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2. Genetic vulnerability to DUSP22 promoter hypermethylation is involved in the relation between in utero famine exposure and schizophrenia

Author

Boks, M. P., Houtepen, L. C., Xu, Z., He, Y., Ursini, G., Maihofer, A. X., Rajarajan, P., Yu, Q., Xu, H., Wu, Y., Wang, S., Shi, J. P., Hulshoff Pol, H. E., Strengman, E., Rutten, B. P. F., Jaffe, A. E., Kleinman, J. E., Baker, D. G., Hol, E. M., Akbarian, S., Nievergelt, C. M., De Witte, L. D., Vinkers, C. H., Weinberger, D. R., Yu, J., and Kahn, R. S.

Published
2018
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3. Maternal anxiety during pregnancy and newborn epigenome-wide DNA methylation

Author

Sammallahti, S. (Sara), Cortes Hidalgo, A. P. (Andrea P.), Tuominen, S. (Samuli), Malmberg, A. (Anni), Mulder, R. H. (Rosa H.), Brunst, K. J. (Kelly J.), Alemany, S. (Silvia), McBride, N. S. (Nancy S.), Yousefi, P. (Paul), Heiss, J. A. (Jonathan A.), McRae, N. (Nia), Page, C. M. (Christian M.), Jin, J. (Jianping), Pesce, G. (Giancarlo), Caramaschi, D. (Doretta), Rifas-Shiman, S. L. (Sheryl L.), Koen, N. (Nastassja), Adams, C. D. (Charleen D.), Magnus, M. C. (Maria C.), Baiz, N. (Nour), Ratanatharathorn, A. (Andrew), Czamara, D. (Darina), Haberg, S. E. (Siri E.), Colicino, E. (Elena), Baccarelli, A. A. (Andrea A.), Cardenas, A. (Andres), DeMeo, D. L. (Dawn L.), Lawlor, D. A. (Deborah A.), Relton, C. L. (Caroline L.), Felix, J. F. (Janine F.), van IJzendoorn, M. H. (Marinus H.), Bakermans-Kranenburg, M. J. (Marian J.), Kajantie, E. (Eero), Raikkonen, K. (Katri), Sunyer, J. (Jordi), Sharp, G. C. (Gemma C.), Houtepen, L. C. (Lotte C.), Nohr, E. A. (Ellen A.), Sorensen, T. I. (Thorkild I. A.), Tellez-Rojo, M. M. (Martha M.), Wright, R. O. (Robert O.), Annesi-Maesano, I. (Isabella), Wright, J. (John), Hivert, M.-F. (Marie-France), Wright, R. J. (Rosalind J.), Zar, H. J. (Heather J.), Stein, D. J. (Dan J.), London, S. J. (Stephanie J.), Cecil, C. A. (Charlotte A. M.), Tiemeier, H. (Henning), Lahti, J. (Jari), Sammallahti, S. (Sara), Cortes Hidalgo, A. P. (Andrea P.), Tuominen, S. (Samuli), Malmberg, A. (Anni), Mulder, R. H. (Rosa H.), Brunst, K. J. (Kelly J.), Alemany, S. (Silvia), McBride, N. S. (Nancy S.), Yousefi, P. (Paul), Heiss, J. A. (Jonathan A.), McRae, N. (Nia), Page, C. M. (Christian M.), Jin, J. (Jianping), Pesce, G. (Giancarlo), Caramaschi, D. (Doretta), Rifas-Shiman, S. L. (Sheryl L.), Koen, N. (Nastassja), Adams, C. D. (Charleen D.), Magnus, M. C. (Maria C.), Baiz, N. (Nour), Ratanatharathorn, A. (Andrew), Czamara, D. (Darina), Haberg, S. E. (Siri E.), Colicino, E. (Elena), Baccarelli, A. A. (Andrea A.), Cardenas, A. (Andres), DeMeo, D. L. (Dawn L.), Lawlor, D. A. (Deborah A.), Relton, C. L. (Caroline L.), Felix, J. F. (Janine F.), van IJzendoorn, M. H. (Marinus H.), Bakermans-Kranenburg, M. J. (Marian J.), Kajantie, E. (Eero), Raikkonen, K. (Katri), Sunyer, J. (Jordi), Sharp, G. C. (Gemma C.), Houtepen, L. C. (Lotte C.), Nohr, E. A. (Ellen A.), Sorensen, T. I. (Thorkild I. A.), Tellez-Rojo, M. M. (Martha M.), Wright, R. O. (Robert O.), Annesi-Maesano, I. (Isabella), Wright, J. (John), Hivert, M.-F. (Marie-France), Wright, R. J. (Rosalind J.), Zar, H. J. (Heather J.), Stein, D. J. (Dan J.), London, S. J. (Stephanie J.), Cecil, C. A. (Charlotte A. M.), Tiemeier, H. (Henning), and Lahti, J. (Jari)

Abstract

Maternal anxiety during pregnancy is associated with adverse foetal, neonatal, and child outcomes, but biological mechanisms remain unclear. Altered foetal DNA methylation (DNAm) has been proposed as a potential underlying mechanism. In the current study, we performed a meta-analysis to examine the associations between maternal anxiety, measured prospectively during pregnancy, and genome-wide DNAm from umbilical cord blood. Sixteen non-overlapping cohorts from 12 independent longitudinal studies of the Pregnancy And Childhood Epigenetics Consortium participated, resulting in a combined dataset of 7243 mother-child dyads. We examined prenatal anxiety in relation to genome-wide DNAm and differentially methylated regions. We observed no association between the general symptoms of anxiety during pregnancy or pregnancy-related anxiety, and DNAm at any of the CpG sites, after multiple-testing correction. Furthermore, we identify no differentially methylated regions associated with maternal anxiety. At the cohort-level, of the 21 associations observed in individual cohorts, none replicated consistently in the other cohorts. In conclusion, contrary to some previous studies proposing cord blood DNAm as a promising potential mechanism explaining the link between maternal anxiety during pregnancy and adverse outcomes in offspring, we found no consistent evidence for any robust associations between maternal anxiety and DNAm in cord blood. Larger studies and analysis of DNAm in other tissues may be needed to establish subtle or subgroup-specific associations between maternal anxiety and the foetal epigenome.

Published
2021

4. Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder

Author

Rutten, Bart P. F., Vermetten, E, Vinkers, C H, Ursini, G, Daskalakis, N.P., Pishva, E., de Nijs, Laurence, Houtepen, L C, Eijssen, L.M., Jaffe, A E, Kenis, G., Viechtbauer, W., Hove, Hanne D., Schraut, K G, Lesch, K.P., Kleinman, J E, Hyde, T M, Weinberger, Daniel R., Schalkwyk, L.C., Lunnon, Katie, Mill, J., Cohen, M.H., Yehuda, R., Baker, Dewleen G., Maihofer, Adam X., Nievergelt, Caroline M., Geuze, E, Boks, M P M, Rutten, Bart P. F., Vermetten, E, Vinkers, C H, Ursini, G, Daskalakis, N.P., Pishva, E., de Nijs, Laurence, Houtepen, L C, Eijssen, L.M., Jaffe, A E, Kenis, G., Viechtbauer, W., Hove, Hanne D., Schraut, K G, Lesch, K.P., Kleinman, J E, Hyde, T M, Weinberger, Daniel R., Schalkwyk, L.C., Lunnon, Katie, Mill, J., Cohen, M.H., Yehuda, R., Baker, Dewleen G., Maihofer, Adam X., Nievergelt, Caroline M., Geuze, E, and Boks, M P M

Published
2018

5. Genetic vulnerability to DUSP22 promoter hypermethylation is involved in the relation between in utero famine exposure and schizophrenia

Author

Boks, M P, Houtepen, L C, Xu, Z, He, Y, Ursini, G, Maihofer, A X, Rajarajan, P, Yu, Q, Xu, H, Wu, Y, Wang, S, Shi, J P, Hulshoff Pol, H E, Strengman, E, Rutten, B P F, Jaffe, A E, Kleinman, J E, Baker, D G, Hol, E M, Akbarian, S, Nievergelt, C M, De Witte, L D, Vinkers, C H, Weinberger, D R, Yu, J, Kahn, R S, Boks, M P, Houtepen, L C, Xu, Z, He, Y, Ursini, G, Maihofer, A X, Rajarajan, P, Yu, Q, Xu, H, Wu, Y, Wang, S, Shi, J P, Hulshoff Pol, H E, Strengman, E, Rutten, B P F, Jaffe, A E, Kleinman, J E, Baker, D G, Hol, E M, Akbarian, S, Nievergelt, C M, De Witte, L D, Vinkers, C H, Weinberger, D R, Yu, J, and Kahn, R S

Published
2018

6. Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder

Author

MGGZ, Brain, Diagnostiek & Vroege Psychose Medisch, Onderzoeksgroep 2, Rutten, Bart P. F., Vermetten, E, Vinkers, C H, Ursini, G, Daskalakis, N.P., Pishva, E., de Nijs, Laurence, Houtepen, L C, Eijssen, L.M., Jaffe, A E, Kenis, G., Viechtbauer, W., Hove, Hanne D., Schraut, K G, Lesch, K.P., Kleinman, J E, Hyde, T M, Weinberger, Daniel R., Schalkwyk, L.C., Lunnon, Katie, Mill, J., Cohen, M.H., Yehuda, R., Baker, Dewleen G., Maihofer, Adam X., Nievergelt, Caroline M., Geuze, E, Boks, M P M, MGGZ, Brain, Diagnostiek & Vroege Psychose Medisch, Onderzoeksgroep 2, Rutten, Bart P. F., Vermetten, E, Vinkers, C H, Ursini, G, Daskalakis, N.P., Pishva, E., de Nijs, Laurence, Houtepen, L C, Eijssen, L.M., Jaffe, A E, Kenis, G., Viechtbauer, W., Hove, Hanne D., Schraut, K G, Lesch, K.P., Kleinman, J E, Hyde, T M, Weinberger, Daniel R., Schalkwyk, L.C., Lunnon, Katie, Mill, J., Cohen, M.H., Yehuda, R., Baker, Dewleen G., Maihofer, Adam X., Nievergelt, Caroline M., Geuze, E, and Boks, M P M

Published
2018

7. Genetic vulnerability to DUSP22 promoter hypermethylation is involved in the relation between in utero famine exposure and schizophrenia

Author

Onderzoeksgroep 2, Brain, Onderzoeksgroep 11, Affectieve & Psychotische Med., Onderzoeksgroep 1, Pathologie, TN groep Hol, Onderzoeksgroep 5, Psychiatrie_Medisch, Boks, M P, Houtepen, L C, Xu, Z, He, Y, Ursini, G, Maihofer, A X, Rajarajan, P, Yu, Q, Xu, H, Wu, Y, Wang, S, Shi, J P, Hulshoff Pol, H E, Strengman, E, Rutten, B P F, Jaffe, A E, Kleinman, J E, Baker, D G, Hol, E M, Akbarian, S, Nievergelt, C M, De Witte, L D, Vinkers, C H, Weinberger, D R, Yu, J, Kahn, R S, Onderzoeksgroep 2, Brain, Onderzoeksgroep 11, Affectieve & Psychotische Med., Onderzoeksgroep 1, Pathologie, TN groep Hol, Onderzoeksgroep 5, Psychiatrie_Medisch, Boks, M P, Houtepen, L C, Xu, Z, He, Y, Ursini, G, Maihofer, A X, Rajarajan, P, Yu, Q, Xu, H, Wu, Y, Wang, S, Shi, J P, Hulshoff Pol, H E, Strengman, E, Rutten, B P F, Jaffe, A E, Kleinman, J E, Baker, D G, Hol, E M, Akbarian, S, Nievergelt, C M, De Witte, L D, Vinkers, C H, Weinberger, D R, Yu, J, and Kahn, R S

Published
2018

9. Acute stress effects on GABA and glutamate levels in the prefrontal cortex: A 7T 1H magnetic resonance spectroscopy study

Author

UMC Utrecht, Onderzoeksgroep 2, Brain, AIOS Psychiatrie, Highfield Research Group, Infection & Immunity, Onderzoek, TN groep Joëls, Regenerative Medicine and Stem Cells, Circulatory Health, Diagnostiek & Vroege Psychose Medisch, Houtepen, L. C., Schür, R. R., Wijnen, J. P., Boer, V. O., Boks, M. P M, Kahn, R. S., Joëls, M., Klomp, D. W., Vinkers, C. H., UMC Utrecht, Onderzoeksgroep 2, Brain, AIOS Psychiatrie, Highfield Research Group, Infection & Immunity, Onderzoek, TN groep Joëls, Regenerative Medicine and Stem Cells, Circulatory Health, Diagnostiek & Vroege Psychose Medisch, Houtepen, L. C., Schür, R. R., Wijnen, J. P., Boer, V. O., Boks, M. P M, Kahn, R. S., Joëls, M., Klomp, D. W., and Vinkers, C. H.

Published
2017

10. Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder

Author

Rutten, B P F, primary, Vermetten, E, additional, Vinkers, C H, additional, Ursini, G, additional, Daskalakis, N P, additional, Pishva, E, additional, de Nijs, L, additional, Houtepen, L C, additional, Eijssen, L, additional, Jaffe, A E, additional, Kenis, G, additional, Viechtbauer, W, additional, van den Hove, D, additional, Schraut, K G, additional, Lesch, K-P, additional, Kleinman, J E, additional, Hyde, T M, additional, Weinberger, D R, additional, Schalkwyk, L, additional, Lunnon, K, additional, Mill, J, additional, Cohen, H, additional, Yehuda, R, additional, Baker, D G, additional, Maihofer, A X, additional, Nievergelt, C M, additional, Geuze, E, additional, and Boks, M P M, additional

Published
2017
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12. Antipsychotic use is associated with a blunted cortisol stress response: A study in euthymic bipolar disorder patients and their unaffected siblings

Author

Diagnostiek & Vroege Psychose Medisch, Brain, Onderzoeksgroep 2, Onderzoek, TN groep Joëls, Houtepen, L. C., Boks, M. P. M., Kahn, R. S., Joels, M., Vinkers, C. H., Diagnostiek & Vroege Psychose Medisch, Brain, Onderzoeksgroep 2, Onderzoek, TN groep Joëls, Houtepen, L. C., Boks, M. P. M., Kahn, R. S., Joels, M., and Vinkers, C. H.

Published
2015

17. Longitudinal analyses of the DNA methylome in deployed military servicemen identify susceptibility loci for post-traumatic stress disorder

Author

Rutten, B P F, Vermetten, E, Vinkers, C H, Ursini, G, Daskalakis, N P, Pishva, E, de Nijs, L, Houtepen, L C, Eijssen, L, Jaffe, A E, Kenis, G, Viechtbauer, W, van den Hove, D, Schraut, K G, Lesch, K-P, Kleinman, J E, Hyde, T M, Weinberger, D R, Schalkwyk, L, Lunnon, K, Mill, J, Cohen, H, Yehuda, R, Baker, D G, Maihofer, A X, Nievergelt, C M, Geuze, E, and Boks, M P M

Abstract

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

Published
2018
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18. Association of Trauma Type, Age of Exposure, and Frequency in Childhood and Adolescence With Psychotic Experiences in Early Adulthood.

Author

Croft J, Heron J, Teufel C, Cannon M, Wolke D, Thompson A, Houtepen L, and Zammit S

Subjects
Adolescent, Age Factors, Child, Child Abuse psychology, Child Abuse statistics & numerical data, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Interview, Psychological, Longitudinal Studies, Male, Prospective Studies, Psychotic Disorders epidemiology, Risk Factors, United Kingdom epidemiology, Young Adult, Adverse Childhood Experiences, Psychotic Disorders etiology
Abstract

Importance: Cross-sectional and longitudinal studies have consistently reported associations between childhood trauma and psychotic experiences and disorders. However, few studies have examined whether the age of exposure or specific trauma types are differently associated with the risk of developing psychotic experiences., Objective: To examine whether exposure to trauma, assessed at multiple age periods between 0 and 17 years of age, is associated with an increased risk of psychotic experiences by age 18 years and whether this association varies according to trauma type as well as age and frequency of exposure., Design, Setting, and Participants: This study used data from the Avon Longitudinal Study of Parents and Children, a large population-based birth cohort in the United Kingdom that recruited women who resided in the Avon Health Authority area and had an expected delivery date between April 1, 1991, and December 31, 1992. Data on psychotic experiences were included in the study, along with trauma variables derived from assessments completed by the parents or self-reported by the participants. The variables represent exposure to any trauma type between ages 0 and 17 years; any trauma type within a distinct age period: early childhood (0-4.9 years), middle childhood (5-10.9 years), or adolescence (11-17 years); specific trauma types between ages 0 and 17 years; and specific trauma types within early childhood, middle childhood, or adolescence. Data were analyzed from January 9, 2017, to November 30, 2017., Main Outcomes and Measures: Suspected or definite psychotic experiences were assessed using the psychosis-like symptoms semistructured interview at age 12 years and then at age 18 years., Results: The sample of 4433 participants included 2504 (56.5%) females, with a mean (SD) age of 17.8 (0.38) years. Exposure to any trauma up to age 17 years was associated with increased odds of psychotic experiences at age 18 years (adjusted odds ratio, 2.91; 95% CI, 2.15-3.93). All trauma types from age 0 to 17 years were associated with an increased odds of psychotic experiences. The population-attributable fraction for childhood and adolescent trauma on psychotic experiences at age 18 years was 45% (95% CI, 25%-60%). Effect sizes for most trauma types were greater for exposure that was more proximal to the outcome, although CIs overlapped with those for more distal trauma. Evidence supported dose-response associations for exposure to multiple trauma types and at multiple age periods. In an analysis aimed at minimizing reverse causality, adolescent trauma was also associated with past-year incident psychotic experiences at age 18 years., Conclusions and Relevance: These findings are consistent with the thesis that trauma could have a causal association with psychotic experiences; if so, identification of modifiable mediators is required to inform prevention strategies.

Published
2019
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19. Acute stress effects on GABA and glutamate levels in the prefrontal cortex: A 7T 1 H magnetic resonance spectroscopy study.

Author

Houtepen LC, Schür RR, Wijnen JP, Boer VO, Boks MP, Kahn RS, Joëls M, Klomp DW, and Vinkers CH

Subjects
Acute Disease, Adolescent, Adult, Female, Humans, Hydrocortisone blood, Male, Prefrontal Cortex diagnostic imaging, Psychiatric Status Rating Scales, Stress, Psychological blood, Surveys and Questionnaires, Young Adult, Glutamic Acid metabolism, Prefrontal Cortex metabolism, Proton Magnetic Resonance Spectroscopy, Stress, Psychological diagnostic imaging, gamma-Aminobutyric Acid metabolism
Abstract

There is ample evidence that the inhibitory GABA and the excitatory glutamate system are essential for an adequate response to stress. Both GABAergic and glutamatergic brain circuits modulate hypothalamus-pituitary-adrenal (HPA)-axis activity, and stress in turn affects glutamate and GABA levels in the rodent brain. However, studies examining stress-induced GABA and glutamate levels in the human brain are scarce. Therefore, we investigated the influence of acute psychosocial stress (using the Trier Social Stress Test) on glutamate and GABA levels in the medial prefrontal cortex of 29 healthy male individuals using 7 Tesla proton magnetic resonance spectroscopy. In vivo GABA and glutamate levels were measured before and 30 min after exposure to either the stress or the control condition. We found no associations between psychosocial stress or cortisol stress reactivity and changes over time in medial prefrontal glutamate and GABA levels. GABA and glutamate levels over time were significantly correlated in the control condition but not in the stress condition, suggesting that very subtle differential effects of stress on GABA and glutamate across individuals may occur. However, overall, acute psychosocial stress does not appear to affect in vivo medial prefrontal GABA and glutamate levels, at least this is not detectable with current practice 1 H-MRS.

Published
2017
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20. Antipsychotic use is associated with a blunted cortisol stress response: a study in euthymic bipolar disorder patients and their unaffected siblings.

Author

Houtepen LC, Boks MP, Kahn RS, Joëls M, and Vinkers CH

Subjects
Adult, Aged, Analysis of Variance, Bipolar Disorder psychology, Female, Heart Rate drug effects, Humans, Male, Middle Aged, Psychiatric Status Rating Scales, Saliva drug effects, Saliva metabolism, Surveys and Questionnaires, Time Factors, Young Adult, alpha-Amylases metabolism, Antipsychotic Agents therapeutic use, Bipolar Disorder drug therapy, Heart Rate physiology, Hydrocortisone blood, Siblings psychology, Stress, Psychological complications
Abstract

There is ample evidence that the acute stress response is altered in schizophrenia and bipolar disorder. However, it is not clear whether such changes are related to the illness, a genetic vulnerability, or is the result of medication that is used in the majority of these patients. Therefore, we investigated determinants of the acute endocrine and autonomic stress response in healthy controls (n=48), euthymic BD1 patients (n=49) and unaffected siblings of BD1 patients (n=27). All participants completed a validated psychosocial stress task, the Trier Social Stress Test for Groups (TSST-G). Saliva levels of alpha-amylase and cortisol were measured before, during, and after exposure to stress. Compared to controls, we found a significantly blunted cortisol stress response in BD1 patients. Conversely, BD1 patients displayed exaggerated alpha-amylase levels in response to stress. Antipsychotic use was a significant contributing factor to the blunted cortisol stress response in BD1 patients. Unaffected BD1 siblings displayed similar stress-induced cortisol and alpha-amylase levels as controls, suggesting that familial risk for BD1 did not have a large effect on the functionality of the stress system. In conclusion, this study shows that euthymic BD1 patients have a substantially blunted endocrine stress response but an exaggerated autonomic stress response and that the endocrine stress response differences can be largely contributed to antipsychotic use rather than constitute a specific BD1 phenotype or vulnerability., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Published
2015
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