Gene-environment correlations and causal effects of childhood maltreatment on physical and mental health: a genetically informed approach.
Kwong, Alex SF
Sallis, Hannah M
Munafò, Marcus R
Nievergelt, Caroline M
Grant, Andrew J
Moore, Tyler M
van IJzendoorn, Marinus H
The lancet. Psychiatry
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Warrier, V., Kwong, A. S., Luo, M., Dalvie, S., Croft, J., Sallis, H. M., Baldwin, J., et al. (2021). Gene-environment correlations and causal effects of childhood maltreatment on physical and mental health: a genetically informed approach.. The lancet. Psychiatry, 8 (5), 373-386. https://doi.org/10.1016/s2215-0366(20)30569-1
Background: Childhood maltreatment is associated with poor mental and physical health. Identifying genetic variants associated with childhood maltreatment can help delineate different mechanisms of gene-environment correlation (rGE) and examine potential causal effects on health outcomes. Methods: We conducted genome-wide association meta-analysis of childhood maltreatment using data from the UK Biobank (N = 143,473), Psychiatric Genomics Consortium (PGC-26K, N = 26,290), Avon Longitudinal Study of Parents and Children (N = 8,346), Adolescent Brain Cognitive Development Study (N = 5,400), and Generation R (N = 1,905). We investigated SNP heritability and genetic correlations among different subtypes, operationalizations and reports of childhood maltreatment. Family- and population-based polygenic score analyses were done to elucidate rGE mechanisms. We used genetic correlation and Mendelian Randomization analyses to identify shared genetics and test causal relationships between childhood maltreatment and mental and physical health conditions. Outcomes: A meta-analysis of genome-wide association studies (N=185,413) identified 14 independent loci associated with having experienced childhood maltreatment (13 novel). We identified high genetic overlap among different maltreatment operationalizations, subtypes, and reporting methods. Within-family analyses provided some support for active and reactive rGE but did not demonstrate the absence of passive rGE. Robust Mendelian Randomization suggested a potential causal role of childhood maltreatment in depression (unidirectional), as well as both schizophrenia and ADHD (bidirectional), but not in physical health conditions (coronary artery disease, type 2 diabetes) or inflammation (C-reactive protein). Interpretation: Childhood maltreatment has a heritable component, with substantial genetic correlations among different operationalizations, subtypes, and retrospective and prospective reports of childhood maltreatment. Family-based analyses point to a role of active and reactive rGE, with equivocal support for passive rGE. Mendelian Randomization supports a (primarily bidirectional) causal role of childhood maltreatment on mental health, but not on physical health conditions. Our study identifies research avenues to inform the prevention of childhood maltreatment and its long-term effects. Funding: Wellcome Trust, UK MRC, Horizon 2020, NIMH, NIHR Biomedical Research Centre.
Humans, Retrospective Studies, Longitudinal Studies, Mental Health, Mental Disorders, Databases, Factual, Adolescent, Adult, Aged, Aged, 80 and over, Middle Aged, Europe, Female, Male, Adult Survivors of Child Abuse, Genome-Wide Association Study, Young Adult, Gene-Environment Interaction, United Kingdom
Is supplemented by: https://doi.org/10.17863/CAM.65339
This work was supported by the Wellcome Trust (Grant refs: 214322/Z/18/Z, 104036/Z/14/Z, 204623/Z/16/Z, and 217065/Z/19/Z). VW was funded by the Bowring Research Fellowship from St. Catharine’s College, Cambridge and Wellcome Trust Collaborative Award (Grant Ref: 214322/Z/18/Z). ASFK and AM are supported by Wellcome Trust Grant 104036/Z/14/Z. ASFK is also supported by an ESRC Postdoctoral Fellowship (Grant ref: ES/V011650/1). ML is supported by the scholarship from the China Scholarship Council (No. 201706990036). The work of CC has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement No 707404 and grant agreement No 848158 (EarlyCause Project). MHvIJ is supported by the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (NWO grant No. 024.001.003, Consortium on Individual Development) and by a Spinoza Prize of the Netherlands Organization for Scientific Research. HMS and MRM are supported by the Medical Research Council and the University of Bristol (MC_UU_00011/7) and by the National Institute for Health Research (NIHR) Biomedical Research Centre at the University Hospitals Bristol National Health Service Foundation Trust and the University of Bristol. HMS is also supported by the European Research Council (Grant ref: 758813 MHINT). CMN is supported by the National Institute for Mental Health NIMH R01MH106595 and the Center of Excellence for Stress and Mental Health (CESAMH), Veterans Affairs San Diego. AJG and SB are supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 204623/Z/16/Z). TMM and RB are supported by the NIMH (R01MH117014, TMM; K23MH120437, RB).The research was conducted in association with the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, and the NIHR Collaboration for Leadership in Applied Health Research and Care East of England at Cambridgeshire and Peterborough NHS Foundation Trust. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care. This research was possible due to two applications to the UK Biobank: Projects 20904 and 23787. This research was co-funded by the NIHR Cambridge Biomedical Research Centre and a Marmaduke Sheild grant. The UK Medical Research Council and Wellcome (Grant Ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. The study website contains details of all data available through a fully searchable data dictionary (http://www.bristol.ac.uk/alspac/researchers/our-data/). Part of this data was collected using REDCap, see the REDCap website for details https://projectredcap.org/resources/citations/). The first phase of the Generation R Study is made possible by financial support from the Erasmus Medical Centre, Rotterdam; the Erasmus University Rotterdam; ZonMw; the Netherlands Organization for Scientific Research (NWO); and the Ministry of Health, Welfare and Sport. The authors gratefully acknowledge the contribution of all children and parents, general practitioners, hospitals, midwives and pharmacies involved in the Generation R Study. The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with the School of Law and Erasmus School of Social and Behavioural Sciences at Erasmus University Rotterdam; the Municipal Health Service Rotterdam area, Rotterdam; the Rotterdam Homecare Foundation, Rotterdam; and the Stichting Trombosedienst & Artsenlaboratorium Rijnmond (STAR-MDC), Rotterdam.
Wellcome Trust (214322/Z/18/Z)
Wellcome Trust (204623/Z/16/Z)
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External DOI: https://doi.org/10.1016/s2215-0366(20)30569-1
This record's URL: https://www.repository.cam.ac.uk/handle/1810/315361
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Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/