Is Cellular Heterogeneity Merely a Confounder to be Removed from Epigenome-Wide Association Studies?

References

• Perfilyev A , DahlmanI , GillbergLet al. Impact of polyunsaturated and saturated fat overfeeding on the DNA-methylation pattern in human adipose tissue: a randomized controlled trial . Am. J. Clin. Nutr.105 ( 4 ), 991 – 1000 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Ligthart S , MarziC , AslibekyanSet al. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases . Genome Biol.17 ( 1 ), 255 ( 2016 ).
   PubMedGoogle Scholar
• Rask-Andersen M , MartinssonD , AhsanMet al. Epigenome-wide association study reveals differential DNA methylation in individuals with a history of myocardial infarction . Hum. Mol. Genet.25 ( 21 ), 4739 – 4748 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Lin X , LimIY , WuYet al. Developmental pathways to adiposity begin before birth and are influenced by genotype, prenatal environment and epigenome . BMC Med.15 ( 1 ), 50 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Mendelson MM , MarioniRE , JoehanesRet al. Association of body mass index with DNA methylation and gene expression in blood cells and relations to cardiometabolic disease: a mendelian randomization approach . PLoS Med.14 ( 1 ), e1002215 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Delgado-Morales R , EstellerM . Opening up the DNA methylome of dementia . Mol. Psychiatry22 ( 4 ), 485 – 496 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Teh AL , PanH , ChenLet al. The effect of genotype and in utero environment on interindividual variation in neonate DNA methylomes . Genome Res.24 ( 7 ), 1064 – 1074 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Van Dongen J , NivardMG , WillemsenGet al. Genetic and environmental influences interact with age and sex in shaping the human methylome . Nat. Commun.7 , 11115 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Holbrook JD . An epigenetic escape route . Trends Genetics31 ( 1 ), 2 – 4 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Holbrook JD . Catching diabetes . Epigenomics8 ( 9 ), 1173 – 1177 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Weaver IC , CervoniN , ChampagneFAet al. Epigenetic programming by maternal behavior . Nat. Neurosci.7 ( 8 ), 847 – 854 ( 2004 ).
   PubMed Web of Science ®Google Scholar
• Mcgowan PO , SasakiA , D’alessioACet al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse . Nat. Neurosci.12 ( 3 ), 342 – 348 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Turecki G , MeaneyMJ . Effects of the social environment and stress on glucocorticoid receptor gene methylation: a systematic review . Biol. Psychiatry79 ( 2 ), 87 – 96 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Godfrey KM , SheppardA , GluckmanPDet al. Epigenetic gene promoter methylation at birth is associated with child’s later adiposity . Diabetes60 ( 5 ), 1528 – 1534 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Fasanelli F , BagliettoL , PonziEet al. Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts . Nat. Commun.6 , 10192 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Baglietto L , PonziE , HaycockPet al. DNA methylation changes measured in pre-diagnostic peripheral blood samples are associated with smoking and lung cancer risk . Int. J. Cancer140 ( 1 ), 50 – 61 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Liu Y , AryeeMJ , PadyukovLet al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis . Nat. Biotechnol.31 ( 2 ), 142 – 147 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Kato N , LohM , TakeuchiFet al. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation . Nat. Genetics47 ( 11 ), 1282 – 1293 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Horvath S , GurvenM , LevineMEet al. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease . Genome Biol.17 ( 1 ), 171 ( 2016 ).
   PubMedGoogle Scholar
• Lin X , BartonS , HolbrookJD . How to make DNA methylome wide association studies more powerful . Epigenomics8 ( 8 ), 1117 – 1129 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Wu D , MolofskyAB , LiangHEet al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis . Science332 ( 6026 ), 243 – 247 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Duncan BB , SchmidtMI , PankowJSet al. Low-grade systemic inflammation and the development of Type 2 diabetes: the atherosclerosis risk in communities study . Diabetes52 ( 7 ), 1799 – 1805 ( 2003 ).
   PubMed Web of Science ®Google Scholar
• Gregor MF , HotamisligilGS . Inflammatory mechanisms in obesity . Annu. Rev. Immunol.29 , 415 – 445 ( 2011 ).
   PubMed Web of Science ®Google Scholar
• Talukdar S , OhDY , BandyopadhyayGet al. Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase . Nat. Med.18 ( 9 ), 1407 – 1412 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Babio N , Ibarrola-JuradoN , BulloMet al. White blood cell counts as risk markers of developing metabolic syndrome and its components in the PREDIMED study . PLoS ONE8 ( 3 ), e58354 ( 2013 ).
   PubMed Web of Science ®Google Scholar
• Dick KJ , NelsonCP , TsaprouniLet al. DNA methylation and body-mass index: a genome-wide analysis . Lancet383 ( 9933 ), 1990 – 1998 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Richmond RC , SharpGC , WardMEet al. DNA methylation and body mass index: investigating identified methylation sites at HIF3A in a causal framework . Diabetes65 ( 5 ), 1231 – 1244 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Holbrook JD . Does diet interact with genotype to cause epigenetic modification of angiogenesis genes, on the trajectory to obesity?Epigenomics8 ( 6 ), 741 – 745 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Su D , WangX , CampbellMRet al. Distinct epigenetic effects of tobacco smoking in whole blood and among leukocyte subtypes . PLoS ONE11 ( 12 ), e0166486 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Jaffe AE , IrizarryRA . Accounting for cellular heterogeneity is critical in epigenome-wide association studies . Genome Biol.15 ( 2 ), R31 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Gluckman PD , HansonMA , BuklijasT , LowFM , BeedleAS . Epigenetic mechanisms that underpin metabolic and cardiovascular diseases . Nat. Rev. Endocrinol.5 ( 7 ), 401 – 408 ( 2009 ).
   PubMed Web of Science ®Google Scholar
• Reinius LE , AcevedoN , JoerinkMet al. Differential DNA methylation in purified human blood cells: implications for cell lineage and studies on disease susceptibility . PLoS ONE7 ( 7 ), e41361 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Kulis M , MerkelA , HeathSet al. Whole-genome fingerprint of the DNA methylome during human B cell differentiation . Nat. Genetics47 ( 7 ), 746 – 756 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Martino D , JooJE , Sexton-OatesAet al. Epigenome-wide association study reveals longitudinally stable DNA methylation differences in CD4+ T cells from children with IgE-mediated food allergy . Epigenetics9 ( 7 ), 998 – 1006 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Heyn H , LiN , FerreiraHJet al. Distinct DNA methylomes of newborns and centenarians . Proc. Natl Acad. Sci. USA109 ( 26 ), 10522 – 10527 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Carmona JJ , SoferT , HutchinsonJet al. Short-term airborne particulate matter exposure alters the epigenetic landscape of human genes associated with the mitogen-activated protein kinase network: a cross-sectional study . Environ. Health13 , 94 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Zhu ZZ , HouL , BollatiVet al. Predictors of global methylation levels in blood DNA of healthy subjects: a combined analysis . Int. J. Epidemiol.41 ( 1 ), 126 – 139 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Houseman EA , AccomandoWP , KoestlerDCet al. DNA methylation arrays as surrogate measures of cell mixture distribution . BMC Bioinformatics13 , 86 ( 2012 ).
   PubMed Web of Science ®Google Scholar
• Chambers JC , LohM , LehneBet al. Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident Type 2 diabetes: a nested case-control study . Lancet Diabetes Endocrinol.3 ( 7 ), 526 – 534 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Teschendorff AE , BreezeCE , ZhengSC , BeckS . A comparison of reference-based algorithms for correcting cell-type heterogeneity in Epigenome-Wide Association Studies . BMC Bioinformatics18 ( 1 ), 105 ( 2017 ).
   PubMedGoogle Scholar
• Breeze CE , PaulDS , Van DongenJet al. eFORGE: a tool for identifying cell type-specific signal in epigenomic data . Cell Rep.17 ( 8 ), 2137 – 2150 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Houseman EA , MolitorJ , MarsitCJ . Reference-free cell mixture adjustments in analysis of DNA methylation data . Bioinformatics30 ( 10 ), 1431 – 1439 ( 2014 ).
   PubMed Web of Science ®Google Scholar
• Rahmani E , ZaitlenN , BaranYet al. Sparse PCA corrects for cell type heterogeneity in epigenome-wide association studies . Nat. Methods13 ( 5 ), 443 – 445 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Van Iterson M , Van ZwetEW , ConsortiumB , HeijmansBT . Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution . Genome Biol.18 ( 1 ), 19 ( 2017 ).
   PubMedGoogle Scholar
• Rahmani E , ZaitlenN , BaranYet al. Correcting for cell-type heterogeneity in DNA methylation: a comprehensive evaluation . Nat. Methods14 ( 3 ), 218 – 219 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Zheng SC , BeckS , JaffeAEet al. Correcting for cell-type heterogeneity in epigenome-wide association studies: revisiting previous analyses . Nat. Methods14 ( 3 ), 216 – 217 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Wagner A , RegevA , YosefN . Revealing the vectors of cellular identity with single-cell genomics . Nat. Biotechnol.34 ( 11 ), 1145 – 1160 ( 2016 ).
   PubMed Web of Science ®Google Scholar
• Farlik M , SheffieldNC , NuzzoAet al. Single-cell DNA methylome sequencing and bioinformatic inference of epigenomic cell-state dynamics . Cell Rep.10 ( 8 ), 1386 – 1397 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Quach A , LevineME , TanakaTet al. Epigenetic clock analysis of diet, exercise, education, and lifestyle factors . Aging (Albany NY)9 ( 2 ), 419 – 446 ( 2017 ).
   PubMedGoogle Scholar
• Lillycrop KA , CostelloPM , TehALet al. Association between perinatal methylation of the neuronal differentiation regulator HES1 and later childhood neurocognitive function and behaviour . Int. J. Epidemiol.44 ( 4 ), 1263 – 1276 ( 2015 ).
   PubMed Web of Science ®Google Scholar
• Lillycrop K , MurrayR , CheongCYet al. ANRIL promoter DNA methylation: a perinatal marker for later adiposity . eBioMedicine19 , 60 – 72 ( 2017 ).
   PubMed Web of Science ®Google Scholar
• Thakore PI , BlackJB , HiltonIB , GersbachCA . Editing the epigenome: technologies for programmable transcription and epigenetic modulation . Nat. Methods13 ( 2 ), 127 – 137 ( 2016 ).
   PubMed Web of Science ®Google Scholar