How can childhood maltreatment affect post-traumatic stress disorder in adult: Results from a composite null hypothesis perspective of mediation analysis

Haibo Xu; Zhonghe Shao; Shuo Zhang; Xin Liu; Ping Zeng

doi:10.3389/fpsyt.2023.1102811

How can childhood maltreatment affect post-traumatic stress disorder in adult: Results from a composite null hypothesis perspective of mediation analysis

Front Psychiatry. 2023 Mar 9:14:1102811. doi: 10.3389/fpsyt.2023.1102811. eCollection 2023.

Authors

Haibo Xu^{1

2}, Zhonghe Shao³, Shuo Zhang⁴, Xin Liu^{1

2}, Ping Zeng^{4

5

6

7}

Affiliations

¹ Center for Mental Health Education and Research, Xuzhou Medical University, Xuzhou, China.
² School of Management, Xuzhou Medical University, Xuzhou, China.
³ Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Department of Biostatistics, School of Public Health, Xuzhou Medical University, Xuzhou, China.
⁵ Center for Medical Statistics and Data Analysis, Xuzhou Medical University, Xuzhou, Jiangsu, China.
⁶ Key Laboratory of Human Genetics and Environmental Medicine, Xuzhou Medical University, Xuzhou, Jiangsu, China.
⁷ Key Laboratory of Environment and Health, Xuzhou Medical University, Xuzhou, Jiangsu, China.

Abstract

Background: A greatly growing body of literature has revealed the mediating role of DNA methylation in the influence path from childhood maltreatment to psychiatric disorders such as post-traumatic stress disorder (PTSD) in adult. However, the statistical method is challenging and powerful mediation analyses regarding this issue are lacking.

Methods: To study how the maltreatment in childhood alters long-lasting DNA methylation changes which further affect PTSD in adult, we here carried out a gene-based mediation analysis from a perspective of composite null hypothesis in the Grady Trauma Project (352 participants and 16,565 genes) with childhood maltreatment as exposure, multiple DNA methylation sites as mediators, and PTSD or its relevant scores as outcome. We effectively addressed the challenging issue of gene-based mediation analysis by taking its composite null hypothesis testing nature into consideration and fitting a weighted test statistic.

Results: We discovered that childhood maltreatment could substantially affected PTSD or PTSD-related scores, and that childhood maltreatment was associated with DNA methylation which further had significant roles in PTSD and these scores. Furthermore, using the proposed mediation method, we identified multiple genes within which DNA methylation sites exhibited mediating roles in the influence path from childhood maltreatment to PTSD-relevant scores in adult, with 13 for Beck Depression Inventory and 6 for modified PTSD Symptom Scale, respectively.

Conclusion: Our results have the potential to confer meaningful insights into the biological mechanism for the impact of early adverse experience on adult diseases; and our proposed mediation methods can be applied to other similar analysis settings.

Keywords: DNA methylation; childhood maltreatment; divide-aggregate composite-null hypothesis test; gene-based mediation analysis; psychiatric disorder.

Grants and funding

This research of PZ was supported in part by the National Natural Science Foundation of China (82173630 and 81402765), the Youth Foundation of Humanity and Social Science Funded by Ministry of Education of China (18YJC910002), the Natural Science Foundation of Jiangsu Province of China (BK20181472), the China Postdoctoral Science Foundation (2018M630607 and 2019T120465), the Qinglan Research Project of Jiangsu Province for Young and Middle-Aged Academic Leaders, the Six-Talent Peaks Project in Jiangsu Province of China (WSN-087), the Training Project for Youth Teams of Science and Technology Innovation at Xuzhou Medical University (TD202008), the Postdoctoral Science Foundation of Xuzhou Medical University, and the Statistical Science Research Project from National Bureau of Statistics of China (2014LY112). This research of HX was also supported by the Industry-University Collaborative Education Project of the Higher Education Department of MOE (202101085008), the Special Subject Key Project Jiangsu Higher Education of Jiangsu Higher Education Association (2022JSGJKT008), and Xuzhou Social Development Key R&D Plan (KC21306). This research of SZ was supported by Postgraduate Research and Practice Innovation Program of Jiangsu Province (KYCX22_2960). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.