Solberg Leah C, Baum Amber E, Ahmadiyeh Nasim, Shimomura Kazuhiro, Li Renhua, Turek Fred W, Takahashi Joseph S, Churchill Gary A, Redei Eva E
Department of Psychiatry and Behavioral Science, Northwestern University Feinberg School of Medicine, Chicago, USA.
Physiol Genomics. 2006 Nov 27;27(3):362-9. doi: 10.1152/physiolgenomics.00052.2006. Epub 2006 Aug 8.
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) x 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 lineage-dependent 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.
应激反应性下丘脑 - 垂体 - 肾上腺（HPA）轴功能个体差异的潜在遗传成分目前了解甚少。为了确定介导肾上腺皮质功能三个方面的基因座，我们在Wistar Kyoto（WKY）×Fischer 344（F344）杂交的分离F2代中进行了数量性状基因座（QTL）分析，这两种近交大鼠品系在几种HPA轴指标上存在差异。已知肾上腺皮质功能的以下三个组成部分受不同机制调节，这些机制通过下丘脑以上、下丘脑、垂体和肾上腺内的影响介导：基础血浆皮质酮（Cort）水平、血浆Cort对10分钟束缚应激的反应以及肾上腺重量。基因组扫描确定了基础Cort表型的复杂遗传结构，包括性别和母系效应。还确定了该性状的成对相互作用。我们确定了三个应激Cort的显著QTL和两个提示性QTL，以及该性状的两对相互作用基因座。确定了四个肾上腺重量的高度显著基因座和两个提示性基因座，没有相互作用基因座。与基础Cort相反，尽管这些表型存在很大的性别差异，但未确定应激Cort或肾上腺重量的性别或谱系依赖性QTL。我们在映射到应激Cort最显著QTL的一个明显候选基因——皮质类固醇结合球蛋白（CBG）中鉴定出三个核苷酸改变，其中一个已知会改变CBG结合。该分析证实，由HPA轴调节的三个独立性状由多个但主要不重叠的QTL控制。
