Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders

Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain

Competitive strategy in socially entrepreneurial nonprofit organizations: innovation and differentiation

Social entrepreneurship has attracted an increasing volume of research in an attempt to understand the basis of successful value creation aimed at solving social problems. In an effort to advance social entrepreneurship research beyond its current focus on conceptualizing the concept, this article addresses the role of innovation in achieving greater social impact. Using multiple theoretical case studies, this research finds that innovation-based competitive strategies of socially entrepreneurial nonprofit organizations substantially contribute to the achievement of social value. Innovation-based strategies are uniquely characterized by a primary focus on differentiation, with innovations directed at product, process, and system change levels. They tend to actively involve both externally and internally focused learning. Nonprofit organizations' innovation strategies are strongly influenced by their organizational characteristics, in particular the need to build sustainable organizations. The article concludes with implications for theory and practice and directions for further research

A mega-analysis of genome-wide association studies for major depressive disorder

<p>Prior genome-wide association studies (GWAS) of major depressive disorder (MDD) have met with limited success. We sought to increase statistical power to detect disease loci by conducting a GWAS mega-analysis for MDD. In the MDD discovery phase, we analyzed more than 1.2 million autosomal and X chromosome single-nucleotide polymorphisms (SNPs) in 18 759 independent and unrelated subjects of recent European ancestry (9240 MDD cases and 9519 controls). In the MDD replication phase, we evaluated 554 SNPs in independent samples (6783 MDD cases and 50 695 controls). We also conducted a cross-disorder meta-analysis using 819 autosomal SNPs with P</p>