多性状分析描绘了甲状腺功能的遗传学特征，并确定了与临床意义相关的因果关联。

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

机构信息

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.

出版信息

Nat Commun. 2024 Jan 30;15(1):888. doi: 10.1038/s41467-024-44701-9.

DOI:10.1038/s41467-024-44701-9

PMID:38291025

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10828500/

Abstract

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

摘要

迄今为止，只有一小部分甲状腺功能的遗传足迹得到了阐明。我们报告了一项全基因组关联研究的荟萃分析，共纳入了多达 271040 名欧洲血统的个体，包括参考范围促甲状腺激素（TSH）、游离甲状腺素（FT4）、游离和总三碘甲状腺原氨酸（T3）、代谢标志物（T3/FT4 比值）以及二分法的高和低 TSH 水平。我们揭示了 259 个与 TSH 相关的独立显著关联（61%为新发现），85 个与 FT4 相关（67%为新发现），62 个与 T3 相关性状相关的新信号。这些位点分别解释了 TSH、FT4、总 T3 和游离 T3 浓度的总变异的 14.1%、6.0%、9.5%和 1.1%。遗传相关性表明，与 TSH 相关的位点反映了由游离 T3 决定的甲状腺功能，而与 FT4 相关的位点则代表了甲状腺激素代谢。多基因风险评分和孟德尔随机化分析表明，甲状腺功能的遗传变异对各种临床结局（包括心血管危险因素和疾病、自身免疫性疾病和癌症）有影响。总之，我们的研究结果提高了对甲状腺激素生理学的认识，并强调了甲状腺功能对各种疾病的多效性影响。