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Genetic approach uncovering the pathways between childhood maltreatment and suicide attempt

Molecular Psychiatry volume 30, pages 3857–3867 (2025)Cite this article

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Abstract

Childhood maltreatment significantly heightens the risk of suicide attempt, but the causal mechanisms and underlying pathways are not fully understood. Using genetic instruments for both childhood maltreatment (n = 185,414) and suicide attempt (cases = 29,782; controls = 519,961), we performed two-sample Mendelian randomization analyses. Our results show that higher level of childhood maltreatment is causally associated with an increased risk of suicide attempt (OR = 3.40; 95% CI, 2.34–4.96, P = 1.3e–10). We then conducted a two-step Mendelian randomization mediation analysis, identifying 11 out of 58 potential mediators between childhood maltreatment and suicide attempt. These mediators included neurobiological, psychopathological and behavioral factors. The psychopathological factors had the most significant impact, accounting for 10.4–50.2% the mediation. This study confirms the causal relationship between childhood maltreatment and suicide attempt, highlighting specific mediators-especially within the psychopathological dimension-that can guide targeted interventions to alleviate the adverse effects of childhood maltreatment and prevent suicide attempt.

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Fig. 1: Overview of the study design.
Fig. 2: This figure summarizes the genetic analyses linking childhood maltreatment (CM) and suicide attempt (SA) through pleiotropic genes.
Fig. 3: This figure illustrates the mediation analysis of childhood maltreatment (CM) on suicide attempt (SA) through four domains: neurobiological, physical, psychopathological, and behavioral factors.
Fig. 4: This figure illustrates the mediation analysis of childhood maltreatment (CM) on suicide attempt (SA) through brain, psychological, and behavioral factors.

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Data availability

The GWAS summary statistics for suicide attempt were provided by the International Suicide Genetics Consortium (https://tinyurl.com/ISGC2021). The GWASs for childhood maltreatment can be obtained from the datasets of University of Cambridge (https://www.repository.cam.ac.uk/bitstreams/e3447890-98db-4409-ba95-470fb7fc341a/download). The GWASs for anxiaty disorder and stress-related disorders are publicly available at iPSYCH (https://ipsych.dk/en/research/downloads), and GWASs for other mental disorders can be downloaded from the PGC (https://www.med.unc.edu/pgc). The GWASs for BMI and WHR can be obtained from the GIANT (http://www.broadinstitute.org/collaboration/giant/index.php/GIANT_consortium). The GWASs for Coronary Artery Disease can be obtained from the CARDIoGRAMplusC4D Consortium (https://www.cardiogramplusc4d.org/). The GWASs for Type 2 diabetes can be obtained from the Program in Complex Trait Genomics (https://cnsgenomics.com). The GWAS dataset for lung cancer is from University of Bristol and can be downloaded from the IEU Open GWASs database (https://GWASs.mrcieu.ac.uk/datasets/ieu-b-4954/). Other GWAS datasets for potential mediators about physical health can be downloaded through the NHGRI-EBI GWASs Catalog (https://www.ebi.ac.uk/GWASs). The GWASs for risk tolerance, number of sexual partner, and relative intake of carbohydrate, fat, protein and sugar can be obtained through the SSGAC data portal (https://www.thessgac.org/). The GWASs for overall sleep duration, short sleep duration and long sleep duration are available at the Sleep Disorder Knowledge Portal (https://sleep.hugeamp.org/). The GWASs for weekly alcohol consumption, daily cigarette consumption and smoking initiation was downloaded from the GSCAN (https://genome.psych.umn.edu/index.php/GSCAN), and the GWASs for lifetime smoking was downloaded from the datasets of University of Bristol (https://data.bris.ac.uk/data/dataset/10i96zb8gm0j81yz0q6ztei23d). The GWASs for cannabis use were provided by the International Cannabis Consortium (https://www.ru.nl/bsi/research/group-pages-0/substance-use-addiction-food-saf/vm-saf/genetics/international-cannabis-consortium). The GWASs for subcortical brain structures are available from the CHARGE dbGaP (accession code: phs000930) and ENIGMA (https://enigma.ini.usc.edu/research/download-enigma-GWASs-results/).

Code availability

All the MR analyses were conducted using R packages TwoSampleMR (version 0.6.3), MRPRESSO (version 1.0) and MRlap (version 0.0.3.0) in R software (version 4.2.2). Custom code that sup ports the findings of this study is available at https://github.com/azhangxu/CM_SA_causal_relationship.

References

  1. Knipe D, Padmanathan P, Newton-Howes G, Chan LF, Kapur N. Suicide and self-harm. Lancet. 2022;399:1903–16.

    Article  PubMed  Google Scholar 

  2. Naghavi M. Global, regional, and national burden of suicide mortality 1990 to 2016: systematic analysis for the Global Burden of Disease Study 2016. BMJ. 2019;364:l94.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Angelakis I, Austin JL, Gooding P. Association of childhood maltreatment with suicide behaviors among young people: a systematic review and meta-analysis. JAMA Netw Open. 2020;3:e2012563.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Cay M, Gonzalez-Heydrich J, Teicher MH, van der Heijden H, Ongur D, Shinn AK, et al. Childhood maltreatment and its role in the development of pain and psychopathology. Lancet Child Adolesc Health. 2022;6:195–206.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sekula P, Del Greco MF, Pattaro C, Köttgen A. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol. 2016;27:3253.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Rytilä-Manninen M, Haravuori H, Fröjd S, Marttunen M, Lindberg N. Mediators between adverse childhood experiences and suicidality. Child Abuse Negl. 2018;77:99–109.

    Article  PubMed  Google Scholar 

  7. Bahk Y-C, Jang S-K, Choi K-H, Lee S-H. The relationship between childhood trauma and suicidal ideation: role of maltreatment and potential mediators. Psychiatry Investig. 2017;14:37–43.

    Article  PubMed  Google Scholar 

  8. Perez NM, Jennings WG, Piquero AR, Baglivio MT. Adverse childhood experiences and suicide attempts: the mediating influence of personality development and problem behaviors. J Youth Adolesc. 2016;45:1527–45.

    Article  PubMed  Google Scholar 

  9. Ammerman BA, Serang S, Jacobucci R, Burke TA, Alloy LB, McCloskey MS. Exploratory analysis of mediators of the relationship between childhood maltreatment and suicidal behavior. J Adolesc. 2018;69:103–12.

    Article  PubMed  Google Scholar 

  10. Lippard ETC, Nemeroff CB. Going beyond risk factor: Childhood maltreatment and associated modifiable targets to improve life-long outcomes in mood disorders. Pharmacol Biochem Behav. 2022;215:173361.

    Article  PubMed  CAS  Google Scholar 

  11. Sachs-Ericsson NJ, Rushing NC, Stanley IH, Sheffler J. In my end is my beginning: developmental trajectories of adverse childhood experiences to late-life suicide. Aging Ment Health. 2016;20:139–65.

    Article  PubMed  Google Scholar 

  12. Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40:304–14.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Carter AR, Sanderson E, Hammerton G, Richmond RC, Davey Smith G, Heron J, et al. Mendelian randomisation for mediation analysis: current methods and challenges for implementation. Eur J Epidemiol. 2021;36:465–78.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37:658–65.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Duprey EB, Handley ED, Wyman PA, Ross AJ, Cerulli C, Oshri A. Child maltreatment and youth suicide risk: a developmental conceptual model and implications for suicide prevention. Dev Psychopathol. 2023;35:1732–55.

    Article  PubMed  Google Scholar 

  16. Angelakis I, Gillespie EL, Panagioti M. Childhood maltreatment and adult suicidality: a comprehensive systematic review with meta-analysis. Psychol Med. 2019;49:1057–78.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Warrier V, Kwong ASF, Luo M, Dalvie S, Croft J, Sallis HM, et al. Gene-environment correlations and causal effects of childhood maltreatment on physical and mental health: a genetically informed approach. Lancet Psychiatry. 2021;8:373–86.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Mullins N, Kang J, Campos AI, Coleman JRI, Edwards AC, Galfalvy H, et al. Dissecting the shared genetic architecture of suicide attempt, psychiatric disorders, and known risk factors. Biol Psychiatry. 2022;91:313–27.

    Article  PubMed  Google Scholar 

  19. Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife. 2018;7:e34408.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Burgess S, Thompson SG, CRP CHD Genetics Collaboration. Avoiding bias from weak instruments in Mendelian randomization studies. Int J Epidemiol. 2011;40:755–64.

    Article  PubMed  Google Scholar 

  21. Tian D, Zhang L, Zhuang Z, Huang T, Fan D. A two-sample Mendelian randomization analysis of modifiable risk factors and intracranial aneurysms. Sci Rep. 2022;12:7659.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Skrivankova VW, Richmond RC, Woolf BAR, Davies NM, Swanson SA, VanderWeele TJ, et al. Strengthening the reporting of observational studies in epidemiology using mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ. 2021;375:n2233.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Burgess S, Scott RA, Timpson NJ, Davey Smith G, Thompson SG, EPIC- InterAct Consortium. Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol. 2015;30:543–52.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Hemani G, Bowden J, Davey Smith G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet. 2018;27:R195–R208.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44:512–25.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017;46:1985–98.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Verbanck M, Chen C-Y, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50:693–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Zhang Z, Wang L, Shigemasu K, Okada A, Imaizumi T, Hoshino T. Methods for evaluating mediation effects: rationale and comparison. N Trends Psychom. 2008:595–604.

  29. Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, Loh P-R, et al. An atlas of genetic correlations across human diseases and traits. Nat Genet. 2015;47:1236–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Ray D, Chatterjee N. A powerful method for pleiotropic analysis under composite null hypothesis identifies novel shared loci between type 2 diabetes and prostate cancer. PLoS Genet. 2020;16:e1009218.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Watanabe K, Taskesen E, van Bochoven A, Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nat Commun. 2017;8:1826.

    Article  PubMed  PubMed Central  Google Scholar 

  32. de Leeuw CA, Mooij JM, Heskes T, Posthuma D. MAGMA: generalized gene-set analysis of GWAS data. PLoS Comput Biol. 2015;11:e1004219.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Favril L, Yu R, Uyar A, Sharpe M, Fazel S. Risk factors for suicide in adults: systematic review and meta-analysis of psychological autopsy studies. Evid Based Ment Health. 2022;25:148–55.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Tomoda A, Nishitani S, Takiguchi S, Fujisawa TX, Sugiyama T, Teicher MH. The neurobiological effects of childhood maltreatment on brain structure, function, and attachment. Eur Arch Psychiatry Clin Neurosci. https://doi.org/10.1007/s00406-024-01779-y 2024.

  35. Chen C, Chen W, Zhang B. Functional alterations of the suicidal brain: a coordinate-based meta-analysis of functional imaging studies. Brain Imaging Behav. 2022;16:291–304.

    Article  PubMed  Google Scholar 

  36. Arsalidou M, Vijayarajah S, Sharaev M. Basal ganglia lateralization in different types of reward. Brain Imaging Behav. 2020;14:2618–46.

    Article  PubMed  Google Scholar 

  37. Schmaal L, van Harmelen A-L, Chatzi V, Lippard ETC, Toenders YJ, Averill LA, et al. Imaging suicidal thoughts and behaviors: a comprehensive review of 2 decades of neuroimaging studies. Mol Psychiatry. 2020;25:408–27.

    Article  PubMed  Google Scholar 

  38. Katikireddi SV, Green MJ, Taylor AE, Davey Smith G, Munafò MR. Assessing causal relationships using genetic proxies for exposures: an introduction to Mendelian randomization. Addict Abingdon Engl. 2018;113:764–74.

    Article  Google Scholar 

  39. Smith GD. Ebrahim S. Mendelian randomization: prospects, potentials, and limitations. Int J Epidemiol. 2004;33:30–42.

    Article  PubMed  Google Scholar 

  40. Debat V, David P. Mapping phenotypes: canalization, plasticity and developmental stability. Trends Ecol Evol. 2001;16:555–61.

    Article  Google Scholar 

  41. Burgess S, Daniel RM, Butterworth AS, Thompson SG, the EPIC-InterAct Consortium. Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. Int J Epidemiol. 2015;44:484–95.

    Article  PubMed  Google Scholar 

  42. McCarthy-Jones S, McCarthy-Jones R. Body mass index and anxiety/depression as mediators of the effects of child sexual and physical abuse on physical health disorders in women. Child Abuse Negl. 2014;38:2007–20.

    Article  PubMed  Google Scholar 

  43. Lu D, Fall K, Sparén P, Ye W, Adami H-O, Valdimarsdóttir U, et al. Suicide and suicide attempt after a cancer diagnosis among young individuals. Ann Oncol. 2013;24:3112–7.

    Article  PubMed  CAS  Google Scholar 

  44. Brunton R, Dryer R Theoretical perspectives of child abuse. In: Brunton R, Dryer R, editors. Perinatal care and considerations for survivors of child abuse challenges and opportunities, Cham: Springer International Publishing; 2023. pp. 29–48.

  45. Yao K, Chen P, Zhou H, Ruan J, Chen D, Yang X, et al. The effect of childhood trauma on suicide risk: the chain mediating effects of resilience and mental distress. BMC Psychiatry. 2023;23:865.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Chen Y-J, Lu M-L, Chiu Y-H, Chen C, Santos VHJ, Goh KK. Linking childhood trauma to the psychopathology of schizophrenia: the role of oxytocin. Schizophrenia. 2024;10:1–11.

    Article  CAS  Google Scholar 

  47. Balazs J, Kereszteny A. Attention-deficit/hyperactivity disorder and suicide: a systematic review. World J Psychiatry. 2017;7:44–59.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Linnér RK, Biroli P, Kong E, Meddens SFW, Wedow R, Fontana MA, et al. Genome-wide association analyses of risk tolerance and risky behaviors in over one million individuals identify hundreds of loci and shared genetic influences. Nat Genet. 2019;51:245–57.

    Article  PubMed Central  Google Scholar 

  49. Zheng Q, Feng Y, Du J, Xu S, Ma Z, Wang Y. Specific effects of cumulative childhood trauma on suicidality among youths. J Affect Disord. 2024;358:260–9.

    Article  PubMed  Google Scholar 

  50. Peng C, Wang M, Cheng J, Tan Y, Huang Y, Rong F, et al. Mediation of Internet addiction on association between childhood maltreatment and suicidal behaviours among Chinese adolescents. Epidemiol Psychiatr Sci. 2021;30:e64.

    Article  PubMed Central  Google Scholar 

  51. Miller AB, Adams LM, Esposito-Smythers C, Thompson R, Proctor LJ. Parents and friendships: a longitudinal examination of interpersonal mediators of the relationship between child maltreatment and suicidal ideation. Psychiatry Res. 2014;220:998–1006.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the International Suicide Genetics Consortium that shared its summary statistics with us. Dr Diayng Qu received support from Tsinghua “Shuimu” project.

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Author notes

  1. These authors contributed equally: Diyang Qu, Xu Zhang, Yuhao He.

Authors and Affiliations

  1. Vanke School of Public Health, Tsinghua University, Beijing, China

    Diyang Qu, Yuhao He, Chang Lei, Junkang Lin, Tongtong Cai & Runsen Chen

  2. Chongqing Clinical Research Center for Reproductive Medicine, Women and Children’s Hospital of Chongqing Medical University, No. 64 Jintang Road, Yuzhong District, Chongqing, 400013, China

    Xu Zhang

  3. Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China

    Yuanxia Han & Yize Mao

  4. Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China. Chongqing Specialized Medical Research Center of Ovarian Cancer, Chongqing, China

    Xueping Zhu

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Contributions

DQ, YH, and RC designed the study, DQ, XZ, YM, and RC led the writing of the protocol and revisions. XZ, YH and YM developed the data analysis plan, conducted the analysis, and interpreted the results. RC supervise the study. All the authors (DQ, XZ, YH, CL, YH, JL, TC, XZ, YM, RC) were all involved in the conduct of the study and revised the paper critically for content and approved the final version.

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Correspondence to Xueping Zhu, Yize Mao or Runsen Chen.

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Qu, D., Zhang, X., He, Y. et al. Genetic approach uncovering the pathways between childhood maltreatment and suicide attempt. Mol Psychiatry 30, 3857–3867 (2025). https://doi.org/10.1038/s41380-025-02966-6

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