Genomewide <scp>DNA</scp> methylation analysis in combat veterans reveals a novel locus for <scp>PTSD</scp>

Mehta, Divya; Bruenig, Dagmar; Carrillo-Roa, Tania; Lawford, Bruce R.; Harvey, Wendy; Morris, Charles P.; Smith, Alicia K.; Binder, Elisabeth B.; Young, Ross McD.; Voisey, Joanne

doi:10.1111/acps.12778

Cited by 61 publications

(59 citation statements)

References 83 publications

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“…Some of the current human EWAS that have examined mDNA alterations in PTSD are summarized in Table 2. EWAS are listed in chronological order (2010–2017) [54•, 55, 56, 57•, 58, 59•, 60, 61]. The sites with differential mDNA together with the nearest gene are reported.…”

Section: Large-scale Genetic and Epigenetic Discovery Studiesmentioning

confidence: 99%

Recent Genetics and Epigenetics Approaches to PTSD

Daskalakis

Rijal

King

et al. 2018

Curr Psychiatry Rep

103

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A substantial portion of the variance explaining differential risk responses to trauma exposure may be explained by differential inherited and acquired genetic and epigenetic risk. This biological risk is complemented by alterations in the functional regulation of genes via environmentally induced epigenetic changes, including prior childhood and adult trauma exposure. This review will cover recent findings from large-scale genome-wide association studies as well as newer epigenome-wide studies. We will also discuss future "phenome-wide" studies utilizing electronic medical records as well as targeted genetic studies focusing on mechanistic ways in which specific genetic or epigenetic alterations regulate the biological risk for PTSD.

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Section: Large-scale Genetic and Epigenetic Discovery Studiesmentioning

confidence: 99%

Recent Genetics and Epigenetics Approaches to PTSD

Daskalakis

Rijal

King

et al. 2018

Curr Psychiatry Rep

103

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“…See reference for details. 142 Potentially traumatic events were identified using Criterion A event. The Clinician Administered PTSD Scale for DSM 5 (CAPS-5) was used to assess PTSD over the prior 2 weeks and lifetime by clinical psychologists.…”

Section: Gmrf-qut (Gmfr; Supplementary Table 1 #55)mentioning

confidence: 99%

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

Nievergelt

Klengel

et al. 2018

Preprint

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Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson's Disease gene, PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.Comparability of PGC2 studies PGC2 compiled the largest collection of global PTSD GWAS to date, with subjects recruited from both clinically deeply characterized, small patient groups and large cohorts with self-reported PTSD symptoms. We did not restrict the type of trauma subjects were exposed to, and trauma included both civilian and/or military events, often with pre-existing exposure to childhood trauma. To evaluate the comparability of these phenotypically heterogeneous studies we first estimated genetic correlations with LDSC, 15 a method that leverages GWAS summary results, the only data type available to PGC-PTSD for several of the larger military and non-US cohorts. We found significant genetic correlations (r g ) between studies using a cross-validation approach including all PGC2 EUA subjects (10 runs with studies randomly placed into 2 groups; mean r g = 0.56, mean SE = 0.23, mean p = 0.029, Supplementary Table 8).Next, additional analyses on the UK Biobank cohort (UKBB) were performed. This cohort comprises a very large proportion of the data, with almost as many EUA cases as the rest of the EUA PGC2 combined (referred to as PGC1.5). PTSD screening in UKBB was based on self-reported symptoms from a mental health survey. 16 We found a considerable genetic correlation between the UKBB and PGC1.5 EUA subjects (r g = 0.73, SE = 0.21, p = 0.0005; Supplementary Table 9). Further, sensitivity analyses in the UKBB using 3 alternative inclusion criteria for PTSD cases and controls showed stable correlations with PGC1.5 (P1 -P3; r g = 0.72 -0.79; Supplementary Table 10). Subsequent analyses were based on the UKBB phenotype including the largest number of subjects (P1; N = 126,188). Sex-stratified genetic correlations support the findings of a significant genetic signal...

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“…Genetic studies of posttraumatic stress disorder (PTSD) diatheses conducted to date have focused primarily on identifying DNA variants (e.g., single-nucleotide polymorphisms, SNPs) that confer risk for the development of the disorder through candidate gene or genome-wide association studies (GWASs; see, e.g., [1,2]). More recently, studies have also examined differences between PTSD cases and controls in patterns of gene expression [3] and/or DNA methylation (DNAm [4][5][6];). DNAm studies involve measurement of a methyl group on the DNA strand at a cytosine-phosphate-guanine (CpG) site, and when this is present in the promoter region of a gene, DNAm tends to be negatively correlated with the expression of the gene.…”

Section: Introductionmentioning

confidence: 99%

“…First, using a DNAm bead chip that interrogated~27K loci in a sample of 100 subjects from an urban community cohort, Smith et al (2011) reported false discovery rate (FDR)-corrected differences between PTSD cases and controls at loci in 5 genes (ACP5, ANXA2, CLEC9A, TLR8, and TPR) [4]. Second, in a study that used a more comprehensive platform measuring methylation at~850K loci in samples from 96 Australian Vietnam veterans, Mehta et al (2017) found genome-wide significant associations between DNAm and PTSD in four genes (BRSK1, DOCK2, LCN8, and NGF) and in one intergenic locus [5]. Rutten et al (2018) examined pre-to post-deployment changes in DNAm in a cohort of 93 soldiers using a~450K platform and found 17 loci in or near 8 genes that were associated with increasing PTSD symptoms over time [6].…”

Section: Introductionmentioning

confidence: 99%

“…Many of the EWASs of PTSD have also used Gene Set Enrichment Analysis or Functional Network Analysis of genome-wide DNAm as a follow up to their genome-wide association analyses. Significant enrichment has been observed for a number of pathways/biological processes with plausible relevance to PTSD including, most notably, inflammation and immune function, HPA axis and glucocorticoid signaling, neurogenesis and neurotransmission, circadian rhythms, and cell adhesion [5,6,[18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci

et al. 2020

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Background: Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD). Methods: In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72).

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Genomewide DNA methylation analysis in combat veterans reveals a novel locus for PTSD

Abstract: These data highlight the role of DNA methylation as biomarkers of PTSD. The results support the role of previous candidates and uncover novel genes associated with PTSD, such as DOCK2. This study contributes to our understanding of the biological underpinnings of PTSD.

Cited by 61 publications

References 83 publications

Recent Genetics and Epigenetics Approaches to PTSD

Recent Genetics and Epigenetics Approaches to PTSD

Largest genome-wide association study for PTSD identifies genetic risk loci in European and African ancestries and implicates novel biological pathways

An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci

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