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
U, V.; Lai, T.; Bianchin, M.; Remigio, R.P.; Armus, L.; Larson, K.L.; ... ; Surace, J. 2022
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
Rodrigues, M.; Koning, L. de; Coupland, S.E.; Jochemsen, A.G.; Marais, R.; Stern, M.H.; ... ; UM Cure 2020 Consortium 2019
We present the first results of a survey of the [C II]157.7 {$μ$}m emission line in 241 luminous infrared galaxies (LIRGs) comprising the Great Observatories All-sky LIRG Survey (GOALS) sample,... Show moreWe present the first results of a survey of the [C II]157.7 {$μ$}m emission line in 241 luminous infrared galaxies (LIRGs) comprising the Great Observatories All-sky LIRG Survey (GOALS) sample, obtained with the PACS instrument on board the Herschel Space Observatory. The [C II] luminosities, L $_{[C II]}$, of the LIRGs in GOALS range from ~{}10$^{7}$ to 2 { imes} 10$^{9}$ L $_{⊙}$. We find that LIRGs show a tight correlation of [C II]/FIR with far-IR (FIR) flux density ratios, with a strong negative trend spanning from ~{}10$^{-2}$ to 10$^{-4}$, as the average temperature of dust increases. We find correlations between the [C II]/FIR ratio and the strength of the 9.7 {$μ$}m silicate absorption feature as well as with the luminosity surface density of the mid-IR emitting region ({$Sigma$}$_{MIR}$), suggesting that warmer, more compact starbursts have substantially smaller [C II]/FIR ratios. Pure star-forming LIRGs have a mean [C II]/FIR ~{} 4 { imes} 10$^{-3}$, while galaxies with low polycyclic aromatic hydrocarbon (PAH) equivalent widths (EWs), indicative of the presence of active galactic nuclei (AGNs), span the full range in [C II]/FIR. However, we show that even when only pure star-forming galaxies are considered, the [C II]/FIR ratio still drops by an order of magnitude, from 10$^{-2}$ to 10$^{-3}$, with {$Sigma$}$_{MIR}$ and {$Sigma$}$_{IR}$, implying that the [C II]157.7 {$μ$}m luminosity is not a good indicator of the star formation rate (SFR) for most local LIRGs, for it does not scale linearly with the warm dust emission most likely associated to the youngest stars. Moreover, even in LIRGs in which we detect an AGN in the mid-IR, the majority (2/3) of galaxies show [C II]/FIR {gt}= 10$^{-3}$ typical of high 6.2 {$μ$}m PAH EW sources, suggesting that most AGNs do not contribute significantly to the FIR emission. We provide an empirical relation between the [C II]/FIR and the specific SFR for star-forming LIRGs. Finally, we present predictions for the starburst size based on the observed [C II] and FIR luminosities which should be useful for comparing with results from future surveys of high-redshift galaxies with ALMA and CCAT. Show less
Background Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed... Show moreBackground Uncertainties persist about the magnitude of associations of diabetes mellitus and fasting glucose concentration with risk of coronary heart disease and major stroke subtypes. We aimed to quantify these associations for a wide range of circumstances. Methods We undertook a meta-analysis of individual records of diabetes, fasting blood glucose concentration, and other risk factors in people without initial vascular disease from studies in the Emerging Risk Factors Collaboration. We combined within-study regressions that were adjusted for age, sex, smoking, systolic blood pressure, and body-mass index to calculate hazard ratios (HRs) for vascular disease. Findings Analyses included data for 698 782 people (52765 non-fatal or fatal vascular outcomes; 8.49 million person-years at risk) from 102 prospective studies. Adjusted HRs with diabetes were: 2.00 (95% CI 1.83-2.19) for coronary heart disease; 2.27 (1.95-2.65) for ischaemic stroke; 1.56 (1.19-2.05) for haemorrhagic stroke; 1.84 (1.59-2.13) for unclassified stroke; and 1.73 (1.51-1.98) for the aggregate of other vascular deaths. HRs did not change appreciably after further adjustment for lipid, inflammatory, or renal markers. HRs for coronary heart disease were higher in women than in men, at 40-59 years than at 70 years and older, and with fatal than with non-fatal disease. At an adult population-wide prevalence of 10%, diabetes was estimated to account for 11% (10-12%) of vascular deaths. Fasting blood glucose concentration was non-linearly related to vascular risk, with no significant associations between 3.90 mmol/L and 5.59 mmol/L. Compared with fasting blood glucose concentrations of 3.90-5.59 mmol/L, HRs for coronary heart disease were: 1.07 (0.97-1.18) for lower than 3.90 mmol/L; 1.11 (1.04-1.18) for 5.60-6-09 mmol/L; and 1.17 (1.08-1.26) for 6.10-6.99 mmol/L. In people without a history of diabetes, information about fasting blood glucose concentration or impaired fasting glucose status did not significantly improve metrics of vascular disease prediction when added to information about several conventional risk factors. Interpretation Diabetes confers about a two-fold excess risk for a wide range of vascular diseases, independently from other conventional risk factors. In people without diabetes, fasting blood glucose concentration is modestly and nonlinearly associated with risk of vascular disease. Show less
