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Maternal attachment insecurity, maltreatment history, and depressive symptoms are associated with broad DNA methylation signatures in infants

Molecular Psychiatry volume 27, pages 3306–3315 (2022)Cite this article

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Abstract

The early environment, including maternal characteristics, provides many cues to young organisms that shape their long-term physical and mental health. Identifying the earliest molecular events that precede observable developmental outcomes could help identify children in need of support prior to the onset of physical and mental health difficulties. In this study, we examined whether mothers’ attachment insecurity, maltreatment history, and depressive symptoms were associated with alterations in DNA methylation patterns in their infants, and whether these correlates in the infant epigenome were associated with socioemotional and behavioral functioning in toddlerhood. We recruited 156 women oversampled for histories of depression, who completed psychiatric interviews and depression screening during pregnancy, then provided follow-up behavioral data on their children at 18 months. Buccal cell DNA was obtained from 32 of their infants for a large-scale analysis of methylation patterns across 5 × 106 individual CpG dinucleotides, using clustering-based significance criteria to control for multiple comparisons. We found that tens of thousands of individual infant CpGs were alternatively methylated in association with maternal attachment insecurity, maltreatment in childhood, and antenatal and postpartum depressive symptoms, including genes implicated in developmental patterning, cell-cell communication, hormonal regulation, immune function/inflammatory response, and neurotransmission. Density of DNA methylation at selected genes from the result set was also significantly associated with toddler socioemotional and behavioral problems. This is the first report to identify novel regions of the human infant genome at which DNA methylation patterns are associated longitudinally both with maternal characteristics and with offspring socioemotional and behavioral problems in toddlerhood.

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Fig. 1: Overlap among biological pathways with components alternatively methylated in infants in association with each maternal variable.
Fig. 2: Radar plot of maternal variable: child outcomes.

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Data availability

Data are accessible at https://figshare.com/articles/dataset/1010i-CGATGT_S1_L001_R1_001_fastq_gz/17027099.

References

  1. Bar-Sadeh B, Rudnizky S, Pnueli L, Bentley GR, Stöger R, Kaplan A, et al. Unravelling the role of epigenetics in reproductive adaptations to early-life environment. Nat Rev Endocrinol. 2020;16:519–33.

    Article  CAS  PubMed  Google Scholar 

  2. Gillman MW. Developmental origins of health and disease. N Engl J Med. 2005;353:1848–50. https://doi.org/10.1056/NEJMe058187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Barker DJ. Early growth and cardiovascular disease. Arch Dis Child. 1999;80:305–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Monk C, Lugo-Candelas C, Trumpff C. Prenatal developmental origins of future psychopathology: mechanisms and pathways. Annu Rev Clin Psychol. 2019;15:317–44.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Boynton-Jarrett R, Wright RJ, Putnam FW, Hibert EL, Michels KB, Forman MR, et al. Childhood abuse and age at menarche. J Adolesc Health. 2013;52:241–7.

    Article  PubMed  Google Scholar 

  6. Watson LF, Taft AJ, Lee C. Associations of self-reported violence with age at menarche, first intercourse, and first birth among a national population sample of young Australian women. Women’s health issues. 2007;17:281–9.

    Article  PubMed  Google Scholar 

  7. Ellis BJ. Timing of pubertal maturation in girls: an integrated life history approach. Psychological Bull. 2004;130:920.

    Article  Google Scholar 

  8. Remsberg KE, Demerath EW, Schubert CM, Chumlea WC, Sun SS, Siervogel RM. Early menarche and the development of cardiovascular disease risk factors in adolescent girls: the Fels Longitudinal Study. J Clin Endocrinol Metab. 2005;90:2718–24.

    Article  CAS  PubMed  Google Scholar 

  9. Boden JM, Fergusson DM, John Horwood L. Early motherhood and subsequent life outcomes. J Child Psychol Psychiatry. 2008;49:151–60.

    Article  PubMed  Google Scholar 

  10. Henretta JC, Grundy EM, Okell LC, Wadsworth ME. Early motherhood and mental health in midlife: a study of British and American cohorts. Aging Ment Health. 2008;12:605–14.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Mollborn S, Morningstar E. Investigating the relationship between teenage childbearing and psychological distress using longitudinal evidence. J health Soc Behav. 2009;50:310–26.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Shonkoff JP, Boyce WT, McEwen BS. Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention. JAMA. 2009;301:2252–9. https://doi.org/10.1001/jama.2009.754.

    Article  CAS  PubMed  Google Scholar 

  13. Hane AA, Henderson HA, Reeb‐Sutherland BC, Fox NA. Ordinary variations in human maternal caregiving in infancy and biobehavioral development in early childhood: a follow‐up study. Developmental Psychobiol. 2010;52:558–67.

    Article  Google Scholar 

  14. Bernier A, Calkins SD, Bell MA. Longitudinal associations between the quality of mother–infant interactions and brain development across infancy. Child Dev. 2016;87:1159–74.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Davis EP, Stout SA, Molet J, Vegetabile B, Glynn LM, Sandman CA, et al. Exposure to unpredictable maternal sensory signals influences cognitive development across species. Proc Natl Acad Sci USA. 2017;114:10390-5.

  16. Kundakovic M, Champagne FA. Early-life experience, epigenetics, and the developing brain. Neuropsychopharmacology. 2015;40:141–53.

    Article  PubMed  Google Scholar 

  17. Ng FFY, Tamis-LeMonda CS, Sze INL. Parenting among Mainland Chinese immigrant mothers in Hong Kong. In: Parental roles and relationships in immigrant families. Cham: Springer; 2018. p. 147–67.

  18. Armstrong-Carter E, Trejo S, Hill LJ, Crossley KL, Mason D, Domingue BW. The earliest origins of genetic nurture: the prenatal environment mediates the association between maternal genetics and child development. Psychological Sci. 2020;31:781–91.

    Article  Google Scholar 

  19. Bosquet Enlow M, Devick KL, Brunst KJ, Lipton LR, Coull BA, Wright RJ. Maternal lifetime trauma exposure, prenatal cortisol, and infant negative affectivity. Infancy. 2017;22:492–513.

    Article  Google Scholar 

  20. Aristizabal MJ, Anreiter I, Halldorsdottir T, Odgers CL, McDade TW, Goldenberg A, et al. Biological embedding of experience: a primer on epigenetics. Proc Natl Acad Sci USA. 2020;117:23261–9.

    Article  CAS  PubMed  Google Scholar 

  21. Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7:847–54.

    Article  CAS  PubMed  Google Scholar 

  22. Weaver IC, Champagne FA, Brown SE, Dymov S, Sharma S, Meaney MJ, et al. Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. J Neurosci. 2005;25:11045–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Naumova OY, Hein S, Suderman M, Barbot B, Lee M, Raefski A, et al. Epigenetic patterns modulate the connection between developmental dynamics of parenting and offspring psychosocial adjustment. Child Dev. 2016;87:98–110.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Suderman M, McGowan PO, Sasaki A, Huang TC, Hallett MT, Meaney MJ, et al. Conserved epigenetic sensitivity to early life experience in the rat and human hippocampus. Proc Natl Acad Sci USA. 2012;109:17266–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Smearman EL, Almli LM, Conneely KN, Brody GH, Sales JM, Bradley B, et al. Oxytocin receptor genetic and epigenetic variations: association with child abuse and adult psychiatric symptoms. Child Dev. 2016;87:122–34.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Non AL, Hollister BM, Humphreys KL, Childebayeva A, Esteves K, Zeanah CH, et al. DNA methylation at stress‐related genes is associated with exposure to early life institutionalization. Am J Phys Anthropol 2016;161:84–93.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Labonte B, Suderman M, Maussion G, Navaro L, Yerko V, Mahar I, et al. Genome-wide epigenetic regulation by early-life trauma. Arch Gen Psychiatry. 2012;69:722–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Essex MJ, Thomas Boyce W, Hertzman C, Lam LL, Armstrong JM, Neumann S, et al. Epigenetic vestiges of early developmental adversity: childhood stress exposure and DNA methylation in adolescence. Child Dev. 2013;84:58–75.

    Article  PubMed  Google Scholar 

  29. Provenzi L, Brambilla M, Scotto di Minico G, Montirosso R, Borgatti R. Maternal caregiving and DNA methylation in human infants and children: systematic review. Genes, Brain Behav. 2020;19:e12616.

    Article  PubMed  Google Scholar 

  30. Roth MC, Humphreys KL, King LS, Mondal S, Gotlib IH, Robakis TK. Attachment security in pregnancy mediates the association between maternal childhood maltreatment and emotional and behavioral problems in offspring. Child Psychiatry Hum Dev. 2021;52:966–77.

    Article  PubMed  Google Scholar 

  31. Cooke JE, Racine N, Plamondon A, Tough S, Madigan S. Maternal adverse childhood experiences, attachment style, and mental health: pathways of transmission to child behavior problems. Child Abus Negl. 2019;93:27–37.

    Article  Google Scholar 

  32. Goodman SH, Rouse MH, Connell AM, Broth MR, Hall CM, Heyward D. Maternal depression and child psychopathology: a meta-analytic review. Clin Child Fam Psychol Rev. 2011;14:1–27.

    Article  PubMed  Google Scholar 

  33. Hetherington E, Racine N, Madigan S, McDonald S, Tough S. Relative contribution of maternal adverse childhood experiences to understanding children’s externalizing and internalizing behaviours at age 5: findings from the All Our Families cohort. CMAJ Open. 2020;8:E352.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Thomas-Argyriou JC, Letourneau N, Dewey D, Campbell TS, Giesbrecht GF, APrON Study Team. The role of HPA-axis function during pregnancy in the intergenerational transmission of maternal adverse childhood experiences to child behavior problems. Dev Psychopathol. 2021;33:284–300.

    Article  PubMed  Google Scholar 

  35. First MB. Structured clinical interview for the DSM (SCID). In: Cautin RL, Lilienfeld SO, editors. The encyclopedia of clinical psychology. Hoboken, NJ: John Wiley and Sons; 2014. p. 1–6.

  36. Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression: development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry. 1987;150:782–6.

    Article  CAS  PubMed  Google Scholar 

  37. Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, et al. Development and validation of a brief screening version of the Childhood Trauma Questionnaire. Child AbusNegl. 2003;27:169–90.

    Article  Google Scholar 

  38. Feeney JA, Noller P, Hanrahan M. Assessing adult attachment. In: Sperling MB, Berman WH, editors. Attachment in adults: clinical and developmental perspectives. New York: Guilford Press; 1994. p. 128–52.

  39. Carter AS, Briggs-Gowan MJ, Jones SM, Little TD. The infant–toddler social and emotional assessment (ITSEA): Factor structure, reliability, and validity. J Abnorm Child Psychol. 2003;31:495–514.

    Article  PubMed  Google Scholar 

  40. Zubaran C, Schumacher M, Roxo MR, Foresti K. Screening tools for postpartum depression: validity and cultural dimensions. Afr J Psychiatry. 2010;13:357–65.

    CAS  Google Scholar 

  41. Alexander R, Feeney J, Hohaus L, Noller P. Attachment style and coping resources as predictors of coping strategies in the transition to parenthood. Pers Relatsh. 2001;8:137–52.

    Article  Google Scholar 

  42. Stein H, Koontz AD, Fonagy P, Allen JG, Fultz J, Brethour JR, et al. Adult attachment: what are the underlying dimensions?. Psychol Psychother. 2002;75:77–91.

    Article  PubMed  Google Scholar 

  43. Axfors C, Sylvén S, Skalkidou A, Ramklint M. Psychometric properties of the attachment style questionnaire in Swedish pregnant women: short and full versions. J Reprod Infant Psychol. 2017;35:450–61.

    Article  PubMed  Google Scholar 

  44. Gibson J, McKenzie‐McHarg K, Shakespeare J, Price J, Gray R. A systematic review of studies validating the Edinburgh Postnatal Depression Scale in antepartum and postpartum women. Acta Psychiatr Scand. 2009;119:350–64.

    Article  CAS  PubMed  Google Scholar 

  45. Robakis TK, Williams KE, Crowe S, Lin KW, Gannon J, Rasgon NL. Maternal attachment insecurity is a potent predictor of depressive symptoms in the early postnatal period. J Affect Disord. 2016;190:623.

    Article  PubMed  Google Scholar 

  46. Robakis TK, Zhang S, Rasgon NL, Li T, Wang T, Roth MC, et al. Epigenetic signatures of attachment insecurity and childhood adversity provide evidence for role transition in the pathogenesis of perinatal depression. Transl Psychiatry. 2020;10:1–14.

    Article  Google Scholar 

  47. Harris PA, Taylor R, Minor BL, Elliot V, Fernandez M, O’Neal L.REDCap Consortium. The REDCap consortium: building an international community of software partners. J Biomed Inform. 2019;95:103208. https://doi.org/10.1016/j.jbi.2019.103208.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Harris PA, Taylor R, Thielke R, Payne J, Gonzales N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–81. https://doi.org/10.1016/j.jbi.2008.08.010.

    Article  PubMed  Google Scholar 

  49. 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;8:445–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lowe R, Slodkowicz G, Goldman N, Rakyan VK. The human blood DNA methylome displays a highly distinctive profile compared with other somatic tissues. Epigenetics. 2015;10:274–81.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Wang Z, Li X, Jiang Y, Shao Q, Liu Q, Chen B, et al. swDMR: a sliding window approach to identify differentially methylated regions based on whole genome bisulfite sequencing. PLoS ONE. 2015;10:e0132866.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;57:289–300.

    Google Scholar 

  53. Mi H, Muruganujan A, Ebert D, Huang X, Thomas PD. PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools. Nucleic Acids Res. 2019;47:D419–26.

    Article  CAS  PubMed  Google Scholar 

  54. Cheverud J. A simple correction for multiple comparisons in interval mapping genome scans. Heredity. 2001;87:52–8. https://doi.org/10.1046/j.1365-2540.2001.00901.x.

    Article  CAS  PubMed  Google Scholar 

  55. Conroy S, Pariante CM, Marks MN, Davies HA, Farrelly S, Schacht R, et al. Maternal psychopathology and infant development at 18 months: the impact of maternal personality disorder and depression. J Am Acad Child Adolesc Psychiatry. 2012;51:51–61.

    Article  PubMed  Google Scholar 

  56. Suardi F, Moser DA, Sancho Rossignol A, Manini A, Vital M, Merminod G, et al. Maternal reflective functioning, interpersonal violence-related posttraumatic stress disorder, and risk for psychopathology in early childhood. Attachment Hum Dev. 2020;22:225–45.

    Article  Google Scholar 

  57. Carter AS, Garrity-Rokous FE, Chazan-Cohen R, Little C, Briggs-Gowan MJ. Maternal depression and comorbidity: predicting early parenting, attachment security, and toddler social-emotional problems and competencies. J Am Acad Child Adolesc Psychiatry. 2001;40:18–26.

    Article  CAS  PubMed  Google Scholar 

  58. Karabekiroglu K, Rodopman-Arman A. Parental attachment style and severity of emotional/behavioral problems in toddlerhood. Arch Neuropsychiatry/Noropsikiatri Arsivi. 2011;48:147–54.

  59. Neuwald MF, Agranonik M, Portella AK, Fleming A, Wazana A, Steiner M, MAVAN Study Team. Transgenerational effects of maternal care interact with fetal growth and influence attention skills at 18 months of age. Early Hum Dev. 2014;90:241–6.

    Article  PubMed  Google Scholar 

  60. Whiffen VE, Kerr MA, Kallos‐Lilly V. Maternal depression, adult attachment, and children’s emotional distress. Fam Process. 2005;44:93–103.

    Article  PubMed  Google Scholar 

  61. Cao-Lei L, Elgbeili G, Massart R, Laplante DP, Szyf M, King S. Pregnant women’s cognitive appraisal of a natural disaster affects DNA methylation in their children 13 years later: Project Ice Storm. Transl Psychiatry. 2015;5:e515. https://doi.org/10.1038/tp.2015.13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Garg E, Chen LI, Nguyen TT, Pokhvisneva I, Chen LM, Unternaehrer E, Mavan Study Team. The early care environment and DNA methylome variation in childhood. Dev Psychopathol. 2018;30:891–903.

    Article  PubMed  Google Scholar 

  63. Moore SR, McEwen LM, Quirt J, Morin A, Mah SM, Barr RG, et al. Epigenetic correlates of neonatal contact in humans. Dev Psychopathol. 2017;29:1517–38.

    Article  PubMed  Google Scholar 

  64. Theda C, Hwang SH, Czajko A, Loke YJ, Leong P, Craig JM. Quantitation of the cellular content of saliva and buccal swab samples. Sci Rep. 2018;8:6944. https://doi.org/10.1038/s41598-018-25311-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Groeger S, Meyle J. Oral mucosal epithelial cells. Front Immunol. 2019;10. https://doi.org/10.3389/fimmu.2019.00208.

  66. Kyrylenko I, Fajda O, Drach O, Popel’ S, Popel’ R, Zukow W. Relationships between Electrokinetic Index of buccal epithelium and some functional and metabolic parameters at men with chronic pyelonephrite. J Educ, Health Sport. 2016;6:302–14. http://www.ojs.ukw.edu.pl/index.php/johs/article/view/3369/4685.

    Google Scholar 

  67. Kroenke CH, Epel E, Adler N, Bush NR, Obradovic J, Lin J. et al. Autonomic and adrenocortical reactivity and buccal cell telomere length in kindergarten children. Psychosom Med. 2011;73:533–40. https://doi.org/10.1097/PSY.0b013e318229acfc.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fowkes RC, Moradi-Bidhendi N, Branceleone V, Zariwala MG, Brady D, Jessop DS, et al. Annexin-A1 protein and its relationship to cortisol in human saliva. Psychoneuroendocrinology. 2013;38:722–7.

    Article  CAS  PubMed  Google Scholar 

  69. Edelman S, Shalev I, Uzefovsky F, Israel S, Knafo A, Kremer I, et al. Epigenetic and genetic factors predict women’s salivary cortisol following a threat to the social self. PLoS ONE. 2012;7:e48597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Smith AK, Kilaru V, Klengel T, Mercer KB, Bradley B, Conneely KN, et al. DNA extracted from saliva for methylation studies of psychiatric traits: evidence tissue specificity and relatedness to brain. Am J Med Genet Part B: Neuropsychiatr Genet. 2015;168:36–44.

    Article  CAS  Google Scholar 

  71. 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;8:445–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Thompson TM, Sharfi D, Lee M, Yrigollen CM, Naumova OY, Grigorenko EL. Comparison of whole-genome DNA methylation patterns in whole blood, saliva, and lymphoblastoid cell lines. Behav Genet. 2013;43:168–76.

    Article  PubMed  Google Scholar 

  73. Braun PR, Han S, Hing B, Nagahama Y, Gaul LN, Heinzman JT, et al. Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals. Transl Psychiatry. 2019;9:1–10.

    Article  Google Scholar 

  74. Stadler MB, Murr R, Burger L, Ivanek R, Lienert F, Schöler A, et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 2011;480:490–5.

    Article  CAS  PubMed  Google Scholar 

  75. Boyes J, Bird A. Repression of genes by DNA methylation depends on CpG density and promoter strength: evidence for involvement of a methyl-CpG binding protein. EMBO J. 1992;11:327–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D’Souza C, Fouse SD, et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010;466:253–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Galit LM, Ahuvi Y, Gil A. The alternative role of DNA methylation in splicing regulation. Trends Genet. 2015;31:274–80.

    Article  Google Scholar 

  78. Robakis TK, Lee S, Werner E, Liu G, Miller M, Wylie D, et al. DNA methylation patterns in T lymphocytes are generally stable in human pregnancies but CD3 methylation is associated with perinatal psychiatric symptoms. Brain, Behav, Immun-health. 2020;3:100044.

    Article  PubMed  Google Scholar 

  79. Monk C, Lugo-Candelas C, Trumpff C. Prenatal developmental origins of future psychopathology: mechanisms and pathways. Annu Rev Clin Psychol. 2019;15:317–44.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Kim DR, Bale TL, Epperson CN. Prenatal programming of mental illness: current understanding of relationship and mechanisms. Curr Psychiatry Rep. 2015;17:5.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Nemoda Z, Massart R, Suderman M, Hallett M, Li T, Coote M, et al. Maternal depression is associated with DNA methylation changes in cord blood T lymphocytes and adult hippocampi. Transl Psychiatry. 2015;5:e545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yehuda R, Daskalakis NP, Desarnaud F, Makotkine I, Lehrner A, Koch E, et al. Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD. Front Psychiatry. 2013;4:118.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Perroud N, Salzmann A, Prada P, Nicastro R, Hoeppli ME, Furrer S, et al. Response to psychotherapy in borderline personality disorder and methylation status of the BDNF gene. Transl Psychiatry. 2013;3:e207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Lopez JP, Mamdani F, Labonte B, Beaulieu MM, Yang JP, Berlim MT, et al. Epigenetic regulation of BDNF expression according to antidepressant response. Mol Psychiatry. 2013;18:398–9.

    Article  CAS  PubMed  Google Scholar 

  85. Drzymalla E, Gladish N, Koen N, Epstein MP, Kobor MS, Zar HJ, et al. Association between maternal depression during pregnancy and newborn DNA methylation. Transl Psychiatry. 2021;11:572. https://doi.org/10.1038/s41398-021-01697-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Viuff AC, Sharp GC, Rai D, Henriksen TB, Pedersen LH, Kyng K, et al. Maternal depression during pregnancy and cord blood DNA methylation: findings from the Avon Longitudinal Study of Parents and Children. Transl Psychiatry. 2018;8:1–10.

    Article  CAS  Google Scholar 

  87. Non AL, Binder AM, Kubzansky LD, Michels KB. Genome-wide DNA methylation in neonates exposed to maternal depression, anxiety, or SSRI medication during pregnancy. Epigenetics. 2014;9:964–72.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Schroeder JW, Smith AK, Brennan PA, Conneely KN, Kilaru V, Knight BT, et al. DNA methylation in neonates born to women receiving psychiatric care. Epigenetics. 2012;7:409–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Carter AS, Little C, Briggs‐Gowan MJ, Kogan N. The infant–toddler social and emotional assessment (ITSEA): comparing parent ratings to laboratory observations of task mastery, emotion regulation, coping behaviors, and attachment status. Infant Ment Health J. 1999;20:375–92.

    Article  Google Scholar 

  90. Van der Toorn SL, Huizink AC, Utens EM, Verhulst FC, Ormel J, Ferdinand RF. Maternal depressive symptoms, and not anxiety symptoms, are associated with positive mother–child reporting discrepancies of internalizing problems in children: a report on the TRAILS Study. Eur Child Adolesc Psychiatry. 2010;19:379–88.

    Article  PubMed  Google Scholar 

  91. Briggs-Gowan MJ, Carter AS. Social-emotional screening status in early childhood predicts elementary school outcomes. Pediatrics. 2008;121:957–62.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by a Stanford Precision Health and Integrated Diagnostics Seed Funding grant to TKR, and by NIH Grants R21-HD090493 and R21-MH111978 to IHG. AEU is a Tashia and John Morgridge Faculty Fellow of the Stanford Child Health Research Institute, is a Project-PI of the Stanford Center of Excellence in Genomics—Center for Personal Dynamic Regulomes (NIH HG007735-0, Center PI Chang), and acknowledges funding from and helpful discussions with Bruce Blackie. The sequencing data were generated on an Illumina HiSeq 4000 that was purchased with funds from NIH under award number S10OD018220. TL and YC are affiliated with Accura Science, LLC, and were financially recompensed for their expert biostatistical analysis. Code availability is at the discretion of Accura Science, by correspondence with TL. The REDCap platform services at Stanford are subsidized by (a) Stanford School of Medicine Research Office and (b) the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through grant UL1 TR001085.

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Authors and Affiliations

  1. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Thalia K. Robakis

  2. Department of Psychology and Human Development, Peabody College of Vanderbilt University, Nashville, TN, USA

    Marissa C. Roth & Kathryn L. Humphreys

  3. Department of Psychology, Stanford University, Stanford, CA, USA

    Lucy S. King & Ian H. Gotlib

  4. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

    Marcus Ho, Xianglong Zhang, Natalie L. Rasgon, Kathleen T. Watson & Alexander E. Urban

  5. Accura Science, LLC, Johnston, IA, USA

    Yuhao Chen & Tongbin Li

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TKR conceived of the study, obtained targeted funding for the project, and wrote the paper. MCR managed data collection and contributed to data analysis, writing and editing. LSK and KLH contributed to study design, data collection, data analysis, interpretation, writing, and editing. MH performed the DNA processing and sequencing. XZ contributed to the analysis plan and to data acquisition and processing. YC and TL performed the bioinformatic analysis. NLR contributed to study design and reviewed and edited the final manuscript. KTW assisted with interpretation of results and reviewed and edited the final manuscript. AEU contributed to study design, oversaw acquisition and analysis of epigenetic data, and reviewed and edited the final manuscript. IHG is PI of the parent study, provided guidance for study design, data acquisition and analysis, and reviewed and edited the manuscript for publication.

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Correspondence to Thalia K. Robakis.

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Robakis, T.K., Roth, M.C., King, L.S. et al. Maternal attachment insecurity, maltreatment history, and depressive symptoms are associated with broad DNA methylation signatures in infants. Mol Psychiatry 27, 3306–3315 (2022). https://doi.org/10.1038/s41380-022-01592-w

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  • DOI: https://doi.org/10.1038/s41380-022-01592-w

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