Uncovering the Genetic Architecture of Major Depression

There have been several recent studies addressing the genetic architecture of depression. This review serves to take stock of what is known now about the genetics of depression, how it has increased our knowledge and understanding of its mechanisms, and how the information and knowledge can be leveraged to improve the care of people affected. We identify four priorities for how the field of MD genetics research may move forward in future years, namely by increasing the sample sizes available for genome-wide association studies (GWASs), greater inclusion of diverse ancestries and low-income countries, the closer integration of psychiatric genetics with electronic medical records, and the development of the neuroscience toolkit for polygenic disorders. A review by McIntosh et al. takes stock of recent rapid progress in the genetics of depression, how it has increased our mechanistic understanding, and how this information could be used to improve patient care in future

Threshold effects of air pollution and climate change on understory plant communities at forested sites in the eastern United States

Forest understory plant communities in the eastern United States are often diverse and are potentially sensitive to changes in climate and atmospheric inputs of nitrogen caused by air pollution. In recent years, empirical and processed-based mathematical models have been developed to investigate such changes in plant communities. In the study reported here, a robust set of understory vegetation response functions (expressed as version 2 of the Probability of Occurrence of Plant Species model for the United States [US-PROPS v2]) was developed based on observations of forest understory and grassland plant species presence/absence and associated abiotic characteristics derived from spatial datasets. Improvements to the US-PROPS model, relative to version 1, were mostly focused on inclusion of additional input data, development of custom species-level input datasets, and implementation of methods to address uncertainty. We investigated the application of US-PROPS v2 to evaluate the potential impacts of atmospheric nitrogen (N) and sulfur (S) deposition, and climate change on forest ecosystems at three forested sites located in New Hampshire, Virginia, and Tennessee in the eastern United States. Species-level N and S critical loads (CLs) were determined under ambient deposition at all three modeled sites. The lowest species-level CLs of N deposition at each site were between 2 and 11 kg N/ha/yr. Similarly, the lowest CLs of S deposition, based on the predicted soil pH response, were less than 2 kg S/ha/yr among the three sites. Critical load exceedance was found at all three model sites. The New Hampshire site included the largest percentage of species in exceedance. Simulated warming air temperature typically resulted in lower maximum occurrence probability, which contributed to lower CLs of N and S deposition. The US-PROPS v2 model, together with the PROPS-CLF model to derive CL functions, can be used to develop site-specific CLs for understory plants within broad regions of the United States. This study demonstrates that species-level CLs of N and S deposition are spatially variable according to the climate, light availability, and soil characteristics at a given location. Although the species niche models generally performed well in predicting occurrence probability, there remains uncertainty with respect to the accuracy of reported CLs. As such, the specific CLs reported here should be considered as preliminary estimates. Graphical abstrac

Lifetime anxiety disorders in women with bulimia nervosa

We examined the prevalence and ages at onset of additional childhood and adult psychiatric disorders in women with bulimia nervosa and evaluated the differential impact of a mood or anxiety disorder on the presentation of bulimia nervosa. One hundred fourteen women participating in a clinical trial of cognitivebehavioral therapy for bulimia nervosa were assessed at pretreatment with structured diagnostic methodology. Although mood disorders were the most frequently occurring additional psychiatric disorder (75%), 64% experienced an additional anxiety disorder. Age at onset of the anxiety disorders was markedly earlier than age at onset of bulimia nervosa or other comorbid conditions. Stratification of the sample on the presence of a mood or anxiety disorder revealed no differences in the core bulimic symptoms across groups. The presence of a mood disorder was associated with greater body dissatisfaction, lower Global Assessment of Functioning Scales (GAFS) score, more externalizing disorders of childhood, and, as expected, higher Hamilton Depression Rating Scale (HDRS) scores. The presence of an anxiety disorder was related to a history of anorexia nervosa and earlier age at onset of drug or alcohol dependence. Early-onset anxiety disorders are prevalent and may represent one potential pathway to bulimia nervosa

Predictors of 1-year treatment outcome in bulimia nervosa

We examined predictors of outcome 1 year after completion of a randomized clinical trial assessing the additive efficacy of two forms of exposure with response prevention to a core of cognitive-behavioral therapy (CBT) for bulimia nervosa (BN). One hundred one women who met DSM-III-R criteria for BN, and who completed the clinical trial, were available for follow-up at 1 year. Predictor variables were assessed prospectively and partitioned temporally to reflect lifetime history (including personality), pretreatment clinical status, and posttreatment clinical status. Outcome was based on the frequency of hinging and purging in the 3 months before assessment based on carefully constructed lifechart interviews. A series of stepwise logistic regressions were performed to determine independent predictors of 1-year outcome while controlling for treatment received. Demographic variables were unrelated to treatment outcome. A history of obesity was predictive of poor outcome, whereas a history of alcohol dependence decreased the odds of poor outcome. High self-directedness on the Temperament and Character Inventory (TCI) predicted favorable outcome at 1 year, whereas personality disorder symptoms were not predictive. Pretreatment global functioning, bulimia scores on the Eating Disorders Inventory (EDI), and the presence of major depression predicted poor outcome. Posttreatment binging, food restriction, and urges to binge on a cue reactivity assessment predicted poor outcome at 1 year. The character trait of self-directedness is a strong predictor of good outcome for CBT, and methods to enhance this trait may be worthy of investigation. Low global functioning and the presence of major depression at presentation may require additional treatment than focused CBT for BN. Our results argue for treatment goals that include abstinence from binging and restricting and decreases in urges to binge in response to high-risk cues

Curvatures and potential of M-theory in D=4 with fluxes and twist

We give the curvatures of the free differential algebra (FDA) of M--theory compactified to D=4 on a twisted seven--torus with the 4--form flux switched on. Two formulations are given, depending on whether the 1--form field strengths of the scalar fields (originating from the 3--form gauge field $\hat{A}^{(3)}$) are included or not in the FDA. We also give the bosonic equations of motion and discuss at length the scalar potential which emerges in this type of compactifications. For flat groups we show the equivalence of this potential with a dual formulation of the theory which has the full \rE_{7(7)} symmetry.Comment: 14 pages, LaTeX source, typos correcte

Eating Disorders and the Intestinal Microbiota: Mechanisms of Energy Homeostasis and Behavioral Influence

Purpose of Review: We reviewed and evaluated recently published scientific studies that explored the role of the intestinal microbiota in eating disorders. Recent Findings: Studies have demonstrated that the intestinal microbiota is a contributing factor to both host energy homeostasis and behavior—two traits commonly disrupted in patients with eating disorders. To date, intestinal microbiota research in eating disorders has focused solely on anorexia nervosa (AN). Initial studies have reported an atypical intestinal microbial composition in patients with AN compared to healthy controls. However, the impact of these AN-associated microbial communities on host metabolism and behavior remains unknown. Summary: The intriguing pattern of findings in patients with AN encourages further investigation of the intestinal microbiota in eating disorders. Elucidating the specific role(s) of these microbial communities may yield novel ideas for augmenting current clinical therapies to promote weight gain, decrease gastrointestinal distress, and even reduce psychological symptomatology

Chronicity and Sex Affect Genetic Risk Prediction in Schizophrenia

Schizophrenia (SCZ) is a severe mental disorder with immense personal and societal costs; identifying individuals at risk is therefore of utmost importance. Genomic risk profile scores (GRPS) have been shown to significantly predict cases-control status. Making use of a large-population based sample from Sweden, we replicate a previous finding demonstrating that the GRPS is strongly associated with admission frequency and chronicity of SCZ. Furthermore, we were able to show a substantial gap in prediction accuracy between males and females. In sum, our results indicate that prediction accuracy by GRPS depends on clinical and demographic characteristics

Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa

OBJECTIVE: The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. METHOD: Following uniform quality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3,495 anorexia nervosa cases and 10,982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes. RESULTS: Results were obtained for 10,641,224 SNPs and insertion-deletion variants with minor allele frequencies >1% and imputation quality scores >0.6. The h2SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. CONCLUSIONS: Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genome-wide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology

Conference Report: Psychiatric Genomics Consortium Meeting: Pathways to Drugs, London, March 2017

[No abstract available

Daily Changes in Composition and Diversity of the Intestinal Microbiota in Patients with Anorexia Nervosa: A Series of Three Cases

Anorexia nervosa, a severe psychiatric illness, is associated with an intestinal microbial dysbiosis. Individual microbial signatures dominate in healthy samples, even over time and under controlled conditions, but whether microbial markers of the disorder overcome inter-individual variation during the acute stage of illness or renourishment is unknown. We characterized daily changes in the intestinal microbiota in three acutely ill patients with anorexia nervosa over the entire course of hospital-based renourishment and found significant, patient-specific changes in microbial composition and diversity. This preliminary case series suggests that even in a state of pathology, individual microbial signatures persist in accounting for the majority of intestinal microbial variation