Previous studies in this lab have investigated the complex interaction between cortisol and its receptor, the glucocorticoid receptor (GR) by exploring the relationship between Cushing’s Syndrome (CS) and metabolic syndrome (MetS). While CS and MetS are phenotypically similar, CS is found in conjunction with elevated cortisol levels, while MetS occurs in the absence of elevated cortisol. We hypothesized that the similar phenotypes are a result of glucocorticoid hypersensitivity mutations in the GR. The lab identified two single-nucleotide polymorphisms (SNPs) in the GR, N363S and Bcl I, which both lead to cortisol hypersensitivity and characterized their prevalence in a population of obese patients.
The scope of the current research has expanded to also explore the relationship between depression and the GR. Studies suggest that mood disorders including bipolar disorder (BD), major depressive disorder (MDD), and unipolar depression result from hypothalamic-pituitary-adrenal (HPA) axis dysregulation, leading to both high and low cortisol levels. Both Cushing’s Syndrome, a result of hypercortisolism, and Addison's disease, a result of hypocortisolism, are partly characterized by neuropsychiatric depressive moods. The Corticosteroid Receptor Hypothesis suggests that depression can be caused by not only by cortisol dysregulation but also by dysfunction of the glucocorticoid receptors. GRs, dependent on serum cortisol or cortisone levels, work in tandem, affecting HPA regulation, due the inhibitory nature of cortisol feedback on the hypothalamus and anterior pituitary.
In addition to the previously studied GR hypersensitivity SNPs, which included Bcl I and N363, two additional GR hypersensitivity polymorphisms (RS296 and RS770), and two GR resistance polymorphisms (TthIII1 and ER/EK) were investigated. The GR polymorphisms were investigated in populations of bariatric patients and Union College students. Based on the results of the allelic frequencies found in the bariatric and student/control populations, we can hypothesize what this same data would look like within a depressed patient population. Improving the understanding of the genotypic causes of HPA axis dysregulation in psychiatric disorders may lead to biomarkers for diagnosis and open new treatment pathways.