Combined effects of genotype and childhood adversity shape variability of DNA methylation across age

Darina Czamara; Elleke Tissink; Johanna Tuhkanen; Jade Martins; Yvonne Awaloff; Amanda J. Drake; Batbayar Khulan; Aarno Palotie; Sibylle M. Winter; Charles B. Nemeroff; W. Edward Craighead; Boadie W. Dunlop; Helen S. Mayberg; Becky Kinkead; Sanjay J. Mathew; Dan V. Iosifescu; Thomas C. Neylan; Christine M. Heim; Jari Lahti; Johan G. Eriksson; Katri Räikkönen; Kerry J. Ressler; Nadine Provençal; Elisabeth B. Binder

doi:10.1038/s41398-020-01147-z

Combined effects of genotype and childhood adversity shape variability of DNA methylation across age

Darina Czamara^*, Elleke Tissink, Johanna Tuhkanen, Jade Martins, Yvonne Awaloff, Amanda J. Drake, Batbayar Khulan, Aarno Palotie, Sibylle M. Winter, Charles B. Nemeroff, W. Edward Craighead, Boadie W. Dunlop, Helen S. Mayberg, Becky Kinkead, Sanjay J. Mathew, Dan V. Iosifescu, Thomas C. Neylan, Christine M. Heim, Jari Lahti, Johan G. ErikssonKatri Räikkönen, Kerry J. Ressler, Nadine Provençal, Elisabeth B. Binder

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

Original language	English
Article number	88
Journal	Translational Psychiatry
Volume	11
DOIs	https://doi.org/10.1038/s41398-020-01147-z
Publication status	Published - 1 Feb 2021

Funding

The authors would like to thank all study participants as well as all involved in the HBCS. The authors also acknowledge the Genetics Core of the Wellcome Trust Clinical Research Facility (Edinburgh, UK) which used the 450K array for the HBCS samples. The PReDICT study was supported by the following National Institutes of Health grants: P50 MH077083; R01 MH080880; UL1 RR025008; and M01 RR0039. Funding for the U19 study was provided from a grant from the National Institute of Mental Health, U19 MH069056, with additional support from VA CSRD Project ID 09S-NIMH-002. The GRADY study was supported by a grant from the National Institute of Mental Health, R01 MH071537-01A1. HBCS has been supported by grants from the British Heart Foundation, Academy of Finland, the Finnish Diabetes Research Society, Folkhälsan Research Foundation, Novo Nordisk Foundation, Finska Läkaresällskapet, Signe and Ane Gyllenberg Foundation, University of Helsinki, Ministry of Education, Ahokas Foundation, and the Emil Aaltonen Foundation. The BerlinLCS study was funded by a research grant from the German Federal Ministry of Education and Research (BMBF) to CMH and EBB (FKZ 01KR1301B). AJD has received a Scottish Senior Clinical Fellowship (SCD/09). DC, ET, JT, JM, YA, AJD, BK, AP, SMW, BK, DVI, CMH, JL, JGE, KR, KJR, and NP report no financial disclosures. CBN: Research/Grants: National Institutes of Health; consulting (last 3 years): Xhale, Takeda, Taisho Pharmaceutical Inc., Signant Health, Sunovion Pharmaceuticals Inc., Janssen Research & Development LLC, Magstim, Inc., Navitor Pharmaceuticals, Inc., Sunovion, TC MSO, Inc., Intra-Cellular Therapies, Inc., EMA Wellness, Gerson Lehrman Group, and Acadia Pharmaceuticals; stockholder: Xhale, Celgene, Seattle Genetics, AbbVie, OPKO Health, Inc., Antares, BI Gen Holdings, Inc., Corcept Therapeutics, TC MSO, Inc., Trends in Pharma Development, LLC, and EMA Wellness; scientific advisory boards: American Foundation for Suicide Prevention (AFSP), Brain and Behavior Research Foundation, Xhale, Anxiety Disorders Association of America (ADAA), Skyland Trail, Signant Health, and Laureate Institute for Brain Research (LIBR), Inc.; board of directors: AFSP, Gratitude America, ADAA, and Xhale Smart, Inc.; income sources or equity of $10,000 or more: American Psychiatric Publishing, Xhale, Signant Health, CME Outfitters, Intra-Cellular Therapies, Inc., Magstim, and EMA Wellness; patents: Method and devices for transdermal delivery of lithium (US 6,375,990B1), Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2), and Compounds, Compositions, Methods of Synthesis, and Methods of Treatment (CRF Receptor Binding Ligand) (US 8,551, 996 B2). WEC is a board member of Hugarheill ehf, an Icelandic company dedicated to the prevention of depression, and he receives book royalties from John Wiley & Sons. His research is also supported by the Mary and John Brock Foundation and the Fuqua family foundations. He is a consultant to the George West Mental Health Foundation and is a member of the Scientific Advisory Board of the ADAA and the AIM for Mental Health Foundation. BWD has received research support from Acadia, Aptinyx, Axsome, Compass Pathways, Intracellular Therapies, Janssen, Sage, and Takeda. He has served as a consultant for Aptinyx, Greenwich Biosciences, Myriad Neuroscience, Otsuka, and Sophren Therapeutics. HSM receives consulting and intellectual property licensing fees from Abbott Neuromodulation. SJM is supported through the use of facilities and resources at the Michael E. Debakey VA Medical Center, Houston, TX, and has served as a consultant to Alkermes, Allergan, Signant Health, Clexio Biosciences, Janssen, Neurocrine, Perception Neurosciences, Praxis Precision Medicines, Sage Therapeutics, and Seelos Therapeutics. He has received research support from Biohaven Pharmaceuticals and VistaGen Therapeutics. In the past 5 years, DVI has received consulting fees from Alkermes, Axsome, Centers for Psychiatric Excellence, Global Medical Education, MYnd Analytics (CNS Response), Jazz, Lundbeck, Otsuka, Precision Neuroscience, Sage, and Sunovion, and has received research support (through his academic institutions) from Alkermes, Astra Zeneca, BrainsWay, LiteCure, NeoSync, Roche, Shire, and Otsuka. TCN has received study medication from Corcept Therapeutics and served as a consultant for Jazz Pharmaceuticals. Over the last 5 years, DVI has received consulting fees from Axsome, Alkermes, Centers of Psychiatric Excellence, MYnd Analytics (CNS Response), Jazz, Lundbeck, Precision Neuroscience, Otsuka, and Sunovion, and has received research support (through his academic institutions) from Alkermes, Astra Zeneca, BrainsWay, LiteCure, NeoSync, Roche, and Shire. EBB is the coinventor of FKBP5: a novel target for antidepressant therapy, European Patent no. EP 1687443 B1, and receives a research grant from Böhringer Ingelheim for a collaboration on functional investigations of FKBP5.

Funders	Funder number
Finnish Diabetes Research Society
Fuqua family foundations	EP 1687443 B1
Mary and John Brock Foundation
Ministry of Education, Ahokas Foundation
VA CSRD	R01 MH071537-01A1, 09S-NIMH-002
National Institutes of Health	UL1 RR025008, M01 RR0039, P50 MH077083
National Institute of Mental Health	R01MH080880, U19 MH069056
Helsingin Yliopisto
Boehringer Ingelheim
Finska Läkaresällskapet
Folkhälsanin Tutkimussäätiö
British Heart Foundation
Suomen Akatemia
Bundesministerium für Bildung und Forschung	FKZ 01KR1301B
Signe ja Ane Gyllenbergin Säätiö
Emil Aaltosen Säätiö
Novo Nordisk Fonden

Access to Document

10.1038/s41398-020-01147-z

Persistent URL (handle)

Persistent link

Cite this

Czamara, D., Tissink, E., Tuhkanen, J., Martins, J., Awaloff, Y., Drake, A. J., Khulan, B., Palotie, A., Winter, S. M., Nemeroff, C. B., Craighead, W. E., Dunlop, B. W., Mayberg, H. S., Kinkead, B., Mathew, S. J., Iosifescu, D. V., Neylan, T. C., Heim, C. M., Lahti, J., ... Binder, E. B. (2021). Combined effects of genotype and childhood adversity shape variability of DNA methylation across age. Translational Psychiatry, 11, Article 88. https://doi.org/10.1038/s41398-020-01147-z

@article{1e52d06b6d694d0fa581982940020efa,

title = "Combined effects of genotype and childhood adversity shape variability of DNA methylation across age",

abstract = "Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.",

author = "Darina Czamara and Elleke Tissink and Johanna Tuhkanen and Jade Martins and Yvonne Awaloff and Drake, {Amanda J.} and Batbayar Khulan and Aarno Palotie and Winter, {Sibylle M.} and Nemeroff, {Charles B.} and Craighead, {W. Edward} and Dunlop, {Boadie W.} and Mayberg, {Helen S.} and Becky Kinkead and Mathew, {Sanjay J.} and Iosifescu, {Dan V.} and Neylan, {Thomas C.} and Heim, {Christine M.} and Jari Lahti and Eriksson, {Johan G.} and Katri R{\"a}ikk{\"o}nen and Ressler, {Kerry J.} and Nadine Proven{\c c}al and Binder, {Elisabeth B.}",

year = "2021",

month = feb,

day = "1",

doi = "10.1038/s41398-020-01147-z",

language = "English",

volume = "11",

journal = "Translational Psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

}

Czamara, D, Tissink, E, Tuhkanen, J, Martins, J, Awaloff, Y, Drake, AJ, Khulan, B, Palotie, A, Winter, SM, Nemeroff, CB, Craighead, WE, Dunlop, BW, Mayberg, HS, Kinkead, B, Mathew, SJ, Iosifescu, DV, Neylan, TC, Heim, CM, Lahti, J, Eriksson, JG, Räikkönen, K, Ressler, KJ, Provençal, N & Binder, EB 2021, 'Combined effects of genotype and childhood adversity shape variability of DNA methylation across age', Translational Psychiatry, vol. 11, 88. https://doi.org/10.1038/s41398-020-01147-z

TY - JOUR

T1 - Combined effects of genotype and childhood adversity shape variability of DNA methylation across age

AU - Czamara, Darina

AU - Tissink, Elleke

AU - Tuhkanen, Johanna

AU - Martins, Jade

AU - Awaloff, Yvonne

AU - Drake, Amanda J.

AU - Khulan, Batbayar

AU - Palotie, Aarno

AU - Winter, Sibylle M.

AU - Nemeroff, Charles B.

AU - Craighead, W. Edward

AU - Dunlop, Boadie W.

AU - Mayberg, Helen S.

AU - Kinkead, Becky

AU - Mathew, Sanjay J.

AU - Iosifescu, Dan V.

AU - Neylan, Thomas C.

AU - Heim, Christine M.

AU - Lahti, Jari

AU - Eriksson, Johan G.

AU - Räikkönen, Katri

AU - Ressler, Kerry J.

AU - Provençal, Nadine

AU - Binder, Elisabeth B.

PY - 2021/2/1

Y1 - 2021/2/1

N2 - Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

AB - Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

UR - http://www.scopus.com/inward/record.url?scp=85100256867&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85100256867&partnerID=8YFLogxK

U2 - 10.1038/s41398-020-01147-z

DO - 10.1038/s41398-020-01147-z

M3 - Article

AN - SCOPUS:85100256867

SN - 2158-3188

VL - 11

JO - Translational Psychiatry

JF - Translational Psychiatry

M1 - 88

ER -

Combined effects of genotype and childhood adversity shape variability of DNA methylation across age

Abstract

Funding

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this