In: Twin research and human genetics: the official journal of the International Society for Twin Studies (ISTS) and the Human Genetics Society of Australasia, Band 14, Heft 1, S. 16-24
We explored the comorbidity between panic attacks (PA), whose symptoms can include gastrointestinal discomfort, and gastrointestinal disorders (GD). Structural equation modeling was used to analyze data from 1,874 MZ and 1,498 DZ male–male twin pairs from the Vietnam Era Twin Registry. PA and GD were associated (relative risk for GD = 2). The percentage of liability due to genetic factors was estimated to be 37% for PA and 31% for GD. There was significant correlation between the genetic risk factors for PA and GD (estimated r = .55, 95% CI of 34% to 82%) and no evidence of correlation between the environmental causes of PA and GD. Therefore, PA and GD comorbidity can be explained by overlapping genetic factors and not overlapping environmental factors. Although these data cannot identify a biological pathway for such a shared liability, it suggests the presence of GD may be informative for genetic studies of panic.
The frequent co-occurrence of antisocial behavior and other disinhibited phenotypes reflects a highly heritable externalizing spectrum. We examined the molecular genetic basis of this spectrum by testing polygenic associations with psychopathology symptoms, impulsive traits, and cognitive functions in two samples of primarily military veterans (n =537, n =194). We also investigated whether polygenic risk for externalizing moderated the effects of trauma on these phenotypes. As hypothesized, polygenic risk positively predicted externalizing psychopathology and negatively predicted performance on inhibitory control tasks. Gene-by-environment effects were also evident, with trauma exposure predicting greater impulsivity and less working memory capacity, but only at high levels of genetic liability. As expected, polygenic risk was not associated with internalizing psychopathology or episodic memory performance. This is the first independent replication of the polygenic score as a measure of genetic predispositions for externalizing and provides preliminary evidence that executive dysfunction is a heritable vulnerability for externalizing psychopathology.
BackgroundResearch on the etiology of post-traumatic stress disorder (PTSD) has rapidly matured, moving from candidate gene studies to interrogation of the entire human genome in genome-wide association studies (GWAS). Here we present the results of a GWAS performed on samples from combat-exposed U.S. Marines and Sailors from the Marine Resiliency Study (MRS) scheduled for deployment to Iraq and/or Afghanistan. The MRS is a large, prospective study with longitudinal follow-up designed to identify risk and resiliency factors for combat-induced stress-related symptoms. Previously implicated PTSD risk loci from the literature and polygenic risk scores across psychiatric disorders were also evaluated in the MRS cohort.MethodsParticipants (N=3494) were assessed using the Clinician-Administered PTSD Scale and diagnosed using the DSM-IV diagnostic criterion. Subjects with partial and/or full PTSD diagnosis were called cases, all other subjects were designated controls, and study-wide maximum CAPS scores were used for longitudinal assessments. Genomic DNA was genotyped on the Illumina HumanOmniExpressExome array. Individual genetic ancestry was determined by supervised cluster analysis for subjects of European, African, Hispanic/Native American, and other descent. To test for association of SNPs with PTSD, logistic regressions were performed within each ancestry group and results were combined in meta-analyses. Measures of childhood and adult trauma were included to test for gene-by-environment (GxE) interactions. Polygenic risk scores from the Psychiatric Genomic Consortium were used for major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SCZ).ResultsThe array produced >800K directly genotyped and >21M imputed markers in 3494 unrelated, trauma-exposed males, of which 940 were diagnosed with partial or full PTSD. The GWAS meta-analysis identified the phosphoribosyl transferase domain containing 1 gene (PRTFDC1) as a genome-wide significant PTSD locus (rs6482463; OR=1.47, SE=0.06, p=2.04×10(-9)), with a similar effect across ancestry groups. Association of PRTFDC1 with PTSD in an independent military cohort showed some evidence for replication. Loci with suggestive evidence of association (n=25 genes, p<5×10(-6)) further implicated genes related to immune response and the ubiquitin system, but these findings remain to be replicated in larger GWASs. A replication analysis of 25 putative PTSD genes from the literature found nominally significant SNPs for the majority of these genes, but associations did not remain significant after correction for multiple comparison. A cross-disorder analysis of polygenic risk scores from GWASs of BPD, MDD, and SCZ found that PTSD diagnosis was associated with risk sores of BPD, but not with MDD or SCZ.ConclusionsThis first multi-ethnic/racial GWAS of PTSD highlights the potential to increase power through meta-analyses across ancestry groups. We found evidence for PRTFDC1 as a potential novel PTSD gene, a finding that awaits further replication. Our findings indicate that the genetic architecture of PTSD may be determined by many SNPs with small effects, and overlap with other neuropsychiatric disorders, consistent with current findings from large GWAS of other psychiatric disorders.
BackgroundResearch on the etiology of post-traumatic stress disorder (PTSD) has rapidly matured, moving from candidate gene studies to interrogation of the entire human genome in genome-wide association studies (GWAS). Here we present the results of a GWAS performed on samples from combat-exposed U.S. Marines and Sailors from the Marine Resiliency Study (MRS) scheduled for deployment to Iraq and/or Afghanistan. The MRS is a large, prospective study with longitudinal follow-up designed to identify risk and resiliency factors for combat-induced stress-related symptoms. Previously implicated PTSD risk loci from the literature and polygenic risk scores across psychiatric disorders were also evaluated in the MRS cohort.MethodsParticipants (N=3494) were assessed using the Clinician-Administered PTSD Scale and diagnosed using the DSM-IV diagnostic criterion. Subjects with partial and/or full PTSD diagnosis were called cases, all other subjects were designated controls, and study-wide maximum CAPS scores were used for longitudinal assessments. Genomic DNA was genotyped on the Illumina HumanOmniExpressExome array. Individual genetic ancestry was determined by supervised cluster analysis for subjects of European, African, Hispanic/Native American, and other descent. To test for association of SNPs with PTSD, logistic regressions were performed within each ancestry group and results were combined in meta-analyses. Measures of childhood and adult trauma were included to test for gene-by-environment (GxE) interactions. Polygenic risk scores from the Psychiatric Genomic Consortium were used for major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SCZ).ResultsThe array produced >800K directly genotyped and >21M imputed markers in 3494 unrelated, trauma-exposed males, of which 940 were diagnosed with partial or full PTSD. The GWAS meta-analysis identified the phosphoribosyl transferase domain containing 1 gene (PRTFDC1) as a genome-wide significant PTSD locus (rs6482463; OR=1.47, SE=0.06, ...
Due to the use of improvised explosive devices, blast exposure and mild traumatic brain injury (mTBI) have become hallmark injuries of the Iraq and Afghanistan wars. Although the mechanisms of the effects of blast on human neurobiology remain active areas of investigation, research suggests that the cerebrovasculature may be particularly vulnerable to blast via molecular processes that impact cerebral blood flow. Given that recent work suggests that blast exposure, even without a subsequent TBI, may have negative consequences on brain structure and function, the current study sought to further understand the effects of blast exposure on perfusion. One hundred and eighty military personnel underwent pseudo-continuous arterial spin labeling (pCASL) imaging and completed diagnostic and clinical interviews. Whole-brain analyses revealed that with an increasing number of total blast exposures, there was significantly increased perfusion in the right middle/superior frontal gyri, supramarginal gyrus, lateral occipital cortex, and posterior cingulate cortex as well as bilateral anterior cingulate cortex, insulae, middle/superior temporal gyri and occipital poles. Examination of other neurotrauma and clinical variables such as close-range blast exposures, mTBI, and PTSD yielded no significant effects. These results raise the possibility that perfusion may be an important neural marker of brain health in blast exposure.
BACKGROUND: Longevity gene klotho (KL) is associated with age-related phenotypes including lifespan, cardiometabolic disorders, cognition, and brain morphology, in part, by conferring protection against inflammation. We hypothesized that the KL/inflammation association might be altered in the presence of psychiatric stress and operate via epigenetic pathways. We examined KL polymorphisms, and their interaction with posttraumatic stress disorder (PTSD) symptoms, in association with KL DNA methylation in blood. We further examined KL DNA methylation as a predictor of longitudinal changes in a peripheral biomarker of inflammation (C-reactive protein; CRP). METHODS: The sample comprised 309 white non-Hispanic military veterans (93.5% male; mean age: 32 years, range: 19-65; 30% PTSD per structured diagnostic interview); 111 were reassessed approximately two years later. RESULTS: Analyses revealed a methylation quantitative trait locus at rs9527025 (C370S, previously implicated in numerous studies of aging) in association with a Cytosine-phosphate-Guanine site (cg00129557; B = −.65, p = 1.29 X 10(−20)), located within a DNase hypersensitivity site in the body of KL. There was also a rs9527025 x PTSD severity interaction (B = .004, p = .035) on methylation at this locus such that the minor allele was associated with reduced cg00129557 methylation in individuals with few or no PTSD symptoms while this effect was attenuated in those with elevated levels of PTSD. Path models revealed that methylation at cg00129557 was inversely associated with CRP over time (B = −.14, p = .005), controlling for baseline CRP. There was also an indirect effect of rs9527025 X PTSD on subsequent CRP via cg00129557 methylation (indirect B = −.002, p = .033). CONCLUSIONS: Results contribute to our understanding of the epigenetic correlates of inflammation in PTSD and suggest that KL methylation may be a mechanism by which KL genotype confers risk vs. resilience to accelerated aging in those experiencing traumatic stress.
Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1 and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.
In: Logue , M W , Miller , M W , Wolf , E J , Huber , B R , Morrison , F G , Zhou , Z , Zheng , Y , Smith , A K , Daskalakis , N P , Ratanatharathorn , A , Uddin , M , Nievergelt , C M , Ashley-Koch , A E , Baker , D G , Beckham , J C , Garrett , M E , Boks , M P , Geuze , E , Grant , G A , Hauser , M A , Kessler , R C , Kimbrel , N A , Maihofer , A X , Marx , C E , Qin , X-J , Risbrough , V B , Rutten , B P F , Stein , M B , Ursano , R J , Vermetten , E , Vinkers , C H , Ware , E B , Stone , A , Schichman , S A , McGlinchey , R E , Milberg , W P , Hayes , J P , Verfaellie , M & Traumatic Stress Brain Study Group 2020 , ' An epigenome-wide association study of posttraumatic stress disorder in US veterans implicates several new DNA methylation loci ' , Clinical epigenetics , vol. 12 , no. 1 , 46 . https://doi.org/10.1186/s13148-020-0820-0
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). Results The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 x 10(-7), p(adj) = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 x 10(-6)), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 x 10(-5), p(adj) = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 x 10(-6), p(adj) = 0.042). Conclusions The cross replication observed in independent cohorts is evidence that ...
Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.
To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.
In: Smith , A K , Ratanatharathorn , A , Maihofer , A X , Naviaux , R K , Aiello , A E , Amstadter , A B , Ashley-Koch , A E , Baker , D G , Beckham , J C , Boks , M P , Bromet , E , Dennis , M , Galea , S , Garrett , M E , Geuze , E , Guffanti , G , Hauser , M A , Katrinli , S , Kilaru , V , Kessler , R C , Kimbrel , N A , Koenen , K C , Kuan , P-F , Li , K , Logue , M W , Lori , A , Luft , B J , Miller , M W , Naviaux , J C , Nugent , N R , Qin , X , Ressler , K J , Risbrough , V B , Rutten , B P F , Stein , M B , Ursano , R J , Vermetten , E , Vinkers , C H , Wang , L , Youssef , N A , Uddin , M , Nievergelt , C M , INTRuST Clinical Consortium , VA Mid-Atlantic MIRECC Workgroup & PGC PTSD Epigenetics Workgroup 2020 , ' Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR ' , Nature Communications , vol. 11 , no. 1 , 5965 . https://doi.org/10.1038/s41467-020-19615-x
Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD. PTSD has been associated with DNA methylation of specific loci in the genome, but studies have been limited by small sample sizes. Here, the authors perform a meta-analysis of DNA methylation data from 10 different cohorts and identify CpGs in AHRR that are associated with PTSD.
To reveal post-traumatic stress disorder (PTSD) genetic risk influences on tissue-specific gene expression, we use brain and non-brain transcriptomic imputation. We impute genetically regulated gene expression (GReX) in 29,539 PTSD cases and 166,145 controls from 70 ancestry-specific cohorts and identify 18 significant GReX-PTSD associations corresponding to specific tissue-gene pairs. The results suggest substantial genetic heterogeneity based on ancestry, cohort type (military versus civilian), and sex. Two study-wide significant PTSD associations are identified in European and military European cohorts; ZNF140 is predicted to be upregulated in whole blood, and SNRNP35 is predicted to be downregulated in dorsolateral prefrontal cortex, respectively. In peripheral leukocytes from 175 marines, the observed PTSD differential gene expression correlates with the predicted differences for these individuals, and deployment stress produces glucocorticoid-regulated expression changes that include downregulation of both ZNF140 and SNRNP35. SNRNP35 knockdown in cells validates its functional role in U12-intron splicing. Finally, exogenous glucocorticoids in mice downregulate prefrontal Snrnp35 expression.
Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.
Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.
In: Smith , A K , Ratanatharathorn , A , Maihofer , A X , Naviaux , R K , Aiello , A E , Amstadter , A B , Ashley-Koch , A E , Baker , D G , Beckham , J C , Boks , M P , Bromet , E , Dennis , M , Galea , S , Garrett , M E , Geuze , E , Guffanti , G , Hauser , M A , Katrinli , S , Kilaru , V , Kessler , R C , Kimbrel , N A , Koenen , K C , Kuan , P F , Li , K , Logue , M W , Lori , A , Luft , B J , Miller , M W , Naviaux , J C , Nugent , N R , Qin , X , Ressler , K J , Risbrough , V B , Rutten , B P F , Stein , M B , Ursano , R J , Vermetten , E , Vinkers , C H , Wang , L , Youssef , N A , Marx , C , Grant , G , Stein , M , Qin , X J , Jain , S , McAllister , T W , Zafonte , R , Lang , A , Coimbra , R , Andaluz , N , Shutter , L , George , M S , Brancu , M , Calhoun , P S , Dedert , E , Elbogen , E B , Fairbank , J A , Hurley , R A , Kilts , J D , Kirby , A , Marx , C E , McDonald , S D , Moore , S D , Morey , R A , Naylor , J C , Rowland , J A , Swinkels , C , Szabo , S T , Taber , K H , Tupler , L A , Van Voorhees , E E , Yoash-Gantz , R E , Basu , A , Brick , L A , Dalvie , S , Daskalakis , N P , Ensink , J B M , Hemmings , S M J , Herringa , R , Ikiyo , S , Koen , N , Kuan , P F , Montalvo-Ortiz , J , Nispeling , D , Pfeiffer , J , Qin , X J , Ressler , K J , Schijven , D , Seedat , S , Shinozaki , G , Sumner , J A , Swart , P , Tyrka , A , Van Zuiden , M , Wani , A , Wolf , E J , Zannas , A , Uddin , M , Nievergelt , C M , INTRuST Clinical Consortium , VA Mid-Atlantic MIRECC Workgroup & PGC PTSD Epigenetics Workgroup 2020 , ' Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR ' , Nature Communications , vol. 11 , no. 1 , 5965 . https://doi.org/10.1038/s41467-020-19615-x
Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.