BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype... Show moreBACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods. Show less
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... Show moreEpigenetic 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. Show less
Mei, W.F. van der; Barbano, A.C.; Ratanatharathorn, A.; Bryant, R.A.; Delahanty, D.L.; DeRoon-Cassini, T.A.; ... ; International Consortium to Predict PTSD 2020
The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and... Show moreThe risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations. Show less
Choi, K.W.; Chen, C.Y.; Stein, M.B.; Klimentidis, Y.C.; Wang, M.J.; Koenen, K.C.; ... ; Major Depressive Disorder Working 2019
IMPORTANCE Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and... Show moreIMPORTANCE Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear; physical activity may protect against depression, and/or depression may result in decreased physical activity.OBJECTIVE To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference.DESIGN, SETTING, AND PARTICIPANTS This 2-sample mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes-self- reported (n = 377 234) and objective accelerometer-based (n = 91 084)-and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in diverse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR-Pleiotropy Residual Sum and Outlier [PRESSO]) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018.MAIN OUTCOMES AND MEASURES MDD and physical activity.RESULTS GWAS summary data were available for a combined sample size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio [ OR], 0.74 for MDD per 1-SD increase in mean acceleration; 95% CI, 0.59-0.92; P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (beta = -0.08 in mean acceleration per MDD vs control status; 95% CI, -0.47 to 0.32; P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity; 95% CI, 0.57-3.37; P = .48), or between MDD and self-reported activity (beta = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status; 95% CI, -0.008 to 0.05; P = .15).CONCLUSIONS AND RELEVANCE Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed-but not self-reported-physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression. Show less
