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 M. J. , 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. ,   PGC-PTSD Epigenetics Workgroup, Alisch Reid S. , Amstadter Ananda B , Armstrong Don , Basu Archana , Bjorklund Nicole L , Chaiyachati Barbara H , Ensink Judith B M , Fleming Leland L , Gelernter Joel , Herringa Ryan J , Jain Sonia , Juvinao-Quintero Diana L , Ketema Elizabeth , Martínez-Magaña José J , Misganaw Burook , Nagamatsu Shiela Tiemi , Nispeling Danny M , Pfeiffer John , Schmahl Christian , Shinozaki Gen , Snijders Clara , Sumner Jennifer A , Swart Patricia C , Tyrka Audrey , van Zuiden Mirjam , Womersley Jaqueline S , Youssef Nagy A , Zheng Yuanchao , Zhu Yiwen , Zillich Lea ,   PsychENCODE PTSD Brainomics Project, Arasappan Dhivya , Berretta Sabina , Bharadwaj Rahul A. , Collado-Torres Leonardo , Chatzinakos Christos , DiPietro Chris P. , Duong Duc M. , Deep-Soboslay Amy , Eagles Nick , Huuki Louise , Hyde Thomas , Iatrou Artemis , Pertea Geo , Ross Deanna , Seyfried Nicholas T. , Shin Joo Heon ,   Traumatic Stress Brain Research Group, Alvarez Victor E. , Benedek David , Che Alicia , Cruz Dianne A. , Davis David A. , Girgenti Matthew J. , Hoffman Ellen , Holtzheimer Paul E. , Kaye Alfred , Krystal John H. , Labadorf Adam T. , Keane Terence M. , McKee Ann , Marx Brian , Noller Crystal , Pierce Meghan , Scott William K. , Schnurr Paula , DiSano Krista , Stein Thor , Williamson Douglas E. , Young Keith A. , Uddin Monica , Nievergelt Caroline M. , Smith Alicia K. , Logue Mark W. 
Published: December 2024

Abstract

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 Illumina HumanMethylation450 or MethylationEPIC (850 K) BeadChips. 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 in AHRR and CDC42BPB. Many of these loci exhibit blood–brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Out of 9 CpGs annotated to a gene expressed in blood, methylation levels at 5 CpGs showed significant correlations with the expression levels of their respective annotated genes.

Conclusions
This study identifies 11 PTSD-associated CpGs and 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.