Institut National de la Santé et de la Recherche Médicale (INSERM), US14-Orphanet, 75014 Paris, France.
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Al-Neelain University, Khartoum 11121, Sudan.
Int J Mol Sci. 2022 Aug 29;23(17):9819. doi: 10.3390/ijms23179819.
The corticotropin-releasing hormone receptor 2 () gene encodes CRHR2, contributing to the hypothalamic-pituitary-adrenal stress response and to hyperglycemia and insulin resistance. mice are hypersensitive to stress, and the locus has been linked to type 2 diabetes and depression. While variants confer risk for mood disorders, MDD, and type 2 diabetes, they have not been investigated in familial T2D and MDD. In 212 Italian families with type 2 diabetes and depression, we tested 17 single nucleotide polymorphisms (SNPs), using two-point parametric-linkage and linkage-disequilibrium (i.e., association) analysis (models: dominant-complete-penetrance-D1, dominant-incomplete-penetrance-D2, recessive-complete-penetrance-R1, recessive-incomplete-penetrance-R2). We detected novel linkage/linkage-disequilibrium/association to/with depression (3 SNPs/D1, 2 SNPs/D2, 3 SNPs/R1, 3 SNPs/R2) and type 2 diabetes (3 SNPs/D1, 2 SNPs/D2, 2 SNPs/R1, 1 SNP/R2). All detected risk variants are novel. Two depression-risk variants within one linkage-disequilibrium block replicate each other. Two independent novel SNPs were comorbid while the most significant conferred either depression- or type 2 diabetes-risk. Although the families were primarily ascertained for type 2 diabetes, depression-risk variants showed higher significance than type 2 diabetes-risk variants, implying has a stronger role in depression-risk than type 2 diabetes-risk. In silico analysis predicted variants' dysfunction. is for the first time linked to/in linkage-disequilibrium/association with depression-type 2 diabetes comorbidity and may underlie the shared genetic pathogenesis via pleiotropy.
促肾上腺皮质激素释放激素受体 2 () 基因编码 CRHR2，有助于下丘脑-垂体-肾上腺应激反应以及高血糖和胰岛素抵抗。CRHR2 敲除小鼠对压力敏感，该基因座与 2 型糖尿病和抑郁症有关。虽然 CRHR2 变体与心境障碍、重度抑郁症和 2 型糖尿病的风险相关，但它们在家族性 2 型糖尿病和重度抑郁症中尚未得到研究。在 212 个有 2 型糖尿病和抑郁症的意大利家族中，我们使用两点参数连锁和连锁不平衡（即关联）分析（模型：显性完全外显-D1、显性不完全外显-D2、隐性完全外显-R1、隐性不完全外显-R2）测试了 17 个单核苷酸多态性 (SNP)。我们检测到与抑郁症（3 个 SNP/D1、2 个 SNP/D2、3 个 SNP/R1、3 个 SNP/R2）和 2 型糖尿病（3 个 SNP/D1、2 个 SNP/D2、2 个 SNP/R1、1 个 SNP/R2）有关的新连锁/连锁不平衡/关联。所有检测到的风险变体都是新的。一个连锁不平衡块内的两个抑郁症风险变体相互复制。两个独立的新 SNP 同时发生共病，而最显著的 SNP 赋予抑郁症或 2 型糖尿病风险。尽管这些家族主要是为 2 型糖尿病而确定的，但抑郁症风险变体的显著性高于 2 型糖尿病风险变体，这意味着 CRHR2 在抑郁症风险中比在 2 型糖尿病风险中发挥更强的作用。计算机分析预测变体的功能障碍。CRHR2 首次与抑郁症-2 型糖尿病共病相关联/处于连锁不平衡/关联中，可能通过多效性导致共同的遗传发病机制。
