Whole exome sequencing analysis of inter‐participant cortisol response: strategies for matching phenotype to genotype (983.1)

Abstract

The overarching goal of this project is to identify genetic variants that are indicative of an individual’s systemic and intracellular responses to corticosteroids. We previously observed inter‐participant variability in cortisol and nuclear hsp90 concentrations following exposure to mild cardiovascular stress, which could not be attributed to demographic or lifestyle characteristics or to single nucleotide polymorphisms (SNPs) in the glucocorticoid receptor, hsp90, or CRHR1 genes. We conducted whole exome sequencing of matched participant pairs who displayed similar demographic and lifestyle characteristics yet possessed distinct cortisol response phenotypes. Using an Agilent V4 exome enrichment platform and Illumina HiSeq2000 paired end (2 x 100 bp) sequencing, >44 million reads per sample were aligned to the hg19 reference build. This analysis resulted in average 30x coverage and combined analysis of >440,000 base pair variants. We developed a bioinformatics analysis pipeline to compare datasets of matched participant samples to one another and against the NHLBI dataset of >6,500 sequenced exomes. Filtering identified candidate causal variants associated with the phenotypic difference in cortisol response. These genes, which have the potential to impact corticosteroid‐mediated signaling and pharmacotherapy, are now being investigated for functional significance.Grant Funding Source: Supported by NIH AREA grant GM086822