Whole Exome Sequencing Analysis Is an Efficient Method for Comprehensively Evaluating Genetic Variability Associated with Interparticipant Response to Glucocorticoid Receptor‐Mediated Signaling

Abstract

The goal of this study was to identify correlations between interpersonal genetic variability and alterations in the intracellular glucocorticoid receptor (GR) signaling response to mild cardiovascular stress. Circulating cortisol concentrations in healthy volunteers varied significantly among participants, both before and after HPA axis stimulation. These differences could not be correlated with biobehavioral survey responses or targeted Sanger sequencing of genes encoding the GR, hsp90, or CRHR1. We consequently hypothesized that whole exome sequencing (WES) would provide a feasible approach for determining variability among phenotypic groups and revealing causal gene candidates that had not been previously considered. WES was conducted using genomic DNA from four participants, one showing the canonical high cortisol response and three showing an enigmatic negative response. Using an Agilent V4 exome enrichment platform and Illumina HiSeq2000 paired end sequencing, >44 million reads per sample were aligned to the hg19 reference build. Comparative analysis of opposing phenotypes showed a variance profile of mutations associated with the negative cortisol response that warrant further investigation. We predict that the statistically significant genetic variants shared among negative cortisol responders may be associated with critical changes in the GR‐mediated signaling pathway and alter a patient's response to stress and glucocorticoid‐based pharmacotherapies.