Malinowski Jennifer R, Denny Joshua C, Bielinski Suzette J, Basford Melissa A, Bradford Yuki, Peissig Peggy L, Carrell David, Crosslin David R, Pathak Jyotishman, Rasmussen Luke, Pacheco Jennifer, Kho Abel, Newton Katherine M, Li Rongling, Kullo Iftikhar J, Chute Christopher G, Chisholm Rex L, Jarvik Gail P, Larson Eric B, McCarty Catherine A, Masys Daniel R, Roden Dan M, de Andrade Mariza, Ritchie Marylyn D, Crawford Dana C
Center for Human Genetics Research, Vanderbilt University, Nashville, TN, United States of America.
Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, United States of America; Department of Medicine, Vanderbilt University, Nashville, TN, United States of America.
PLoS One. 2014 Dec 1;9(12):e111301. doi: 10.1371/journal.pone.0111301. eCollection 2014.
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)水平通常在个体内受到严格调控;因此,相对较小的变化可能表明患有甲状腺疾病。全基因组关联研究(GWAS)已确定PDE8B和FOXE1中的变异与TSH水平相关。然而,先前的研究缺乏种族/民族多样性,限制了这些发现推广到非欧洲种族个体。电子病历与基因组学(eMERGE)网络是一个跨机构合作项目,其生物样本库与电子病历(EMR)相连接。eMERGE网络利用源自电子病历的表型,在不同人群中对多种表型进行GWAS。在本报告中,我们在eMERGE网络中确定了4501名欧美甲状腺功能正常个体和351名非裔美国甲状腺功能正常个体的血清TSH水平,并已有GWAS数据。使用线性回归进行关联测试,并对年龄、性别、体重指数(BMI)和主成分进行校正,假设为加性遗传模型。我们的结果重复了PDE8B与欧美人群血清TSH水平之间已知的关联(rs2046045 p = 1.85×10-17,β = 0.09)。与甲状腺功能减退相关的FOXE1变异在全基因组范围内不显著(rs10759944:p = 1.08×10-6,β = -0.05)。在非裔美国人中,没有单核苷酸多态性(SNP)达到全基因组显著水平。然而,在欧洲血统中多个与TSH水平已知的关联在非裔美国人中名义上显著,包括PDE8B(rs2046045 p = 0.03,β = -0.09)、血管内皮生长因子A(VEGFA,rs11755845 p = 0.01,β = -0.13)和神经纤维瘤病I型基因(NFIA,rs334699 p = 1.50×10-3,β = -0.17)。在本研究中,我们几乎没有发现先前与其他甲状腺相关疾病相关的SNP与血清TSH水平相关的证据。这些结果支持了先前报道的欧美人群中PDE8B与血清TSH水平之间的关联,并强调了在更多样化人群中进行额外基因研究的必要性。