudinal study of epigenetic variation in twins. Epigenetics 5 516 26

11. BocklandtSLinWSehlMESanchezFJSinsheimerJS 2011 Epigenetic predictor of age. PLoS ONE 6 e14821 doi:10.1371/journal.pone.0014821

12. FragaMFBallestarEPazMFRoperoSSetienF 2005 Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102 10604 10609

13. HernandezDGNallsMAGibbsJRArepalliSvan der BrugM 2011 Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum Mol Genet 20 1164 1172

14. RakyanVKDownTAMaslauSAndrewTYangTP 2010 Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains. Genome Res 20 434 439

15. TeschendorffAEMenonUGentry-MaharajARamusSJWeisenbergerDJ 2010 Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res 20 440 446

16. VijgJCampisiJ 2008 Puzzles, promises and a cure for ageing. Nature 454 1065 1071

17. BakerGT3rdSprottRL 1988 Biomarkers of aging. Exp Gerontol 23 223 239

18. JohnsonTE 2006 Recent results: biomarkers of aging. Exp Gerontol 41 1243 1246

19. SimmANassNBartlingBHofmannBSilberRE 2008 Potential biomarkers of ageing. Biol Chem 389 257 265

20. ZhangDChengLBadnerJAChenCChenQ 2010 Genetic control of individual differences in gene-specific methylation in human brain. Am J Hum Genet 86 411 419

21. NicaACPartsLGlassDNisbetJBarrettA 2011 The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet 7 e1002003 doi:10.1371/journal.pgen.1002003

22. GrimaldiMPCandoreGVastoSCarusoMCaimiG 2006 Role of the pyrin M694V (A2080G) allele in acute myocardial infarction and longevity: a study in the Sicilian population. J Leukoc Biol 79 611 615

23. Nikolova-KarakashianMKarakashianARutkuteK 2008 Role of neutral sphingomyelinases in aging and inflammation. Subcell Biochem 49 469 486

24. WhitelawCMRobinsonJEChambersGBHastiePPadmanabhanV 2009 Expression of mRNA for galanin, galanin-like peptide and galanin receptors 1–3 in the ovine hypothalamus and pituitary gland: effects of age and gender. Reproduction 137 141 150

25. PlanasBKolbPERaskindMAMillerMA 1998 Galanin receptors in the hippocampus and entorhinal cortex of aged Fischer 344 male rats. Neurobiol Aging 19 427 435

26. ShenSLiuALiJWolubahCCasaccia-BonnefilP 2008 Epigenetic memory loss in aging oligodendrocytes in the corpus callosum. Neurobiol Aging 29 452 463

27. DempsterELPidsleyRSchalkwykLCOwensSGeorgiadesA 2011 Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol Genet 20 4786 96

28. ChristensenBCHousemanEAMarsitCJZhengSWrenschMR 2009 Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5 e1000602 doi:10.1371/journal.pgen.1000602

29. ZambelliFPesoleGPavesiG 2009 Pscan: finding over-represented transcription factor binding site motifs in sequences from co-regulated or co-expressed genes. Nucleic Acids Res 37 W247 252

30. Portales-CasamarEThongjueaSKwonATArenillasDZhaoX 2010 JASPAR 2010: the greatly expanded open-access database of transcription factor binding profiles. Nucleic Acids Res 38 D105 110

31. EdenENavonRSteinfeldILipsonDYakhiniZ 2009 GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics 10 48

32. De-FrajaCContiLGovoniSBattainiFCattaneoE 2000 STAT signalling in the mature and aging brain. Int J Dev Neurosci 18 439 446

33. VicentSChenRSaylesLCLinCWalkerRG 2010 Wilms tumor 1 (WT1) regulates KRAS-driven oncogenesis and senescence in mouse and human models. J Clin Invest 120 3940 3952

34. FragaMFEstellerM 2007 Epigenetics and aging: the targets and the marks. Trends Genet 23 413 418

35. PriceALHelgasonAThorleifssonGMcCarrollSAKongA 2011 Single-tissue and cross-tissue heritability of gene expression via identity-by-descent in related or unrelated individuals. PLoS Genet 7 e1001317 doi:10.1371/journal.pgen.1001317

36. ShoemakerRDengJWangWZhangK 2010 Allele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome. Genome Res 20 883 889

37. SpectorTDWilliamsFM 2006 The UK Adult Twin Registry (TwinsUK). Twin Res Hum Genet 9 899 906

38. AndrewTHartDJSniederHde LangeMSpectorTD 2001 Are twins and singletons comparable? A study of disease-related and lifestyle characteristics in adult women. Twin Res 4 464 477

39. ManginoMRichardsJBSoranzoNZhaiGAvivA 2009 A genome-wide association study identifies a novel locus on chromosome 18q12.2 influencing white cell telomere length. J Med Genet 46 451 454

40. ValdesAMAndrewTGardnerJPKimuraMOelsnerE 2005 Obesity, cigarette smoking, and telomere length in women. Lancet 366 662 664

41. PoulterNRChangCLMacGregorAJSniederHSpectorTD 1999 Association between birth weight and adult blood pressure in twins: historical cohort study. BMJ 319 1330 1333

42. ZhaiGValdesAMCherkasLClementGStrachanD 2007 The interaction of genes and smoking on forced expiratory volume: a classic twin study. Chest 132 1772 1777

43. ArdenNKSpectorTD 1997 Genetic influences on muscle strength, lean body mass, and bone mineral density: a twin study. J Bone Miner Res 12 2076 2081

44. SpectorTDKeenRWArdenNKMorrisonNAMajorPJ 1995 Influence of vitamin D receptor genotype on bone mineral density in postmenopausal women: a twin study in Britain. BMJ 310 1357 1360

45. RichardsJBRivadeneiraFInouyeMPastinenTMSoranzoN 2008 Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371 1505 1512

46. ZhaiGTeumerAStolkLPerryJRVandenputL 2011 Eight common genetic variants associated with serum DHEAS levels suggest a key role in ageing mechanisms. PLoS Genet 7 e1002025 doi:10.1371/journal.pgen.1002025

47. JamshidiYGooljarSBSniederHWangXGeD 2007 SHP-2 and PI3-kinase genes PTPN11 and PIK3R1 may influence serum apoB and LDL cholesterol levels in normal women. Atherosclerosis 194 e26 33

48. GoyenecheaECollinsLJParraDLiuGSniederH 2008 CD36 gene promoter polymorphisms are associated with low density lipoprotein-cholesterol in normal twins and after a low-calorie diet in obese subjects. Twin Res Hum Genet 11 621 628

49. WainLVVerwoertGCO'ReillyPFShiGJohnsonT 2011 Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet 43 1005 1011

50. SwaminathanRMajorPSniederHSpectorT 2000 Serum creatinine and fat-free mass (lean body mass). Clin Chem 46 1695 1696

51. NallsMACouperDJTanakaTvan RooijFJChenMH 2011 Multiple loci are associated with white blood cell phenotypes. PLoS Genet 7 e1002113 doi:10.1371/journal.pgen.1002113

52. SmallKSHedmanAKGrundbergENicaACThorleifssonG 2011 Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes. Nat Genet 43 561 564

53. HowieBNDonnellyPMarchiniJ 2009 A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5 e1000529 doi:10.1371/journal.pgen.1000529

54. Gardiner-GardenMFrommerM 1987 CpG islands in vertebrate genomes. J Mol Biol 196 261 282