International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

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 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

Protein-coding variants implicate novel genes related to lipid homeostasis contributing to body-fat distribution.

Body-fat distribution is a risk factor for adverse cardiovascular health consequences. We analyzed the association of body-fat distribution, assessed by waist-to-hip ratio adjusted for body mass index, with 228,985 predicted coding and splice site variants available on exome arrays in up to 344,369 individuals from five major ancestries (discovery) and 132,177 European-ancestry individuals (validation). We identified 15 common (minor allele frequency, MAF ≥5%) and nine low-frequency or rare (MAF <5%) coding novel variants. Pathway/gene set enrichment analyses identified lipid particle, adiponectin, abnormal white adipose tissue physiology and bone development and morphology as important contributors to fat distribution, while cross-trait associations highlight cardiometabolic traits. In functional follow-up analyses, specifically in Drosophila RNAi-knockdowns, we observed a significant increase in the total body triglyceride levels for two genes (DNAH10 and PLXND1). We implicate novel genes in fat distribution, stressing the importance of interrogating low-frequency and protein-coding variants

Epigenomeâ wide association of PTSD from heterogeneous cohorts with a common multiâ site analysis pipeline

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138305/1/ajmgb32568.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138305/2/ajmgb32568_am.pd

Large epigenome-wide association study identifies multiple novel differentially methylated CpG sites associated with suicidal thoughts and behaviors in veterans

Introduction The U.S. suicide mortality rate has steadily increased during the past two decades, particularly among military veterans; however, the epigenetic basis of suicidal thoughts and behaviors (STB) remains largely unknown. Methods To address this issue, we conducted an epigenome-wide association study of DNA methylation (DNAm) of peripheral blood samples obtained from 2,712 U.S. military veterans. Results Three DNAm probes were significantly associated with suicide attempts, surpassing the multiple testing threshold (FDR q-value <0.05), including cg13301722 on chromosome 7, which lies between the genes SLC4A2 and CDK5; cg04724646 in PDE3A; and cg04999352 in RARRES3. cg13301722 was also found to be differentially methylated in the cerebral cortex of suicide decedents in a publicly-available dataset (p = 0.03). Trait enrichment analysis revealed that the CpG sites most strongly associated with STB in the present sample were also associated with smoking, alcohol consumption, maternal smoking, and maternal alcohol consumption, whereas pathway enrichment analysis revealed significant associations with circadian rhythm, adherens junction, insulin secretion, and RAP-1 signaling, each of which was recently associated with suicide attempts in a large, independent genome-wide association study of suicide attempts of veterans. Discussion Taken together, the present findings suggest that SLC4A2, CDK5, PDE3A, and RARRES3 may play a role in STB. CDK5, a member of the cyclin-dependent kinase family that is highly expressed in the brain and essential for learning and memory, appears to be a particularly promising candidate worthy of future study; however, additional work is still needed to replicate these finding in independent samples

Load carriage changes tibiofemoral arthrokinematics during ambulatory tasks in recruit-aged women

The introduction of women into U.S. military ground close combat roles requires research into sex-specific effects of military training and operational activities. Knee osteoarthritis is prevalent among military service members; its progression has been linked to occupational tasks such as load carriage. Analyzing tibiofemoral arthrokinematics during load carriage is important to understand potentially injurious motion and osteoarthritis progression. The study purpose was to identify effects of load carriage on knee arthrokinematics during walking and running in recruit-aged women. Twelve healthy recruit-aged women walked and ran while unloaded (bodyweight [BW]) and carrying additional + 25%BW and + 45%BW. Using dynamic biplane radiography and subject-specific bone models, tibiofemoral arthrokinematics, subchondral joint space and center of closest contact location between subchondral bone surfaces were analyzed over 0–30% stance (separate one-way repeated measures analysis of variance, load by locomotion). While walking, medial compartment contact location was 5% (~ 1.6 mm) more medial for BW than + 45%BW at foot strike (p = 0.03). While running, medial compartment contact location was 4% (~ 1.3 mm) more lateral during BW than + 25%BW at 30% stance (p = 0.04). Internal rotation was greater at + 45%BW compared to + 25%BW (p < 0.01) at 30% stance. Carried load affects tibiofemoral arthrokinematics in recruit-aged women. Prolonged load carriage could increase the risk of degenerative joint injury in physically active women

Methamphetamine and Viagra Use: Relationship to Sexual Risk Behaviors

Recent studies show that Viagra and methamphetamine use are associated with unprotected anal intercourse among men who have sex with men (MSM). In Long Beach, California, we have reported on an association between Viagra use and the use of amphetamines during sex. The current research investigated the use of both Viagra and amphetamine in men in Long Beach, California. Data on 1,839 men recruited into HIV prevention and testing programs were collected using the Risk Behavior Assessment. A generalized logit model was constructed comparing ever having used both amphetamine and Viagra together and separately, as compared to never having used either (referent). Men who used both methamphetamine and Viagra showed a significantly higher prevalence of hepatitis B, syphilis, and HIV compared to those who used only one or neither drug. Of the 1,794 complete cases, 11.1% (199/1794) had used both amphetamine and Viagra. Of 20 potential risk and protective factors for use of amphetamine and Viagra, 12 were significant predictors: ever used gamma-hydroxybutyrate (GHB), ever used cocaine, ever used ecstasy, being infected with HIV, race = White compared to other, ever having hepatitis B, ever using crack, ever given money to have sex, living in a hotel, ever been in drug treatment, and ever using heroin. The protective factor was being heterosexual. Viagra use was associated with insertive, and methamphetamine was associated with receptive, anal intercourse. GHB use appears to play a more important role than previously thought

Military maladaptation : counterinsurgency and the politics of failure

Tactical learning is critical to battlefield success, especially in a counterinsurgency. This article tests the existing model of military adaption against a ‘most-likely’ case: the British Army’s counterinsurgency in the Southern Cameroons (1960–61). Despite meeting all preconditions thought to enable adaptation – decentralization, leadership turnover, supportive leadership, poor organizational memory, feedback loops, and a clear threat – the British still failed to adapt. Archival evidence suggests politicians subverted bottom-up adaptation, because winning came at too high a price in terms of Britain’s broader strategic imperatives. Our finding identifies an important gap in the extant adaptation literature: it ignores politics.PostprintPeer reviewe

Gemini Observations of Galaxies in Rich Early Environments (GOGREEN) I : survey description

We describe a new Large Program in progress on the Gemini North and South telescopes: Gemini Observations of Galaxies in Rich Early Environments (GOGREEN). This is an imaging and deep spectroscopic survey of 21 galaxy systems at 1 10 in halo mass. The scientific objectives include measuring the role of environment in the evolution of low-mass galaxies, and measuring the dynamics and stellar contents of their host haloes. The targets are selected from the SpARCS, SPT, COSMOS, and SXDS surveys, to be the evolutionary counterparts of today's clusters and groups. The new red-sensitive Hamamatsu detectors on GMOS, coupled with the nod-and-shuffle sky subtraction, allow simultaneous wavelength coverage over lambda similar to 0.6-1.05 mu m, and this enables a homogeneous and statistically complete redshift survey of galaxies of all types. The spectroscopic sample targets galaxies with AB magnitudes z' <24.25 and [3.6] mu m <22.5, and is therefore statistically complete for stellar masses M* greater than or similar to 10(10.3) M-circle dot, for all galaxy types and over the entire redshift range. Deep, multiwavelength imaging has been acquired over larger fields for most systems, spanning u through K, in addition to deep IRAC imaging at 3.6 mu m. The spectroscopy is similar to 50 per cent complete as of semester 17A, and we anticipate a final sample of similar to 500 new cluster members. Combined with existing spectroscopy on the brighter galaxies from GCLASS, SPT, and other sources, GOGREEN will be a large legacy cluster and field galaxy sample at this redshift that spectroscopically covers a wide range in stellar mass, halo mass, and clustercentric radius.Peer reviewe

Evaluation of the efficacy and safety of olanzapine as an adjunctive treatment for anorexia nervosa in adolescent females: a randomized, double-blind, placebo-controlled trial

<p>Abstract</p> <p>Background</p> <p>Anorexia Nervosa (AN) is a serious, debilitating condition that causes significant physical, emotional, and functional impairment. The condition is characterized by destructive weight loss behaviours and a refusal to maintain body weight at or above a minimally normal weight for age and height. AN often develops in adolescence and is a predominantly female disorder. Treatment for AN typically involves medical, nutritional and psychological interventions. Pharmacotherapy is also often used; however, the literature on the effectiveness of these drugs in a pediatric population is very limited. Olanzapine, which is an 'atypical' antipsychotic, is becoming more widespread in the treatment of AN. Olanzapine is hypothesized to facilitate weight gain, while decreasing levels of agitation and decreasing resistance to treatment in young women with AN. This randomized, double-blind placebo-controlled trial seeks to examine the effectiveness and safety of olanzapine in female youth with AN.</p> <p>Methods/Design</p> <p>Adolescent females between the ages of 12 and 17 diagnosed with AN (either restricting or binge/purge type) or Eating Disorder Not Otherwise Specified with a Body Mass Index of less than or equal to 17.5, will be offered inclusion in the study. Patients will be randomly assigned to receive either olanzapine or placebo. Patients assigned to receive olanzapine will start at a low dose of 1.25 mg/day for three days, followed by 2.5 mg/day for four days, 5 mg/day for one week, then 7.5 mg/day (the target dose chosen) for 10 weeks. After 10 weeks at 7.5 mg the medication will be tapered and discontinued over a period of two weeks. The effectiveness of olanzapine versus placebo will be determined by investigating the change from baseline on measures of eating attitudes and behaviors, depression and anxiety, and change in Body Mass Index at week 12, and after a follow-up period at week 40. It is anticipated that 67 participants will be recruited over two years to complete enrollment.</p> <p>Discussion</p> <p>Randomized controlled trials designed to measure the safety and effectiveness of olanzapine in comparison to placebo are desperately needed, particularly in the adolescent population.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN23032339</p

Protective Unfolded Protein Response in Human Pancreatic Beta Cells Transplanted into Mice

Background: There is great interest about the possible contribution of ER stress to the apoptosis of pancreatic beta cells in the diabetic state and with islet transplantation. Methods and Findings: Expression of genes involved in ER stress were examined in beta cell enriched tissue obtained with laser capture microdissection (LCM) from frozen sections of pancreases obtained from non-diabetic subjects at surgery and from human islets transplanted into ICR-SCID mice for 4 wk. Because mice have higher glucose levels than humans, the transplanted beta cells were exposed to mild hyperglycemia and the abnormal environment of the transplant site. RNA was extracted from the LCM specimens, amplified and then subjected to microarray analysis. The transplanted beta cells showed an unfolded protein response (UPR). There was activation of many genes of the IRE-1 pathway that provide protection against the deleterious effects of ER stress, increased expression of ER chaperones and ERAD (ER-associated protein degradation) proteins. The other two arms of ER stress, PERK and ATF-6, had many down regulated genes. Downregulation of EIF2A could protect by inhibiting protein synthesis. Two genes known to contribute to apoptosis, CHOP and JNK, were downregulated. Conclusions: Human beta cells in a transplant site had UPR changes in gene expression that protect against the proapoptotic effects of unfolded proteins