Objective: We aimed to validate the association of genome-wide association study (GWAS)-identified loci and polygenic risk score with serum thyroid-stimulating hormone (TSH) concentrations and the diagnosis of hypothyroidism. Then, the causal relationship between serum TSH and osteoporotic bone fracture risk was tested. Methods: A cross-sectional study was done among patients of European Caucasian ethnicity recruited in Tayside (Scotland, UK). Electronic medical records (EMRs) were used to identify patients and average serum TSH concentration and linked to genetic biobank data. Genetic associations were performed by linear and logistic regression models. One-sample Mendelian randomization (MR) was used to test causality of serum TSH on bone fracture risk. Results: Replication in 9,452 euthyroid individuals confirmed known loci previously reported. The 58 polymorphisms accounted for 11.08% of the TSH variation (p #x3c; 1e−04). TSH-GRS was directly associated with the risk of hypothyroidism with an odds ratio (OR) of 1.98 for the highest quartile compared to the first quartile (p = 2.2e−12). MR analysis of 5,599 individuals showed that compared with those in the lowest tertile of the TSH-GRS, men in the highest tertile had a decreased risk of osteoporotic bone fracture (OR = 0.59, p = 2.4e−03), while no difference in a similar comparison was observed in women (OR = 0.93, p = 0.61). Sensitivity analysis yielded similar results. Conclusions: EMRs linked to genomic data in large populations allow replication of GWAS discoveries without additional genotyping costs. This study suggests that genetically raised serum TSH concentrations are causally associated with decreased bone fracture risk in men.
Eur Thyroid J

中文翻译：

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血清促甲状腺激素与骨质疏松性骨折之间因果关系的证据

目的：我们旨在验证全基因组关联研究 (GWAS) 确定的位点和多基因风险评分与血清促甲状腺激素 (TSH) 浓度和甲状腺功能减退症诊断之间的关联。然后，测试了血清TSH与骨质疏松性骨折风险之间的因果关系。方法：在 Tayside（苏格兰，英国）招募的欧洲高加索族裔患者中进行了一项横断面研究。电子病历 (EMR) 用于识别患者和平均血清 TSH 浓度，并与基因生物库数据相关联。通过线性和逻辑回归模型进行遗传关联。单样本孟德尔随机化 (MR) 用于测试血清 TSH 对骨折风险的因果关系。结果：在 9,452 名甲状腺功能正常的个体中的复制证实了先前报道的已知位点。58 个多态性占 TSH 变异的 11.08% ( p #x3c; 1e-04)。TSH-GRS 与甲状腺功能减退的风险直接相关，与第一个四分位数相比，最高四分位数的优势比 (OR) 为 1.98 ( p = 2.2e-12)。对 5,599 名个体的 MR 分析显示，与 TSH-GRS 最低三分位数的男性相比，处于最高三分位数的男性骨质疏松性骨折的风险降低（OR = 0.59，p = 2.4e-03），而在在女性中观察到类似的比较（OR = 0.93，p = 0.61）。敏感性分析产生了类似的结果。结论：与大量人群中的基因组数据相关联的 EMR 允许复制 GWAS 发现而无需额外的基因分型成本。这项研究表明，基因升高的血清 TSH 浓度与男性骨折风险降低有因果关系。
欧洲甲状腺杂志