Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
Nat Commun. 2020 Aug 7;11(1):3981. doi: 10.1038/s41467-020-17718-z.
Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.
促甲状腺激素（TSH）对正常发育和新陈代谢至关重要。为了更好地了解 TSH 水平的遗传贡献，我们在多达 119715 个人的 2240 万个遗传标记物上进行了 GWAS 荟萃分析，确定了 74 个 TSH 的全基因组显著位点，其中 28 个是以前未报道过的。功能实验表明，甲状腺球蛋白蛋白改变的变体 P118L 和 G67S 影响甲状腺球蛋白的分泌。在英国生物库中的表型全基因组关联分析表明 TSH 相关变体具有多效性效应，并且较高 TSH 水平的多基因评分与英国生物库和其他三个独立研究中甲状腺癌风险降低相关。使用 TSH 指数变体作为工具变量的两样本 Mendelian 随机化表明，较高的 TSH 水平（表示较低的甲状腺功能）对甲状腺癌和甲状腺肿的风险有保护作用。我们的研究结果强调了 TSH 相关变体对甲状腺功能和恶性和良性甲状腺肿瘤生长的多效性效应。
