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Current Behavioral Neuroscience Reports

, Volume 3, Issue 3, pp 264–274 | Cite as

Epigenetic Research in Neuropsychiatric Disorders: the “Tissue Issue”

  • Kelly M. Bakulski
  • Alycia Halladay
  • Valerie W. Hu
  • Jonathan Mill
  • M. Daniele FallinEmail author
Genetics and Neuroscience (B Maher, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genetics and Neuroscience

Abstract

Purpose of Review

Evidence has linked neuropsychiatric disorders with epigenetic marks as either a biomarker of disease, biomarker of exposure, or mechanism of disease processes. Neuropsychiatric epidemiologic studies using either target brain tissue or surrogate blood tissue each have methodological challenges and distinct advantages.

Recent findings

Brain tissue studies are challenged by small sample sizes of cases and controls, incomplete phenotyping, post-mortem timing, and cellular heterogeneity, but the use of a primary disease relevant tissue is critical. Blood-based studies have access to much larger sample sizes and more replication opportunities, as well as the potential for longitudinal measurements, both prior to onset and during the course of treatments. Yet, blood studies also are challenged by cell-type heterogeneity, and many question the validity of using peripheral tissues as a brain biomarker. Emerging evidence suggests that these limitations to blood-based epigenetic studies are surmountable, but confirmation in target tissue remains important.

Summary

Epigenetic mechanisms have the potential to help elucidate biology connecting experiential risk factors with neuropsychiatric disease manifestation. Cross-tissue studies as well as advanced epidemiologic methods should be employed to more effectively conduct neuropsychiatric epigenetic research.

Keywords

Neuropsychiatric disorders DNA methylation Epigenetics Tissue Blood 

Notes

Compliance with Ethical Standards

Conflict of Interest

Dr. Kelly M. Bakulski, Dr. Alycia Halladay, Dr. Valerie W. Hu, Dr. Jonathan Mill, and Dr. M. Daniele Fallin declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Funding Sources

Drs. Bakulski and Fallin were supported by the National Institute of Environmental Health Sciences (ES017646). Dr. Hu was supported by the National Institute of Environmental Health Sciences (ES023061). Dr. Mill was supported by the UK Medical Research Council (MRC; MR/K013807/1) and the US National Institutes of Health (AG036039).

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Goldberg AD, Allis CD, Bernstein E. Epigenetics: a landscape takes shape. Cell. 2007;128(4):635–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33:245–54.PubMedCrossRefGoogle Scholar
  3. 3.
    Feinberg AP. Phenotypic plasticity and the epigenetics of human disease. Nature. 2007;447(7143):433–40.PubMedCrossRefGoogle Scholar
  4. 4.
    Anderson OS, Sant KE, Dolinoy DC. Nutrition and epigenetics: an interplay of dietary methyl donors, one-carbon metabolism and DNA methylation. J Nutr Biochem. 2012;23(8):853–9.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Bjornsson HT, Fallin MD, Feinberg AP. An integrated epigenetic and genetic approach to common human disease. Trends Gen. 2004;20(8):350–8.CrossRefGoogle Scholar
  6. 6.
    Ladd-Acosta C. Epigenetic signatures as biomarkers of exposure. Curr Environ Health Rep. 2015;2(2):117–25.PubMedCrossRefGoogle Scholar
  7. 7.
    Tobi EW, Goeman JJ, Monajemi R, Gu H, Putter H, Zhang Y, et al. DNA methylation signatures link prenatal famine exposure to growth and metabolism. Nat Commun. 2014;5:5592.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Rodenhiser D, Mann M. Epigenetics and human disease: translating basic biology into clinical applications. Can Med Assoc J. 2006;174(3):341–8.CrossRefGoogle Scholar
  9. 9.
    Hsieh J, Eisch AJ. Epigenetics, hippocampal neurogenesis, and neuropsychiatric disorders: Unraveling the genome to understand the mind. Neurobiol Dis. 2010;39(1):73–84.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Sweatt JD. The emerging field of neuroepigenetics. Neuron. 2013;80(3):624–32.PubMedCrossRefGoogle Scholar
  11. 11.
    Loke YJ, Hannan AJ, Craig JM. The Role of Epigenetic Change in Autism Spectrum Disorders. Front Neurol. 2015;6:107.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Abdolmaleky HM, Zhou JR, Thiagalingam S. An update on the epigenetics of psychotic diseases and autism. Epigenomics. 2015;7(3):427–49.PubMedCrossRefGoogle Scholar
  13. 13.
    Ibi D, Gonzalez-Maeso J. Epigenetic signaling in schizophrenia. Cell Signal. 2015;27(10):2131–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Shorter KR, Miller BH. Epigenetic mechanisms in schizophrenia. Prog Biophys Mol Biol. 2015;118(1-2):1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Vinkers CH, Kalafateli AL, Rutten BP, Kas MJ, Kaminsky Z, Turner JD, et al. Traumatic stress and human DNA methylation: a critical review. Epigenomics. 2015;7(4):593–608.PubMedCrossRefGoogle Scholar
  16. 16.
    Cadet JL, McCoy MT, Jayanthi S. Epigenetics and Addiction. Clin Pharmacol Ther. 2016;99(5):502–511.Google Scholar
  17. 17.•
    Davies MN, Volta M, Pidsley R, Lunnon K, Dixit A, Lovestone S, et al. Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood. Genome Biol. 2012;13(6):R43. Blood and brain DNA methylation comparison, including mQTLs.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Mohammad-Rezazadeh I, Frohlich J, Loo SK, Jeste SS. Brain connectivity in autism spectrum disorder. Curr Opin Neurol. 2016;29(2):137–47.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Angermueller C, Clark SJ, Lee HJ, Macaulay IC, Teng MJ, Hu TX, et al. Parallel single-cell sequencing links transcriptional and epigenetic heterogeneity. Nat Methods. 2016;13(3):229–32.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Krishnaswami SR, Grindberg RV, Novotny M, Venepally P, Lacar B, Bhutani K, et al. Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. Nat Protoc. 2016;11(3):499–524.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Guintivano J, Aryee MJ, Kaminsky ZA. A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression. Epigenetics. 2013;8(3):290–302.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Montano CM, Irizarry RA, Kaufmann WE, Talbot K, Gur RE, Feinberg AP, et al. Measuring cell-type specific differential methylation in human brain tissue. Genome Biol. 2013;14(8):R94.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Tasic B, Menon V, Nguyen TN, Kim TK, Jarsky T, Yao Z, et al. Adult mouse cortical cell taxonomy revealed by single cell transcriptomics. Nat Neurosci. 2016;19(2):335–46.PubMedCrossRefGoogle Scholar
  24. 24.
    Darmanis S, Sloan SA, Zhang Y, Enge M, Caneda C, Shuer LM, et al. A survey of human brain transcriptome diversity at the single cell level. Proc Natl Acad Sci U S A. 2015;112(23):7285–90.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Lodato MA, Woodworth MB, Lee S, Evrony GD, Mehta BK, Karger A, et al. Somatic mutation in single human neurons tracks developmental and transcriptional history. Science. 2015;350(6256):94–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Fuzik J, Zeisel A, Mate Z, Calvigioni D, Yanagawa Y, Szabo G, et al. Integration of electrophysiological recordings with single-cell RNA-seq data identifies neuronal subtypes. Nat Biotechnol. 2016;34(2):175–83.PubMedCrossRefGoogle Scholar
  27. 27.
    Halder R, Hennion M, Vidal RO, Shomroni O, Rahman RU, Rajput A, et al. DNA methylation changes in plasticity genes accompany the formation and maintenance of memory. Nat Neurosci. 2016;19(1):102–10.PubMedGoogle Scholar
  28. 28.
    Heyward FD, Gilliam D, Coleman MA, Gavin CF, Wang J, Kaas G, et al. Obesity Weighs down Memory through a Mechanism Involving the Neuroepigenetic Dysregulation of Sirt1. J Neurosci. 2016;36(4):1324–35.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Barton AJ, Pearson RC, Najlerahim A, Harrison PJ. Pre- and postmortem influences on brain RNA. J Neurochem. 1993;61(1):1–11.PubMedCrossRefGoogle Scholar
  30. 30.
    Harrison PJ, Heath PR, Eastwood SL, Burnet PW, McDonald B, Pearson RC. The relative importance of premortem acidosis and postmortem interval for human brain gene expression studies: selective mRNA vulnerability and comparison with their encoded proteins. Neurosci Lett. 1995;200(3):151–4.PubMedCrossRefGoogle Scholar
  31. 31.
    Li JZ, Vawter MP, Walsh DM, Tomita H, Evans SJ, Choudary PV, et al. Systematic changes in gene expression in postmortem human brains associated with tissue pH and terminal medical conditions. Hum Mol Genet. 2004;13(6):609–16.PubMedCrossRefGoogle Scholar
  32. 32.
    Tomita H, Vawter MP, Walsh DM, Evans SJ, Choudary PV, Li J, et al. Effect of agonal and postmortem factors on gene expression profile: quality control in microarray analyses of postmortem human brain. Biol Psychiatry. 2004;55(4):346–52.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Ernst C, McGowan PO, Deleva V, Meaney MJ, Szyf M, Turecki G. The effects of pH on DNA methylation state: In vitro and post-mortem brain studies. J Neurosci Methods. 2008;174(1):123–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Pidsley R, Mill J. Epigenetic studies of psychosis: current findings, methodological approaches, and implications for postmortem research. Biol Psychiatry. 2011;69(2):146–56.PubMedCrossRefGoogle Scholar
  35. 35.
    Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Hansen KD, Sabunciyan S, Langmead B, Nagy N, Curley R, Klein G, et al. Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization. Genome Res. 2014;24(2):177–84.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Sarachana T, Xu M, Wu RC, Hu VW. Sex hormones in autism: androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism. PLoS One. 2011;6(2):e17116.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Nguyen A, Rauch TA, Pfeifer GP, Hu VW. Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain. FASEB J. 2010;24(8):3036–51.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Lowe R, Gemma C, Beyan H, Hawa MI, Bazeos A, Leslie RD, et al. Buccals are likely to be a more informative surrogate tissue than blood for epigenome-wide association studies. Epigenetics. 2013;8(4):445–54.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Prilutsky D, Palmer NP, Smedemark-Margulies N, Schlaeger TM, Margulies DM, Kohane IS. iPSC-derived neurons as a higher-throughput readout for autism: promises and pitfalls. Trends Mol Med. 2014;20(2):91–104.PubMedCrossRefGoogle Scholar
  41. 41.
    Kim K, Zhao R, Doi A, Ng K, Unternaehrer J, Cahan P, et al. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat Biotechnol. 2011;29(12):1117–9.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. 2011;471(7336):68–73.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Cahan P, Daley GQ. Origins and implications of pluripotent stem cell variability and heterogeneity. Nat Rev Mol Cell Biol. 2013;14(6):357–68.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Newschaffer CJ, Croen LA, Fallin MD, Hertz-Picciotto I, Nguyen DV, Lee NL, et al. Infant siblings and the investigation of autism risk factors. J Neurodev Disord. 2012;4(1):7.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Roadmap Epigenomics C, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518(7539):317–30.CrossRefGoogle Scholar
  46. 46.
    Bernstein BE, Stamatoyannopoulos JA, Costello JF, Ren B, Milosavljevic A, Meissner A, et al. The NIH Roadmap Epigenomics Mapping Consortium. Nat Biotechnol. 2010;28(10):1045–8.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.••
    Hannon E, Lunnon K, Schalkwyk L, Mill J. Interindividual methylomic variation across blood, cortex, and cerebellum: implications for epigenetic studies of neurological and neuropsychiatric phenotypes. Epigenetics. 2015;10(11):1024–32. Cross-tissue blood and brain DNA methylation comparisons.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Farre P, Jones MJ, Meaney MJ, Emberly E, Turecki G, Kobor MS. Concordant and discordant DNA methylation signatures of aging in human blood and brain. Epigenetics Chromatin. 2015;8:19.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Wen L, Li X, Yan L, Tan Y, Li R, Zhao Y, et al. Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain. Genome Biol. 2014;15(3):R49.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.•
    Houseman EA, Accomando WP, Koestler DC, Christensen BC, Marsit CJ, Nelson HH, et al. DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics. 2012;13:86. Estimate cell proportions from a mixed cell DNA methylation measure.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Jaffe AE, Irizarry RA. Accounting for cellular heterogeneity is critical in epigenome-wide association studies. Genome Biol. 2014;15(2):R31.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Bakulski KM, Feinberg JI, Andrews SV, Yang J, Brown S, McKenney S, et al. DNA methylation of cord blood cell types: applications for mixed cell birth studies. Epigenetics. 2016;11(5):354–362.Google Scholar
  53. 53.
    Liu Y, Aryee MJ, Padyukov L, Fallin MD, Hesselberg E, Runarsson A, et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat Biotechnol. 2013;31(2):142–7.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Estes ML, McAllister AK. Immune mediators in the brain and peripheral tissues in autism spectrum disorder. Nat Rev Neurosci. 2015;16(8):469–86.PubMedCrossRefGoogle Scholar
  55. 55.
    Muller N, Weidinger E, Leitner B, Schwarz MJ. The role of inflammation in schizophrenia. Front Neurosci. 2015;9:372.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Rosenblat JD, McIntyre RS. Bipolar Disorder and Inflammation. Psychiatr Clin North Am. 2016;39(1):125–37.PubMedCrossRefGoogle Scholar
  57. 57.
    Gibbs JR, van der Brug MP, Hernandez DG, Traynor BJ, Nalls MA, Lai SL, et al. Abundant quantitative trait loci exist for DNA methylation and gene expression in human brain. PLoS Genet. 2010;6(5):e1000952.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Gamazon ER, Badner JA, Cheng L, Zhang C, Zhang D, Cox NJ, et al. Enrichment of cis-regulatory gene expression SNPs and methylation quantitative trait loci among bipolar disorder susceptibility variants. Mol Psychiatry. 2013;18(3):340–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Marzi SJ, Meaburn EL, Dempster EL, Lunnon K, Paya-Cano JL, Smith RG, et al. Tissue-specific patterns of allelically-skewed DNA methylation. Epigenetics. 2016;11(1):24–35.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Smith AK, Kilaru V, Kocak M, Almli LM, Mercer KB, Ressler KJ, et al. Methylation quantitative trait loci (meQTLs) are consistently detected across ancestry, developmental stage, and tissue type. BMC Genomics. 2014;15:145.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Hannon E, Spiers H, Viana J, Pidsley R, Burrage J, Murphy TM, et al. Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci. Nat Neurosci. 2016;19(1):48–54.PubMedCrossRefGoogle Scholar
  62. 62.
    Masliah E, Dumaop W, Galasko D, Desplats P. Distinctive patterns of DNA methylation associated with Parkinson disease: identification of concordant epigenetic changes in brain and peripheral blood leukocytes. Epigenetics. 2013;8(10):1030–8.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Barault L, Ellsworth RE, Harris HR, Valente AL, Shriver CD, Michels KB. Leukocyte DNA as surrogate for the evaluation of imprinted Loci methylation in mammary tissue DNA. PLoS One. 2013;8(2):e55896.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Bartolomei MS, Ferguson-Smith AC. Mammalian genomic imprinting. Cold Spring Harb Perspect Biol. 2011. doi: 10.1101/cshperspect.a002592.
  65. 65.
    Walton E, Hass J, Liu J, Roffman JL, Bernardoni F, Roessner V, et al. Correspondence of DNA Methylation Between Blood and Brain Tissue and Its Application to Schizophrenia Research. Schizophr Bull. 2016;42(2):406–14.PubMedCrossRefGoogle Scholar
  66. 66.
    Horvath S, Zhang Y, Langfelder P, Kahn RS, Boks MP, van Eijk K, et al. Aging effects on DNA methylation modules in human brain and blood tissue. Genome Biol. 2012;13(10):R97.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Byun HM, Siegmund KD, Pan F, Weisenberger DJ, Kanel G, Laird PW, et al. Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual-specific DNA methylation patterns. Hum Mol Genet. 2009;18(24):4808–17.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Ma B, Wilker EH, Willis-Owen SA, Byun HM, Wong KC, Motta V, et al. Predicting DNA methylation level across human tissues. Nucleic Acids Res. 2014;42(6):3515–28.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Zwaigenbaum L, Bauman ML, Choueiri R, Fein D, Kasari C, Pierce K, et al. Early Identification and Interventions for Autism Spectrum Disorder: Executive Summary. Pediatrics. 2015;136 Suppl 1:S1–9.PubMedCrossRefGoogle Scholar
  70. 70.
    Bollati V, Baccarelli A. Environmental epigenetics. Heredity. 2010;105(1):105–12.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Panni T, Mehta AJ, Schwartz JD, Baccarelli AA, Just AC, Wolf K, et al. A Genome-Wide Analysis of DNA Methylation and Fine Particulate Matter Air Pollution in Three Study Populations: KORA F3, KORA F4, and the Normative Aging Study. Environ Health Perspect. 2016. doi: 10.1289/ehp.1509966.
  72. 72.
    Bakulski KM, Lee H, Feinberg JI, Wells EM, Brown S, Herbstman JB, et al. Prenatal mercury concentration is associated with changes in DNA methylation at TCEANC2 in newborns. Int J Epidemiol. 2015;44(4):1249–62.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Joubert BR, Herman T, Felix JF, Bohlin J, Ligthart S, Beckett E, et al. Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns. Nat Commun. 2016. doi: 10.1038/ncomms10577.
  74. 74.
    Joubert Bonnie R, Felix Janine F, Yousefi P, Bakulski Kelly M, Just Allan C, Breton C, et al. DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis. Am J Hum Genet. 2016;98(4):680–696.Google Scholar
  75. 75.
    Ewald ER, Wand GS, Seifuddin F, Yang X, Tamashiro KL, Potash JB, et al. Alterations in DNA methylation of Fkbp5 as a determinant of blood-brain correlation of glucocorticoid exposure. Psychoneuroendocrinology. 2014;44:112–22.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Kundakovic M, Gudsnuk K, Herbstman JB, Tang D, Perera FP, Champagne FA. DNA methylation of BDNF as a biomarker of early-life adversity. Proc Natl Acad Sci U S A. 2015;112(22):6807–13.PubMedCrossRefGoogle Scholar
  77. 77.
    Ursini G, Bollati V, Fazio L, Porcelli A, Iacovelli L, Catalani A, et al. Stress-related methylation of the catechol-O-methyltransferase Val 158 allele predicts human prefrontal cognition and activity. J Neurosci. 2011;31(18):6692–8.PubMedCrossRefGoogle Scholar
  78. 78.
    Sabunciyan S, Aryee MJ, Irizarry RA, Rongione M, Webster MJ, Kaufman WE, et al. Genome-wide DNA methylation scan in major depressive disorder. PLoS One. 2012;7(4):e34451.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Gregory SG, Connelly JJ, Towers AJ, Johnson J, Biscocho D, Markunas CA, et al. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med. 2009;7:62.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Rothman KJ, Greenland S. Causation and causal inference in epidemiology. Am J Public Health. 2005;95 Suppl 1:S144–50.PubMedCrossRefGoogle Scholar
  81. 81.
    Relton CL, Davey SG. Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease. Int J Epidemiol. 2012;41(1):161–76.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Mackinnon DP. Integrating Mediators and Moderators in Research Design. Res Soc Work Pract. 2011;21(6):675–81.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Bakulski KM, Fallin MD. Epigenetic epidemiology: promises for public health research. Environ Mol Mutagen. 2014;55(3):171–83.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Ladd-Acosta C, Fallin MD. The role of epigenetics in genetic and environmental epidemiology. Epigenomics. 2016;8(2):271–83.PubMedCrossRefGoogle Scholar
  85. 85.
    Houseman EA, Kim S, Kelsey KT, Wiencke JK. DNA Methylation in Whole Blood: Uses and Challenges. Curr Environ Health Rep. 2015;2(2):145–54.PubMedCrossRefGoogle Scholar
  86. 86.
    Nagarajan RP, Hogart AR, Gwye Y, Martin MR, LaSalle JM. Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics. 2006;1(4):e1–11.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, et al. Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet. 2008;82(3):696–711.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Abdolmaleky HM, Yaqubi S, Papageorgis P, Lambert AW, Ozturk S, Sivaraman V, et al. Epigenetic dysregulation of HTR2A in the brain of patients with schizophrenia and bipolar disorder. Schizophr Res. 2011;129(2-3):183–90.PubMedCrossRefGoogle Scholar
  89. 89.
    James SJ, Shpyleva S, Melnyk S, Pavliv O, Pogribny IP. Complex epigenetic regulation of engrailed-2 (EN-2) homeobox gene in the autism cerebellum. Transl Psychiatry. 2013;3:e232.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Ladd-Acosta C, Hansen KD, Briem E, Fallin MD, Kaufmann WE, Feinberg AP. Common DNA methylation alterations in multiple brain regions in autism. Mol Psychiatry. 2014;19(8):862–71.PubMedCrossRefGoogle Scholar
  91. 91.
    Zhu L, Wang X, Li XL, Towers A, Cao X, Wang P, et al. Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders. Hum Mol Genet. 2014;23(6):1563–78.PubMedCrossRefGoogle Scholar
  92. 92.
    Nardone S, Sams DS, Reuveni E, Getselter D, Oron O, Karpuj M, et al. DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Transl Psychiatry. 2014;4:e433.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Wockner LF, Noble EP, Lawford BR, Young RM, Morris CP, Whitehall VL, et al. Genome-wide DNA methylation analysis of human brain tissue from schizophrenia patients. Transl Psychiatry. 2014;4(1):e339.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Pidsley R, Viana J, Hannon E, Spiers H, Troakes C, Al-Saraj S, et al. Methylomic profiling of human brain tissue supports a neurodevelopmental origin for schizophrenia. Genome Biol. 2014;15(10):483.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.•
    Jaffe AE, Gao Y, Deep-Soboslay A, Tao R, Hyde TM, Weinberger DR, et al. Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex. Nat Neurosci. 2016;19(1):40–7. Large brain tissue study considering development.PubMedCrossRefGoogle Scholar
  96. 96.
    Pandey GN, Rizavi HS, Zhang H, Bhaumik R, Ren X. The Expression of the Suicide-Associated Gene SKA2 is Decreased in the Prefrontal Cortex of Suicide Victims, but Not of Non-Suicidal Patients. Int J Neuropsychopharmacol. 2016.Google Scholar
  97. 97.
    Carrard A, Salzmann A, Malafosse A, Karege F. Increased DNA methylation status of the serotonin receptor 5HTR1A gene promoter in schizophrenia and bipolar disorder. J Affect Disord. 2011;132(3):450–3.PubMedCrossRefGoogle Scholar
  98. 98.
    Dempster EL, Pidsley R, Schalkwyk LC, Owens S, Georgiades A, Kane F, et al. Disease-associated epigenetic changes in monozygotic twins discordant for schizophrenia and bipolar disorder. Hum Mol Genet. 2011;20(24):4786–96.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Rusiecki JA, Byrne C, Galdzicki Z, Srikantan V, Chen L, Poulin M, et al. PTSD and DNA Methylation in Select Immune Function Gene Promoter Regions: A Repeated Measures Case-Control Study of U.S. Military Service Members. Front Psychiatry. 2013;4:56.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Nishioka M, Bundo M, Koike S, Takizawa R, Kakiuchi C, Araki T, et al. Comprehensive DNA methylation analysis of peripheral blood cells derived from patients with first-episode schizophrenia. J Hum Genet. 2013;58(2):91–7.PubMedCrossRefGoogle Scholar
  101. 101.
    Zhang H, Wang F, Kranzler HR, Zhao H, Gelernter J. Profiling of childhood adversity-associated DNA methylation changes in alcoholic patients and healthy controls. PLoS One. 2013;8(6):e65648.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Aldinger KA, Plummer JT, Levitt P. Comparative DNA methylation among females with neurodevelopmental disorders and seizures identifies TAC1 as a MeCP2 target gene. J Neurodev Disord. 2013;5(1):15.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Wong CC, Meaburn EL, Ronald A, Price TS, Jeffries AR, Schalkwyk LC, et al. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol Psychiatry. 2014;19(4):495–503.PubMedCrossRefGoogle Scholar
  104. 104.
    Dempster EL, Wong CC, Lester KJ, Burrage J, Gregory AM, Mill J, et al. Genome-wide methylomic analysis of monozygotic twins discordant for adolescent depression. Biol Psychiatry. 2014;76(12):977–83.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Fisher HL, Murphy TM, Arseneault L, Caspi A, Moffitt TE, Viana J, et al. Methylomic analysis of monozygotic twins discordant for childhood psychotic symptoms. Epigenetics. 2015;10(11):1014–23.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Kang HJ, Kim JM, Kim SY, Kim SW, Shin IS, Kim HR, et al. A Longitudinal Study of BDNF Promoter Methylation and Depression in Breast Cancer. Psychiatry Investig. 2015;12(4):523–31.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Kim D, Kubzansky LD, Baccarelli A, Sparrow D, Spiro 3rd A, Tarantini L, et al. Psychological factors and DNA methylation of genes related to immune/inflammatory system markers: the VA Normative Aging Study. BMJ Open. 2016;6(1):e009790.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Kahl KG, Georgi K, Bleich S, Muschler M, Hillemacher T, Hilfiker-Kleinert D, et al. Altered DNA methylation of glucose transporter 1 and glucose transporter 4 in patients with major depressive disorder. J Psychiatr Res. 2016;76:66–73.PubMedCrossRefGoogle Scholar
  109. 109.••
    Montano C, Taub MA, Jaffe A, Briem E, Feinberg JI, Trygvadottir R, et al. Association of DNA methylation differences with schizophrenia in an epigenome-wide association study. JAMA Psychiatry. 2016;73(5):506–14. Large, well replicated surrogate tissue study.Google Scholar

Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Kelly M. Bakulski
    • 1
  • Alycia Halladay
    • 2
    • 3
  • Valerie W. Hu
    • 4
  • Jonathan Mill
    • 5
    • 6
  • M. Daniele Fallin
    • 7
    • 8
    Email author
  1. 1.Department of EpidemiologyUniversity of Michigan School of Public HealthAnn ArborUSA
  2. 2.Autism Science FoundationNew York CityUSA
  3. 3.Department of Pharmacology and ToxicologyRutgers UniversityNew BrunswickUSA
  4. 4.Department of Biochemistry and Molecular MedicineSchool of Medicine and Health Sciences, George Washington UniversityWashingtonUSA
  5. 5.University of Exeter Medical SchoolUniversity of ExeterExeterUK
  6. 6.Institute for Psychiatry, Psychology and NeuroscienceKing’s College LondonLondonUK
  7. 7.Department of Mental HealthJohns Hopkins University Bloomberg School of Public HealthBaltimoreUSA
  8. 8.Wendy Klag Center for Autism and Developmental DisabilitiesJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA

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