Genetic influences on testosterone and PTSD.

Females are twice as likely to experience PTSD as compared to males. Although sex differences in prevalence are well-established, little is known about why such sex differences occur. Biological factors that vary with sex, including sex hormone production, may contribute to these differences.

Integrative analyses highlight functional regulatory variants associated with neuropsychiatric diseases.

Noncoding variants of presumed regulatory function contribute to the heritability of neuropsychiatric disease. A total of 2,221 noncoding variants connected to risk for ten neuropsychiatric disorders, including autism spectrum disorder, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, major depression, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder and schizophrenia, were studied in developing human neural cells. Integrating epigenomic and transcriptomic data with massively parallel reporter assays identified differentially-active single-nucleotide variants (daSNVs) in specific neural cell types.

Shared genetic influences on depression and menopause symptoms.

Background: Women experience major depression and post-traumatic stress disorder (PTSD) approximately twice as often as men. Estrogen is thought to contribute to sex differences in these disorders, and reduced estrogen is also known to be a key driver of menopause symptoms such as hot flashes. Moreover, estrogen is used to treat menopause symptoms.

Examining Sex-Differentiated Genetic Effects Across Neuropsychiatric and Behavioral Traits.

Background: The origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits.

Methods: Using European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (r < 1).

Analysis of Genetically Regulated Gene Expression Identifies a Prefrontal PTSD Gene, SNRNP35, Specific to Military Cohorts.

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.

Shared molecular genetic risk of alcohol dependence and posttraumatic stress disorder (PTSD).

Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) frequently co-occur, highlighting the importance of understanding the etiology of these comorbid conditions. Although AUD and PTSD are moderately heritable with modest overlap in genetic risk as estimated from family studies, there has been a paucity of work using molecular genetic data to estimate shared genetic effects on these conditions. This study used large-scale genomewide molecular data to examine shared genetic risk for AUD, specifically alcohol dependence (AD), and PTSD through cross-trait linkage disequilibrium (LD) score regression (LDSC; also known as LDSR).

Genomic influences on self-reported childhood maltreatment.

Childhood maltreatment is highly prevalent and serves as a risk factor for mental and physical disorders. Self-reported childhood maltreatment appears heritable, but the specific genetic influences on this phenotype are largely unknown. The aims of this study were to (1) identify genetic variation associated with self-reported childhood maltreatment, (2) estimate SNP-based heritability (h), (3) assess predictive value of polygenic risk scores (PRS) for childhood maltreatment, and (4) quantify genetic overlap of childhood maltreatment with mental and physical health-related phenotypes, and condition the top hits from our analyses when such overlap is present.

Molecular genetic overlap between posttraumatic stress disorder and sleep phenotypes.

Study Objectives: Sleep problems are common, serving as both a predictor and symptom of posttraumatic stress disorder (PTSD), with these bidirectional relationships well established in the literature. While both sleep phenotypes and PTSD are moderately heritable, there has been a paucity of investigation into potential genetic overlap between sleep and PTSD. Here, we estimate genetic correlations between multiple sleep phenotypes (including insomnia symptoms, sleep duration, daytime sleepiness, and chronotype) and PTSD, using results from the largest genome-wide association study (GWAS) to date of PTSD, as well as publicly available GWAS results for sleep phenotypes within UK Biobank data (23 variations, encompassing four main phenotypes).

Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations.

Genome-wide association studies (GWASs) have focused primarily on populations of European descent, but it is essential that diverse populations become better represented. Increasing diversity among study participants will advance our understanding of genetic architecture in all populations and ensure that genetic research is broadly applicable. To facilitate and promote research in multi-ancestry and admixed cohorts, we outline key methodological considerations and highlight opportunities, challenges, solutions, and areas in need of development.

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.

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness, affecting 0.9-4% of women and 0.3% of men, with twin-based heritability estimates of 50-60%.

Correction to: Robust Findings From 25 Years of PTSD Genetics Research.

The original version of this article contained an error in the title. The correct title should read "Robust Findings From 25 Years of PTSD Genetics Research" as shown above. The original article has been corrected.

Robust Findings From 25 Years of PTSD Genetics Research.

Purpose Of Review: The purpose of this review is to contextualize findings from the first 25 years of PTSD genetics research, focusing on the most robust findings and interpreting results in light of principles that have emerged from modern genetics studies.

Recent Findings: Genome-wide association studies (GWAS) encompassing tens of thousands of participants enabled the first molecular genetic heritability and genetic correlation estimates for PTSD in 2017. In 2018, highly promising loci for PTSD were reported, including variants in and near the CAMKV, KANSL1, and TCF4 genes.

Chromosomes to Social Contexts: Sex and Gender Differences in PTSD.

Purpose Of Review: This review highlights recent research on sex- and gender-related factors in the prevalence, symptom expression, and treatment of PTSD. Further discoveries about the underlying mechanisms of sex and gender effects have the potential to shape innovative directions for research.

Recent Findings: The prevalence of PTSD is substantially higher among women, but women show a modest advantage with respect to treatment response.

The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods.

Background: Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research.

Genetic Correlation Profile of Schizophrenia Mirrors Epidemiological Results and Suggests Link Between Polygenic and Rare Variant (22q11.2) Cases of Schizophrenia.

New methods in genetics research, such as linkage disequilibrium score regression (LDSR), quantify overlap in the common genetic variants that influence diverse phenotypes. It is becoming clear that genetic effects often cut across traditional diagnostic boundaries. Here, we introduce genetic correlation analysis (using LDSR) to a nongeneticist audience and report transdisciplinary discoveries about schizophrenia.

Analysis of protein-coding genetic variation in 60,706 humans.

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence.

The evaluation of tools used to predict the impact of missense variants is hindered by two types of circularity.

Prioritizing missense variants for further experimental investigation is a key challenge in current sequencing studies for exploring complex and Mendelian diseases. A large number of in silico tools have been employed for the task of pathogenicity prediction, including PolyPhen-2, SIFT, FatHMM, MutationTaster-2, MutationAssessor, Combined Annotation Dependent Depletion, LRT, phyloP, and GERP++, as well as optimized methods of combining tool scores, such as Condel and Logit. Due to the wealth of these methods, an important practical question to answer is which of these tools generalize best, that is, correctly predict the pathogenic character of new variants.