Prenatal exposures and cell type proportions are main drivers of FKBP5 DNA methylation in maltreated and non-maltreated children
DNA methylation in peripheral tissues may be a relevant biomarker of risk for developing mental disorders after exposure to early life adversity. Genes involved in HPA axis regulation, such as FKBP5, might play a key role. In this study, we aimed to identify the main drivers of salivary FKBP5 methyl...
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Elsevier
2024-11-01
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| Series: | Neurobiology of Stress |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352289524000833 |
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| author | Vera N. Karlbauer Jade Martins Monika Rex-Haffner Susann Sauer Simone Roeh Katja Dittrich Peggy Doerr Heiko Klawitter Sonja Entringer Claudia Buss Sibylle M. Winter Christine Heim Darina Czamara Elisabeth B. Binder |
| author_facet | Vera N. Karlbauer Jade Martins Monika Rex-Haffner Susann Sauer Simone Roeh Katja Dittrich Peggy Doerr Heiko Klawitter Sonja Entringer Claudia Buss Sibylle M. Winter Christine Heim Darina Czamara Elisabeth B. Binder |
| author_sort | Vera N. Karlbauer |
| collection | DOAJ |
| description | DNA methylation in peripheral tissues may be a relevant biomarker of risk for developing mental disorders after exposure to early life adversity. Genes involved in HPA axis regulation, such as FKBP5, might play a key role. In this study, we aimed to identify the main drivers of salivary FKBP5 methylation in a cohort of 162 maltreated and non-maltreated children aged 3–5 years at two measurement timepoints. We combined data from a targeted bisulfite sequencing approach for fine-mapping 49 CpGs in regulatory regions of FKBP5 and epigenetic scores for exposure to alcohol, cigarette smoke, and glucocorticoids derived from the EPICv1 microarray.Most variability of methylation in the FKBP5 locus was explained by estimated cell type proportions as well as epigenetic exposure scores, most prominently by the glucocorticoid exposure score. While not surviving correction for multiple testing, we replicated previously reported associations of FKBP5 methylation with CM. We also detected synergistic effects of both rs1360780 genotype and the glucocorticoid exposure score on FKBP5 hypomethylation. These effects were identified in the 3′TAD, a distal regulatory region of FKBP5 which is not extensively covered in Illumina arrays, emphasizing the need for fine mapping approaches. Additionally, the epigenetic glucocorticoid exposure score was associated with childhood maltreatment, maternal mental disorders, and pregnancy complications, thereby highlighting the role of glucocorticoid signaling in the epigenetic consequences of early adversity.These results underscore the need to assess cell type heterogeneity in targeted assessments of DNA methylation and show the impact of exposures beyond just childhood maltreatment such as glucocorticoid exposure. |
| format | Article |
| id | doaj-art-9029532bc4814b2abb45b68a31406752 |
| institution | Kabale University |
| issn | 2352-2895 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Stress |
| spelling | doaj-art-9029532bc4814b2abb45b68a314067522024-11-30T07:10:37ZengElsevierNeurobiology of Stress2352-28952024-11-0133100687Prenatal exposures and cell type proportions are main drivers of FKBP5 DNA methylation in maltreated and non-maltreated childrenVera N. Karlbauer0Jade Martins1Monika Rex-Haffner2Susann Sauer3Simone Roeh4Katja Dittrich5Peggy Doerr6Heiko Klawitter7Sonja Entringer8Claudia Buss9Sibylle M. Winter10Christine Heim11Darina Czamara12Elisabeth B. Binder13Dept. Genes and Environment, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany; Graduate School of Systemic Neurosciences, Ludwig-Maximilians-Universität Munich, GermanyDept. Genes and Environment, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, GermanyDept. Genes and Environment, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, GermanyDept. Genes and Environment, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, GermanyDept. Genes and Environment, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, GermanyCharité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Child and Adolescent Psychiatry, Augustenburger Platz 1, 13353 Berlin, GermanyCharité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Child and Adolescent Psychiatry, Augustenburger Platz 1, 13353 Berlin, GermanyCharité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Medical Psychology, Campus Charité Mitte, Luisenstraße 57, 10117 Berlin, GermanyCharité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Medical Psychology, Campus Charité Mitte, Luisenstraße 57, 10117 Berlin, Germany; Deutsches Zentrum für Psychische Gesundheit (DZPG), LMU Klinikum. Klinik für Psychiatrie und Psychotherapie, Nußbaumstr, 80336 München & Virchowweg 23, 10117 Berlin, Germany; Development, Health and Disease Research Program, Department of Pediatrics, University of California Irvine, Irvine, USACharité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Medical Psychology, Campus Charité Mitte, Luisenstraße 57, 10117 Berlin, Germany; Deutsches Zentrum für Psychische Gesundheit (DZPG), LMU Klinikum. Klinik für Psychiatrie und Psychotherapie, Nußbaumstr, 80336 München & Virchowweg 23, 10117 Berlin, Germany; Development, Health and Disease Research Program, Department of Pediatrics, University of California Irvine, Irvine, USACharité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Department of Child and Adolescent Psychiatry, Augustenburger Platz 1, 13353 Berlin, Germany; Deutsches Zentrum für Psychische Gesundheit (DZPG), LMU Klinikum. Klinik für Psychiatrie und Psychotherapie, Nußbaumstr, 80336 München & Virchowweg 23, 10117 Berlin, GermanyCharité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Institute of Medical Psychology, Campus Charité Mitte, Luisenstraße 57, 10117 Berlin, Germany; Deutsches Zentrum für Psychische Gesundheit (DZPG), LMU Klinikum. Klinik für Psychiatrie und Psychotherapie, Nußbaumstr, 80336 München & Virchowweg 23, 10117 Berlin, Germany; Cluster of Excellence NeuroCure (EXC25), Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30329, USADept. Genes and Environment, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, GermanyDept. Genes and Environment, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany; Deutsches Zentrum für Psychische Gesundheit (DZPG), LMU Klinikum. Klinik für Psychiatrie und Psychotherapie, Nußbaumstr, 80336 München & Virchowweg 23, 10117 Berlin, Germany; Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30329, USA; Corresponding author. Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804, Munich, Germany.DNA methylation in peripheral tissues may be a relevant biomarker of risk for developing mental disorders after exposure to early life adversity. Genes involved in HPA axis regulation, such as FKBP5, might play a key role. In this study, we aimed to identify the main drivers of salivary FKBP5 methylation in a cohort of 162 maltreated and non-maltreated children aged 3–5 years at two measurement timepoints. We combined data from a targeted bisulfite sequencing approach for fine-mapping 49 CpGs in regulatory regions of FKBP5 and epigenetic scores for exposure to alcohol, cigarette smoke, and glucocorticoids derived from the EPICv1 microarray.Most variability of methylation in the FKBP5 locus was explained by estimated cell type proportions as well as epigenetic exposure scores, most prominently by the glucocorticoid exposure score. While not surviving correction for multiple testing, we replicated previously reported associations of FKBP5 methylation with CM. We also detected synergistic effects of both rs1360780 genotype and the glucocorticoid exposure score on FKBP5 hypomethylation. These effects were identified in the 3′TAD, a distal regulatory region of FKBP5 which is not extensively covered in Illumina arrays, emphasizing the need for fine mapping approaches. Additionally, the epigenetic glucocorticoid exposure score was associated with childhood maltreatment, maternal mental disorders, and pregnancy complications, thereby highlighting the role of glucocorticoid signaling in the epigenetic consequences of early adversity.These results underscore the need to assess cell type heterogeneity in targeted assessments of DNA methylation and show the impact of exposures beyond just childhood maltreatment such as glucocorticoid exposure.http://www.sciencedirect.com/science/article/pii/S2352289524000833DNA methylationEarly-life adversityGlucocorticoidsFKBP5HAM-TBS |
| spellingShingle | Vera N. Karlbauer Jade Martins Monika Rex-Haffner Susann Sauer Simone Roeh Katja Dittrich Peggy Doerr Heiko Klawitter Sonja Entringer Claudia Buss Sibylle M. Winter Christine Heim Darina Czamara Elisabeth B. Binder Prenatal exposures and cell type proportions are main drivers of FKBP5 DNA methylation in maltreated and non-maltreated children Neurobiology of Stress DNA methylation Early-life adversity Glucocorticoids FKBP5 HAM-TBS |
| title | Prenatal exposures and cell type proportions are main drivers of FKBP5 DNA methylation in maltreated and non-maltreated children |
| title_full | Prenatal exposures and cell type proportions are main drivers of FKBP5 DNA methylation in maltreated and non-maltreated children |
| title_fullStr | Prenatal exposures and cell type proportions are main drivers of FKBP5 DNA methylation in maltreated and non-maltreated children |
| title_full_unstemmed | Prenatal exposures and cell type proportions are main drivers of FKBP5 DNA methylation in maltreated and non-maltreated children |
| title_short | Prenatal exposures and cell type proportions are main drivers of FKBP5 DNA methylation in maltreated and non-maltreated children |
| title_sort | prenatal exposures and cell type proportions are main drivers of fkbp5 dna methylation in maltreated and non maltreated children |
| topic | DNA methylation Early-life adversity Glucocorticoids FKBP5 HAM-TBS |
| url | http://www.sciencedirect.com/science/article/pii/S2352289524000833 |
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