A genome-wide association study to identify chromosomal regions influencing ovine cortisol response

Stress-induced hypothalamic-pituitary-adrenal axis (HPAA) activation and subsequent glucocorticoid production has a significant impact on behavior, metabolism and immune function in both humans and animals. Therefore, elucidating functional mechanisms that regulate stress-induced glucocorticoid production would benefit the development of alternative and improve existing treatment and management strategies supporting animal health. Animal studies have demonstrated considerable variation in stress-induced cortisol responses, and the phenotype appears to be moderately-to-highly heritable. Therefore, the objective of the current study was to identify key genetic determinants that putatively influence the ovine cortisol response to a bacterial endotoxin-induced stress (BEIS) model. The ovine50K BeadChip containing 54,241 single nucleotide polymorphisms (SNPs) was used to selectively genotype 75 sheep with high (HCR) and low cortisol responses (LCR) (38 HCR and 37 LCR). The selective genotyping approach yielded statistical power equal to roughly 190 randomly genotyped animals. A statistical analysis was performed via a univariate logistic regression model and a total of 16 SNPs were identified to be significantly associated with the cortisol levels in this population. These SNPs were grouped, based on proximity on the same chromosome, into 13 chromosomal regions that harbored 9 ovine RefSeq genes. Although the ovine genome is not well annotated, important genes such as CD14, ITGAM, SNX2 and ITGAL were found to reside within the identified QTLs. A positional candidate gene approach was also used subsequently to identify three novel SNPs in SNX2, and one of these SNPs (ss974768716) was found to be significantly associated with the cortisol response phenotype (p=0.017). A brief description of the ovine BEIS population, statistical analyses and identified genes is presented herein.