Genetics of Behavior Traits Dependent on Glucocorticoid Receptor Activity – Grtraits

Global crises, such as pandemics and wars, lead to an increase in stress-related mental health problems. Among the most debilitating are depression and chronic anxiety disorders, including post-traumatic stress disorder (PTSD). Current pharmacological treatments for stress-related disorders have limited effectiveness.

Despite decades of research, the biological mechanisms translating stress effects into long-lasting mental health disturbances remain poorly understood. It is known that the physiological response to negative stimuli is controlled by the hypothalamic-pituitary-adrenal (HPA) axis, regulated through the release of glucocorticoids (GCs). The action of GCs is systemic and occurs across various tissues and cell types via the glucocorticoid receptor (GR), a transcription factor coordinating gene expression patterns across organs by activating or repressing specific target genes.

The goal of this project is to map GR-regulated genes to their corresponding biological pathways and link them to the development of stress-induced mental disorders. This will involve analyzing large-scale population datasets, clinical data, and genomic sequences available in the UK Biobank. The project aims to define a multidimensional profile of human traits dependent on GR activity and identify associations between genetic variants in GR-regulated genes and human phenotypic traits across four categories: metabolism, physiology, psychiatry, and pharmacology.

The research will analyze polygenic risk scores for individual behavioral traits and parameters, and will develop a database of GR-dependent gene expression profiles across various human neuronal cell types. The cell model will be based on neuronal and glial cells differentiated from human induced pluripotent stem cells (iPSCs). Identified correlations between GR-regulated genes and human behavioral traits will be validated through functional experiments in iPSC-based models.

Ultimately, the project seeks to define a set of GR-dependent behavioral traits based on the genetic associations and biological functions of GR-regulated genes. The results will provide new insights into the molecular basis of stress-related disorders, such as depression and anxiety, and may pave the way for novel psychoactive compounds targeting previously unexplored molecular pathways.