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

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.