Meta-analysis of longitudinal epigenome-wide association studies of military cohorts reveals multiple CpG sites associated with post-traumatic stress disorder

Abstract

Background: Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts composed of male military members were combined to assess whether DNA methylation profiles are associated with the development of PTSD. Methods: A total of 123 cases and 143 trauma-exposed controls were included. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis. We first combined two cohorts in a discovery stage (N=126 and 78), sought targeted replication in the third cohort (N=62) and then performed a meta-analysis of all three datasets. Results: The discovery stage identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was associated with PTSD status after adjustment for multiple comparisons. The most significant CpG (p = 1.0 x 10 -08 ) was located on 5q31 and replicated in the third cohort. When combining all cohorts, this intergenic site remained most significant along with two CpGs located in MAD1L1 and HEXDC. Interestingly, the CpG site of MAD1L1 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP. Twelve differential methylated regions (DMRs) were also identified, one of which was located in MAD1L1 and four were situated in the human leukocyte antigen (HLA) region. Conclusion: This study suggests that the development of PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent finding points to the involvement of MAD1L1 which was previously associated with PTSD.

Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: A meta-analysis of 23 military and civilian cohorts

“…While prior EWASs of PTSD have reported promising results, the small sample sizes and variability of analysis methods across studies make it difficult to combine and interpret the findings effectively. Recent meta-analyses led by the PGC-PTSD Epigenetics Workgroup minimized these issues by increasing sample size, increasing sample diversity, and using a common quality control and analysis pipeline (29)(30)(31)(32)(33). These meta-analyses identified multiple new loci associated with PTSD, including NRG1, AHRR, MAD1L1, and TBXAS1, implicating immune dysregulation in those with PTSD (30)(31)(32)(33).…”

“…Recent meta-analyses led by the PGC-PTSD Epigenetics Workgroup minimized these issues by increasing sample size, increasing sample diversity, and using a common quality control and analysis pipeline (29)(30)(31)(32)(33). These meta-analyses identified multiple new loci associated with PTSD, including NRG1, AHRR, MAD1L1, and TBXAS1, implicating immune dysregulation in those with PTSD (30)(31)(32)(33).…”