Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD: A meta-analysis of 23 military and civilian cohorts
Authors: Katrinli Seyma , Wani Agaz H , Maihofer Adam X , Ratanatharathorn Andrew , Daskalakis Nikolaos P , Montalvo-Ortiz Janitza , Núñez-Ríos Diana L , Zannas Anthony S , Zhao Xiang , Aiello Allison E , Ashley-Koch Allison E , Avetyan Diana , Baker Dewleen G , Beckham Jean C , Boks Marco P , Brick Leslie A , Bromet Evelyn , Champagne Frances A , Chen Chia-Yen , Dalvie Shareefa , Dennis Michelle F , Fatumo Segun , Fortier Catherine , Galea Sandro , Garrett Melanie E , Geuze Elbert , Grant Gerald , Hauser Michael A , Hayes Jasmeet P , Hemmings Sian MJ , Huber Bertrand Russel , Jajoo Aarti , Jansen Stefan , Kessler Ronald C , Kimbrel Nathan A , King Anthony P , Kleinman Joel E , Koen Nastassja , Koenen Karestan C , Kuan Pei-Fen , Liberzon Israel , Linnstaedt Sarah D , Lori Adriana , Luft Benjamin J , Luykx Jurjen J , Marx Christine E , McLean Samuel A , Mehta Divya , Milberg William , Miller Mark W , Mufford Mary S , Musanabaganwa Clarisse , Mutabaruka Jean , Mutesa Leon , Nemeroff Charles B , Nugent Nicole R , Orcutt Holly K , Qin Xue-Jun , Rauch Sheila A M , Ressler Kerry J , Risbrough Victoria B , Rutembesa Eugène , Rutten Bart P F , Seedat Soraya , Stein Dan J , Stein Murray B , Toikumo Sylvanus , Ursano Robert J , Uwineza Annette , Verfaellie Mieke H , Vermetten Eric , Vinkers Christiaan H , Ware Erin B , Wildman Derek E , Wolf Erika J , Young Ross McD , Zhao Ying , van den Heuvel Leigh L , Uddin Monica , Nievergelt Caroline M , Smith Alicia K , Logue Mark W ,   PGC-PTSD Epigenetics Workgroup,   PsychENCODE PTSD Brainomics Project,   Traumatic Stress Brain Research Group
Published: July 2024

Background

The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions.

Methods

As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress.

Results

We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 <p< 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs inAHRRandCDC42BPB. Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels.

Conclusions

This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD.