Genetic analysis of the stress-responsive adrenocortical axis

Abstract

The underlying genetic components contributing to individual variability in functions of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis are poorly understood. To determine genetic loci mediating three aspects of the adrenocortical function, we conducted a quantitative trait locus (QTL) analysis in the segregating F2 generation of a Wistar Kyoto (WKY) ϫ Fischer 344 (F344) cross, two inbred rat strains that differ in several HPA axis measures. The following three components of adrenocortical function are known to be regulated by different mechanisms that are mediated via suprahypothalamic, hypothalamic, pituitary, and intra-adrenal influences: basal plasma corticosterone (Cort) levels, plasma Cort response to a 10-min restraint stress, and adrenal weight. Genome scans identified a complex genetic architecture for the basal Cort phenotype, including sex and maternal lineage effects. Pairwise interactions were also identified for this trait. We identified three significant and two suggestive QTLs for stress Cort, along with two pairs of interacting loci for this trait. Four highly significant and two suggestive loci were identified for adrenal weight, with no interacting loci. In contrast to basal Cort, no sex-or lineagedependent QTL were identified for stress Cort or adrenal weight, despite the large sex differences in these phenotypes. We identified three nucleotide alterations in an obvious candidate gene mapped to the most significant QTL for stress Cort, Cort-binding globulin (CBG), one of which is known to alter CBG binding. This analysis confirms that three separate traits regulated by the HPA axis are controlled by multiple, but mainly nonoverlapping, QTLs.hypothalamic-pituitary-adrenal axis; corticosterone; quantitative trait loci analysis; Wistar Kyoto rat GENES INVOLVED IN individual variation of hypothalamic-pituitary-adrenal (HPA) axis activity, particularly in regard to disease-causing aspects of chronic stress, are unknown. While acute activation of the HPA axis during stress, "a state of threatened homeostasis," leads to a cascade of physiological and behavioral adaptive responses that increase survival of an organism (e.g., increased arousal, increased respiratory rate, and decreased appetite), chronic stress, which results in constant high levels of circulating glucocorticoids, can lead to pathophysiologies such as depression, diabetes, cardiovascular disease, and hypertension (10). There is a high degree of individual variation in response to both acute and chronic stress, and some individuals will not develop any of the abovementioned diseases when exposed to chronic stress. Family and twin studies have demonstrated that individual variation of HPA axis activity is regulated, at least in part, by genetics (e.g., Refs. 4, 16). Identification of the underlying genetic components, however, is difficult, because HPA axis function is so dependent on the environment.Although molecular techniques have been used to study the stress response (for a review, see Ref. 37), very little is kno...

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