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Cited by 224Child Abuse and TraumaGenetic Associations and EpidemiologyChild Welfare and Adoption

Gene–environment correlations and causal effects of childhood maltreatment on physical and mental health: a genetically informed approach

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Warrier, Varun, Kwong, Alex S F, Luo, Mannan, Dalvie, Shareefa, Croft, Jazz, Sallis, Hannah M, Baldwin, Jessie, Munafò, Marcus R +8 more·2021·The Lancet Psychiatry
DOI 10.1016/s2215-0366(20)30569-1PMC PMC8055541
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Abstract

BACKGROUND: Childhood maltreatment is associated with poor mental and physical health. However, the mechanisms of gene-environment correlations and the potential causal effects of childhood maltreatment on health are unknown. Using genetics, we aimed to delineate the sources of gene-environment correlation for childhood maltreatment and the causal relationship between childhood maltreatment and health. METHODS: We did a genome-wide association study meta-analysis of childhood maltreatment using data from the UK Biobank (n=143 473), Psychiatric Genomics Consortium (n=26 290), Avon Longitudinal Study of Parents and Children (n=8346), Adolescent Brain Cognitive Development Study (n=5400), and Generation R (n=1905). We included individuals who had phenotypic and genetic data available. We investigated single nucleotide polymorphism heritability and genetic correlations among different subtypes, operationalisations, and reports of childhood maltreatment. Family-based and population-based polygenic score analyses were done to elucidate gene-environment correlation mechanisms. We used genetic correlation and Mendelian randomisation analyses to identify shared genetics and test causal relationships between childhood maltreatment and mental and physical health conditions. FINDINGS: Our meta-analysis of genome-wide association studies (N=185 414) identified 14 independent loci associated with childhood maltreatment (13 novel). We identified high genetic overlap (genetic correlations 0·24-1·00) among different maltreatment operationalisations, subtypes, and reporting methods. Within-family analyses provided some support for active and reactive gene-environment correlation but did not show the absence of passive gene-environment correlation. Robust Mendelian randomisation 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 concentration). INTERPRETATION: Childhood maltreatment has a heritable component, with substantial genetic correlations among different operationalisations, subtypes, and retrospective and prospective reports of childhood maltreatment. Family-based analyses point to a role of active and reactive gene-environment correlation, with equivocal support for passive correlation. Mendelian randomisation 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 Medical Research Council, Horizon 2020, National Institute of Mental Health, and National Institute for Health Research Biomedical Research Centre.

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  • Evidence of a causal effect of maltreatment in childhood on the risk of major depression was found in a recent GWAS meta-analysis using Mendelian Randomisation.

    “Evidence of a causal effect of maltreatment in childhood on the risk of major depression was also found in a recent genome-wide association study (GWAS) meta-analysis using Mendelian Randomisation (Warrier et al., 2021).”

    From Stressful life events increase the risk of major depressive episodes: A population-based twin study (2023) · cites this paper as Warrier et al., 2021

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  1. [2]Gilbert R Widom CS Browne K Fergusson D Webb E Janson S Burden and consequences of child maltreatment in high-income countries Lancet 373 2009 68 81 19056114
  2. [6]Pezzoli P Antfolk J Hatoum AS Santtila P Genetic vulnerability to experiencing child maltreatment Front Genet 10 2019 852 31608106 PMC6758596
  3. [7]Fisher HL Caspi A Moffitt TE Measuring adolescents' exposure to victimization: the environmental risk (E-Risk) longitudinal twin study Dev Psychopathol 27 2015 1399 1416 26535933 PMC4778729
  4. [8]Pittner K Bakermans-Kranenburg MJ Alink LRA Estimating the heritability of experiencing child maltreatment in an extended family design Child Maltreat 25 2020 289 299 31773993 PMC7370654
  5. [9]Dalvie S Maihofer AX Coleman JRI Genomic influences on self-reported childhood maltreatment Transl Psychiatry 10 2020 38 32066696 PMC7026037
  6. [10]Knafo A Jaffee SR Gene-environment correlation in developmental psychopathology Dev Psychopathol 25 2013 1 6 23398748
  7. [11]Jaffee SR Price TS Gene-environment correlations: a review of the evidence and implications for prevention of mental illness Mol Psychiatry 12 2007 432 442 17453060 PMC3703541
  8. [12]Plomin R DeFries JC Loehlin JC Genotype-environment interaction and correlation in the analysis of human behavior Psychol Bull 84 1977 309 322 557211
  9. [13]Griffiths LJ Wolke D Page AS Horwood JP Obesity and bullying: different effects for boys and girls Arch Dis Child 91 2006 121 125 16174642 PMC2082670
  10. [14]Sanderud K Murphy S Elklit A Child maltreatment and ADHD symptoms in a sample of young adults Eur J Psychotraumatol 7 2016 32061 PMC4910305 27306866
  11. [15]Warrier V Baron-Cohen S Childhood trauma, life-time self-harm, and suicidal behaviour and ideation are associated with polygenic scores for autism Mol Psychiatry 2019 published online Oct 29. 10.1038/s41380-019-0550-x PMC8159746 31659270 · DOI
  12. [16]Croft J Heron J Teufel C Association of trauma type, age of exposure, and frequency in childhood and adolescence with psychotic experiences in early adulthood JAMA Psychiatry 76 2019 79 86 30477014 PMC6490231
  13. [18]Shields ME Hovdestad WE Pelletier C Dykxhoorn JL O'Donnell SC Tonmyr L Childhood maltreatment as a risk factor for diabetes: findings from a population-based survey of Canadian adults BMC Public Health 16 2016 879 27557933 PMC4997676
  14. [19]Suglia SF Koenen KC Boynton-Jarrett R Childhood and adolescent adversity and cardiometabolic outcomes: a scientific statement from the American Heart Association Circulation 137 2018 e15 e28 29254928 PMC7792566
  15. [20]Jackson Y McGuire A Tunno AM Makanui PK A reasonably large review of operationalization in child maltreatment research: assessment approaches and sources of information in youth samples Child Abuse Negl 87 2019 5 17 30392993
  16. [21]Clemens V Huber-Lang M Plener PL Brähler E Brown RC Fegert JM Association of child maltreatment subtypes and long-term physical health in a German representative sample Eur J Psychotraumatol 9 2018 1510278 PMC6136347 30220980
  17. [23]South SC Schafer MH Ferraro KF Genetic and environmental overlap between childhood maltreatment and adult physical health Twin Res Hum Genet 18 2015 533 544 26379062 PMC6058311
  18. [24]Schaefer JD Moffitt TE Arseneault L Adolescent victimization and early-adult psychopathology: approaching causal inference using a longitudinal twin study to rule out noncausal explanations Clin Psychol Sci 6 2018 352 371 29805917 PMC5952301
  19. [25]Brown RC Berenz EC Aggen SH Trauma exposure and axis I psychopathology: a co-twin control analysis in Norwegian young adults Psychol Trauma 6 2014 652 660 25544868 PMC4276315
  20. [26]Davey Smith G Hemani G Mendelian randomization: genetic anchors for causal inference in epidemiological studies Hum Mol Genet 23 2014 R89 R98 25064373 PMC4170722
  21. [28]Sudlow C Gallacher J Allen N UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age PLoS Med 12 2015 e1001779 PMC4380465 25826379
  22. [29]Casey BJ Cannonier T Conley MI The Adolescent Brain Cognitive Development (ABCD) study: imaging acquisition across 21 sites Dev Cogn Neurosci 32 2018 43 54 29567376 PMC5999559
  23. [30]Fraser A Macdonald-Wallis C Tilling K Cohort profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort Int J Epidemiol 42 2013 97 110 22507742 PMC3600619
  24. [31]Boyd A Golding J Macleod J Cohort profile: the ‘children of the 90s’—the index offspring of the Avon Longitudinal Study of Parents and Children Int J Epidemiol 42 2013 111 127 22507743 PMC3600618
  25. [32]Hofman A Jaddoe VWV Mackenbach JP Growth, development and health from early fetal life until young adulthood: the Generation R Study Paediatr Perinat Epidemiol 18 2004 61 72 14738548
  26. [34]Glaesmer H Schulz A Häuser W Freyberger HJ Brähler E Grabe H-J Der Childhood Trauma Screener (CTS) - Entwicklung und Validierung von Schwellenwerten zur Klassifikation Psychiatr Prax 40 2013 220 226 (in German). 23564353
  27. [35]Geller B Zimerman B Williams M Reliability of the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia (WASH-U-KSADS) mania and rapid cycling sections J Am Acad Child Adolesc Psychiatry 40 2001 450 455 11314571
  28. [36]Schaefer ES Children's reports of parental behavior: an inventory Child Dev 36 1965 413 424 14300862
  29. [37]Dunn EC Nishimi K Neumann A Time-dependent effects of exposure to physical and sexual violence on psychopathology symptoms in late childhood: in search of sensitive periods in development J Am Acad Child Adolesc Psychiatry 59 2020 283 295 31078631 PMC7448802
  30. [38]Loh P-R Kichaev G Gazal S Schoech AP Price AL Mixed-model association for biobank-scale datasets Nat Genet 50 2018 906 908 29892013 PMC6309610
  31. [39]Jiang L Zheng Z Qi T A resource-efficient tool for mixed model association analysis of large-scale data Nat Genet 51 2019 1749 1755 31768069
  32. [40]Purcell S Neale B Todd-Brown K PLINK: a tool set for whole-genome association and population-based linkage analyses Am J Hum Genet 81 2007 559 575 17701901 PMC1950838
  33. [43]Delaneau O Marchini J McVean GA Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel Nat Commun 5 2014 3934 PMC4338501 25653097
  34. [44]Lonsdale J Thomas J Salvatore M The Genotype-Tissue Expression (GTEx) project Nat Genet 45 2013 580 585 23715323 PMC4010069
  35. [46]Hoffman GE Bendl J Voloudakis G CommonMind Consortium provides transcriptomic and epigenomic data for schizophrenia and bipolar disorder Sci Data 6 2019 180 31551426 PMC6760149
  36. [47]Akbarian S Liu C Knowles JA The PsychENCODE project Nat Neurosci 18 2015 1707 1712 26605881 PMC4675669
  37. [48]Watanabe K Taskesen E van Bochoven A Posthuma D Functional mapping and annotation of genetic associations with FUMA Nat Commun 8 2017 1826 PMC5705698 29184056
  38. [49]de Leeuw CA Mooij JM Heskes T Posthuma D MAGMA: generalized gene-set analysis of GWAS data PLoS Comput Biol 11 2015 e1004219 PMC4401657 25885710
  39. [50]Finucane HK Reshef YA Anttila V Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types Nat Genet 50 2018 621 629 29632380 PMC5896795
  40. [51]Bernstein BE Birney E Dunham I Green ED Gunter C Snyder M An integrated encyclopedia of DNA elements in the human genome Nature 489 2012 57 74 22955616 PMC3439153
  41. [53]Yang J Lee SH Goddard ME Visscher PM GCTA: a tool for genome-wide complex trait analysis Am J Hum Genet 88 2011 76 82 21167468 PMC3014363
  42. [54]Bulik-Sullivan B Finucane HK Anttila V An atlas of genetic correlations across human diseases and traits Nat Genet 47 2015 1236 1241 26414676 PMC4797329
  43. [55]Choi SW O'Reilly PF PRSice-2: Polygenic Risk Score software for biobank-scale data Gigascience 8 2019 giz082 PMC6629542 31307061
  44. [56]Choi SW Mak TSH O'Reilly PF Tutorial: a guide to performing polygenic risk score analyses Nat Protoc 15 2020 2759 2772 32709988 PMC7612115
  45. [57]Riglin L Collishaw S Richards A Schizophrenia risk alleles and neurodevelopmental outcomes in childhood: a population-based cohort study Lancet Psychiatry 4 2017 57 62 27932233
  46. [59]Demange PA Hottenga JJ Abdellaoui A Parental influences on offspring education: indirect genetic effects of non-cognitive skills bioRxiv 2020 published online Sept 16. 10.1101/2020.09.15.296236 (preprint). · DOI
  47. [60]Weiner DJ Wigdor EM Ripke S Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders Nat Genet 49 2017 978 985 28504703 PMC5552240
  48. [61]Fischbach GD Lord C The Simons Simplex Collection: a resource for identification of autism genetic risk factors Neuron 68 2010 192 195 20955926
  49. [62]Feliciano P Daniels AM Snyder LG SPARK: a US cohort of 50,000 families to accelerate autism research Neuron 97 2018 488 493 29420931 PMC7444276
  50. [63]Slob EAW Burgess S A comparison of robust Mendelian randomization methods using summary data Genet Epidemiol 44 2020 313 329 32249995 PMC7317850
  51. [64]Byrne EM Yang J Wray NR Inference in psychiatry via 2-sample Mendelian randomization-from association to causal pathway? JAMA Psychiatry 74 2017 1191 1192 29094155
  52. [66]Wray NR Ripke S Mattheisen M Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression Nat Genet 50 2018 668 681 29700475 PMC5934326
  53. [67]Stahl EA Breen G Forstner AJ Genome-wide association study identifies 30 loci associated with bipolar disorder Nat Genet 51 2019 793 803 31043756 PMC6956732
  54. [68]Demontis D Walters RK Martin J Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder Nat Genet 51 2019 63 75 30478444 PMC6481311
  55. [71]Morris AP Voight BF Teslovich TM Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes Nat Genet 44 2012 981 990 22885922 PMC3442244
  56. [72]Wojcik GL Graff M Nishimura KK Genetic analyses of diverse populations improves discovery for complex traits Nature 570 2019 514 518 31217584 PMC6785182
  57. [73]Burgess S Davies NM Thompson SG Bias due to participant overlap in two-sample Mendelian randomization Genet Epidemiol 40 2016 597 608 27625185 PMC5082560
  58. [77]Hill WD Hagenaars SP Marioni RE Molecular genetic contributions to social deprivation and household income in UK Biobank Curr Biol 26 2016 3083 3089 27818178 PMC5130721
  59. [78]Sunley AK Lok A White MJ Ethnic and sex differences in the association of child maltreatment and depressed mood. The HELIUS study Child Abuse Negl 99 2020 104239 31731139
  60. [80]Cecil CAM Zhang Y Nolte T Childhood maltreatment and DNA methylation: a systematic review Neurosci Biobehav Rev 112 2020 392 409 32081689
  61. [81]Cabeza de Baca T Ellis BJ Early stress, parental motivation, and reproductive decision-making: applications of life history theory to parental behavior Curr Opin Psychol 15 2017 1 6 28813248 PMC5657424
  62. [83]Warrier V Toro R Won H Social and non-social autism symptoms and trait domains are genetically dissociable Commun Biol 2 2019 328 31508503 PMC6722082
  63. [84]Adams MJ Hill WD Howard DM Factors associated with sharing e-mail information and mental health survey participation in large population cohorts Int J Epidemiol 49 2019 410 421 PMC7266553 31263887

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Authors
Warrier, V., Kwong, A. S. F., Luo, M., Dalvie, S., Croft, J., Sallis, H. M., Baldwin, J., Munafò, M. R., Nievergelt, C. M., Grant, A. J., Burgess, S., Moore, T. M., Barzilay, R., McIntosh, A., van IJzendoorn, M. H., & Cecil, C. A. M.
Affiliations
  • University of Cambridge (GB)
  • University of Bristol (GB)
  • Erasmus MC (NL)
  • University of Cape Town (ZA)
  • King's College London (GB)
  • University of California San Diego (US)
  • Children's Hospital of Philadelphia (US)
  • University of Edinburgh (GB)
  • Leiden University Medical Center (NL)
Corresponding author
Warrier, Varun
ORCID
Venue
The Lancet Psychiatry
Publisher
Elsevier BV
Published
2021-05
Volume
8
Issue
5
Pages
373-386
ISSN
2215-0366 (ISSN-L)
DOI
10.1016/s2215-0366(20)30569-1
PMC
PMC8055541
OpenAlex
W3114167483
Cited by
224
References
20
Citations by year
2026: 36 · 2025: 55 · 2024: 45 · 2023: 35 · 2022: 43 · 2021: 9 · 2020: 1
FWCI
4.38
Type
journal article
Language
en
Update notices
erratum (2022-04-01)
Open access
Licence
Locations
  • The Lancet Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
  • Bristol Research (University of Bristol) (acceptedVersion, cc-by)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
  • Apollo
Funders
  • European Research Council (758813 MHINT)
  • University of Bristol (MC_UU_00011/7)
  • ZonMw
  • National Institute of Mental Health (R01MH106595)
  • St Catharine's College, University of Cambridge
  • National Institute for Health and Care Research
  • NIHR Cambridge Biomedical Research Centre
  • Royal Society (K23MH120437, R01MH117014)
  • Center of Excellence for Stress and Mental Health
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (024.001.003)
  • Medical Research Council
  • China Scholarship Council (201706990036)
  • Economic and Social Research Council (ES/V011650/1)
  • Erasmus Universiteit Rotterdam
  • Wellcome Trust (214322/Z/18/Z)
  • Ministerie van Volksgezondheid, Welzijn en Sport
  • H2020 Marie Skłodowska-Curie Actions (707404, 848158)
  • Erasmus Medisch Centrum
Topics
  • Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Social Sciences › Safety Research › Child Welfare and Adoption
Keywords
child abuse, gene-environment correlation, genetic correlation, polygenic risk score, Mendelian randomization, depression, schizophrenia, attention deficit hyperactivity disorder, physical health, coronary artery disease, type 2 diabetes, C-reactive protein, inflammation, heritability, genetic loci, mental health
MeSH terms
Adolescent, Adult, Aged, Aged, 80 and over, Mental Disorders, Europe, Female, United Kingdom, Humans, Longitudinal Studies, Male, Mental Health, Middle Aged, Retrospective Studies, Databases, Factual, Adult Survivors of Child Abuse, Genome-Wide Association Study, Young Adult, Gene-Environment Interaction

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