Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands.
Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
J Clin Endocrinol Metab. 2022 May 17;107(6):e2276-e2283. doi: 10.1210/clinem/dgac136.
While most of the variation in thyroid function is determined by genetic factors, single nucleotide polymorphisms (SNPs) identified via genome-wide association analyses have only explained ~5% to 9% of this variance so far. Most SNPs were in or nearby genes with no known role in thyroid hormone (TH) regulation. Therefore, we performed a large-scale candidate gene study investigating the effect of common genetic variation in established TH regulating genes on serum thyrotropin [thyroid-stimulating hormone (TSH)] and thyroxine (FT4) concentrations.
SNPs in or within 10 kb of 96 TH regulating genes were included (30 031 TSH SNPs, and 29 962 FT4 SNPs). Associations were studied in 54 288 individuals from the ThyroidOmics Consortium. Linkage disequilibrium-based clumping was used to identify independently associated SNPs. SNP-based explained variances were calculated using SumHer software.
We identified 23 novel TSH-associated SNPs in predominantly hypothalamic-pituitary-thyroid axis genes and 25 novel FT4-associated SNPs in mainly peripheral metabolism and transport genes. Genome-wide SNP variation explained ~21% (SD 1.7) of the total variation in both TSH and FT4 concentrations, whereas SNPs in the 96 TH regulating genes explained 1.9% to 2.6% (SD 0.4).
Here we report the largest candidate gene analysis on thyroid function, resulting in a substantial increase in the number of genetic variants determining TSH and FT4 concentrations. Interestingly, these candidate gene SNPs explain only a minor part of the variation in TSH and FT4 concentrations, which substantiates the need for large genetic studies including common and rare variants to unravel novel, yet unknown, pathways in TH regulation.
尽管甲状腺功能的大部分变异是由遗传因素决定的，但通过全基因组关联分析发现的单核苷酸多态性（SNP）迄今为止仅解释了这种变异的 5%至 9%左右。大多数 SNP 位于或附近的基因中，这些基因在甲状腺激素（TH）调节中没有已知作用。因此，我们进行了一项大规模的候选基因研究，调查了已确定的调节 TH 的基因中的常见遗传变异对血清促甲状腺激素[甲状腺刺激激素（TSH）]和甲状腺素（FT4）浓度的影响。
纳入了 96 个 TH 调节基因中的或附近 10kb 内的 SNP（30031 个 TSH SNP 和 29962 个 FT4 SNP）。在甲状腺转录组学联盟的 54288 名个体中研究了关联。基于连锁不平衡的聚类用于鉴定独立相关的 SNP。使用 SumHer 软件计算 SNP 解释的变异。
我们在主要的下丘脑-垂体-甲状腺轴基因中发现了 23 个新的 TSH 相关 SNP，在主要的外周代谢和转运基因中发现了 25 个新的 FT4 相关 SNP。全基因组 SNP 变异解释了 TSH 和 FT4 浓度总变异的约 21%（SD 1.7），而 96 个 TH 调节基因中的 SNP 解释了 1.9%至 2.6%（SD 0.4）。
在这里，我们报告了最大的甲状腺功能候选基因分析，导致确定 TSH 和 FT4 浓度的遗传变异数量显著增加。有趣的是，这些候选基因 SNP 仅解释了 TSH 和 FT4 浓度变异的一小部分，这证实了需要进行包括常见和罕见变异在内的大型遗传研究，以揭示 TH 调节中的新的未知途径。
