Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function
Meta-analysis of two genome-wide association studies identifies four genetic loci associated with thyroid function
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DOI：
10.1093/hmg/dds136
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发表时间：
2012-07-15
影响因子：
3.5
通讯作者：
Homuth, Georg
中科院分区：
文献类型：
--
作者：
Rawal, Rajesh;Teumer, Alexander;Homuth, Georg
甲状腺激素在细胞生长、发育和代谢中发挥着关键作用。尽管遗传对甲状腺激素水平有很强的影响，但所涉及的基因却广为人知。循环甲状腺激素的水平受到促甲状腺素 (TSH) 的严格调节，促甲状腺素也是甲状腺功能最重要的诊断标志物。因此，为了确定与 TSH 水平相关的遗传位点，我们对两项全基因组关联研究进行了发现性荟萃分析，其中包括来自德国的两个队列 KORA (n 1287) 和 SHIP (n 2449)，总样本量为 3736。位于 5q13.3、1p36、16q23 和 4q31 的四个遗传位点与血清 TSH 水平相关。这四个基因座的主要单核苷酸多态性位于编码磷酸二酯酶8B的PDE8B内、编码带刺端F-肌动蛋白结合蛋白的亚基的CAPZB上游、位于最近被证明编码与甲状腺体积相关的功能基因(LOC440389)的前基因荒漠中、以及编码盐皮质激素受体的NR3C2上游。后一种关联首次表明盐皮质激素对甲状腺功能的调节。所有四个位点均在另外三个队列中重复：来自挪威的 HUNT 研究 (n 1487) 和两项德国研究 CARLA (CARLA, n 1357) 和 SHIP-TREND (n 883)。这四个数量性状位点合计约占 TSH 血清水平方差的 3.3 倍。这些结果有助于我们了解介导甲状腺功能的遗传因素和生理机制。
Thyroid hormones play key roles in cellular growth, development and metabolism. Although there is a strong genetic influence on thyroid hormone levels, the genes involved are widely unknown. The levels of circulating thyroid hormones are tightly regulated by thyrotropin (TSH), which also represents the most important diagnostic marker for thyroid function. Therefore, in order to identify genetic loci associated with TSH levels, we performed a discovery meta-analysis of two genome-wide association studies including two cohorts from Germany, KORA (n 1287) and SHIP (n 2449), resulting in a total sample size of 3736. Four genetic loci at 5q13.3, 1p36, 16q23 and 4q31 were associated with serum TSH levels. The lead single-nucleotide polymorphisms of these four loci were located within PDE8B encoding phosphodiesterase 8B, upstream of CAPZB that encodes the -subunit of the barbed-end F-actin-binding protein, in a former ogene desert' that was recently demonstrated to encode a functional gene (LOC440389) associated with thyroid volume, and upstream of NR3C2 encoding the mineralocorticoid receptor. The latter association for the first time suggests the modulation of thyroid function by mineral corticoids. All four loci were replicated in three additional cohorts: the HUNT study from Norway (n 1487) and the two German studies CARLA (CARLA, n 1357) and SHIP-TREND (n 883). Together, these four quantitative trait loci accounted for approximate to 3.3 of the variance in TSH serum levels. These results contribute to our understanding of genetic factors and physiological mechanisms mediating thyroid function.