Applied Molecular Genomics Group, Department of Molecular Genetics, VIB, Belgium.
Bipolar Disord. 2011 Nov-Dec;13(7-8):614-23. doi: 10.1111/j.1399-5618.2011.00960.x.
Dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis is one of the most consistent findings in the pathophysiology of mood disorders. The potential role of genes related to HPA axis function has been investigated extensively in major depression. However, in bipolar disorder (BPD) such studies are scarce. We performed a systematic HapMap-based association study of six genes crucial for HPA axis function in relation to BPD.
Haplotype tagging single nucleotide polymorphisms (htSNPs) were selected in order to identify all haplotypes with a frequency of more than 1% in the genes encoding the glucocorticoid receptor (GR), mineralocorticoid receptor (MR), corticotrophin releasing hormone receptor 1 (CRH-R1) and 2 (CRH-R2), CRH binding protein (CRH-BP), and FK binding protein 5 (FKBP5). This resulted in a total selection of 225 SNPs that were genotyped and analyzed in 309 BPD patients and 364 matched control individuals all originating from an isolated northern Swedish population.
Consistent evidence for an association with BPD was found for NR3C1, the gene encoding GR. Almost all SNPs in two adjacent haplotype blocks contributed to the positive signal, comprised of significant single marker, sliding window, and haplotype-specific p-values. All these results point to a moderately frequent (10-15%) susceptibility haplotype covering the entire coding region and 3' untranslated region (UTR) of NR3C1.
This study contributes to the growing evidence for a role of the glucocorticoid receptor gene (NR3C1) in vulnerability to mood disorders, and BPD in particular, and warrants further in vitro investigation of the at-risk haplotypes with respect to disease etiology. However, this association might be restricted to this specific population, as it is observed in a rather small sample from an isolated population without replication, and data from large meta-analyses for genome-wide association studies in BPD do not show the GR as a very strong candidate.
下丘脑-垂体-肾上腺（HPA）轴功能障碍是心境障碍病理生理学中最一致的发现之一。与 HPA 轴功能相关的基因的潜在作用已在重度抑郁症中得到广泛研究。然而，在双相情感障碍（BPD）中，此类研究很少。我们进行了一项基于 HapMap 的系统关联研究，研究了与 BPD 相关的六个对 HPA 轴功能至关重要的基因。
选择单核苷酸多态性（htSNP）进行单体型标记，以鉴定编码糖皮质激素受体（GR）、盐皮质激素受体（MR）、促肾上腺皮质激素释放激素受体 1（CRH-R1）和 2（CRH-R2）、促肾上腺皮质激素释放激素结合蛋白（CRH-BP）和 FK 结合蛋白 5（FKBP5）的基因中频率超过 1%的所有单体型。这总共选择了 225 个 SNP，对来自瑞典北部一个孤立人群的 309 名 BPD 患者和 364 名匹配对照个体进行了基因分型和分析。
与 BPD 相关的证据一致，与编码 GR 的 NR3C1 基因相关。两个相邻单体型块中的几乎所有 SNP 都为阳性信号做出了贡献，包括显著的单标记、滑动窗口和单体型特异性 p 值。所有这些结果都指向一个中等频率（10-15%）的易感单体型，覆盖 NR3C1 的整个编码区和 3'非翻译区（UTR）。
这项研究为糖皮质激素受体基因（NR3C1）在易感性情绪障碍、特别是 BPD 中的作用提供了更多证据，并进一步需要对风险单体型进行体外研究，以了解疾病的病因。然而，由于该关联仅在一个相对较小的、来自孤立人群的样本中观察到，且 BPD 的全基因组关联研究的大型荟萃分析数据并未显示 GR 是一个非常强的候选基因，因此该关联可能仅限于该特定人群。
