Genetic Variants Associated with Serum Thyroid Stimulating Hormone (TSH) Levels in European Americans and African Americans from the eMERGE Network

Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10−17, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10−6, β = −0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = −0.09), VEGFA (rs11755845 p = 0.01, β = −0.13), and NFIA (rs334699 p = 1.50×10−3, β = −0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations.

促甲状腺激素（TSH）的水平在个体内通常受到严格调控，因此即便相对微小的波动，也可能提示甲状腺疾病。全基因组关联研究（GWAS）已发现PDE8B与FOXE1的基因变异与TSH水平相关。然而，既往研究的种族/族群多样性不足，限制了这些研究结果在非欧洲族群个体中的推广应用。电子病历与基因组学（eMERGE）网络是跨机构的合作项目，其整合了与电子病历（EMRs）关联的生物样本库。该网络利用源自电子病历的表型数据，针对多种表型在多样化人群中开展全基因组关联研究。在本报告中，我们从eMERGE网络中已具备全基因组关联研究数据的4501名欧洲裔美国人和351名非洲裔美国人甲状腺功能正常个体中，提取了血清TSH水平数据。我们采用线性回归进行关联检验，并针对年龄、性别、体重指数（BMI）以及主成分进行校正，假设采用加性遗传模型。研究结果验证了欧洲裔美国人中PDE8B与血清TSH水平的已知关联（rs2046045，p=1.85×10⁻¹⁷，β=0.09）。与甲状腺功能减退症相关的FOXE1基因变异未达到全基因组显著性水平（rs10759944：p=1.08×10⁻⁶，β=−0.05）。在非洲裔美国人群体中，未发现达到全基因组显著性水平的单核苷酸多态性（Single Nucleotide Polymorphism, SNP）。不过，在欧洲血统人群中已明确的多个与TSH水平相关的关联位点，在非洲裔美国人中呈现名义显著性，其中包括PDE8B（rs2046045，p=0.03，β=−0.09）、VEGFA（rs11755845，p=0.01，β=−0.13）以及NFIA（rs334699，p=1.50×10⁻³，β=−0.17）。本研究未发现足够证据表明，既往与其他甲状腺相关疾病存在关联的单核苷酸多态性（SNP）与血清TSH水平存在关联。上述结果验证了此前关于欧洲裔美国人中PDE8B与血清TSH水平关联的报道，并强调需要在更多样化的人群中开展后续遗传学研究。