TY - UNPB
T1 - Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD
T2 - A meta-analysis of 23 military and civilian cohorts
AU - Katrinli, Seyma
AU - Wani, Agaz H
AU - Maihofer, Adam X
AU - Ratanatharathorn, Andrew
AU - Daskalakis, Nikolaos P
AU - Montalvo-Ortiz, Janitza
AU - Núñez-Ríos, Diana L
AU - Zannas, Anthony S
AU - Zhao, Xiang
AU - Aiello, Allison E
AU - Ashley-Koch, Allison E
AU - Avetyan, Diana
AU - Baker, Dewleen G
AU - Beckham, Jean C
AU - Boks, Marco P
AU - Brick, Leslie A
AU - Bromet, Evelyn
AU - Champagne, Frances A
AU - Chen, Chia-Yen
AU - Dalvie, Shareefa
AU - Dennis, Michelle F
AU - Fatumo, Segun
AU - Fortier, Catherine
AU - Galea, Sandro
AU - Garrett, Melanie E
AU - Geuze, Elbert
AU - Grant, Gerald
AU - Michael A Hauser, null
AU - Hayes, Jasmeet P
AU - Hemmings, Sian Mj
AU - Huber, Bertrand Russel
AU - Jajoo, Aarti
AU - Jansen, Stefan
AU - Kessler, Ronald C
AU - Kimbrel, Nathan A
AU - King, Anthony P
AU - Kleinman, Joel E
AU - Koen, Nastassja
AU - Koenen, Karestan C
AU - Kuan, Pei-Fen
AU - Liberzon, Israel
AU - Linnstaedt, Sarah D
AU - Lori, Adriana
AU - Luft, Benjamin J
AU - Luykx, Jurjen J
AU - Marx, Christine E
AU - McLean, Samuel A
AU - Rutten, Bart P F
AU - Vermetten, Eric
AU - Vinkers, Christiaan H
PY - 2024/7/15
Y1 - 2024/7/15
N2 - 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 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. 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.
AB - 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 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. 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.
U2 - 10.1101/2024.07.15.24310422
DO - 10.1101/2024.07.15.24310422
M3 - Preprint
C2 - 39072012
T3 - medRxiv
BT - Epigenome-wide association studies identify novel DNA methylation sites associated with PTSD
PB - medRxiv
ER -