丹麦儿童和青少年促甲状腺激素及游离甲状腺素的全基因组关联研究。
A genome-wide association study of thyroid stimulating hormone and free thyroxine in Danish children and adolescents.
作者信息
Nielsen Tenna Ruest Haarmark, Appel Emil Vincent Rosenbaum, Svendstrup Mathilde, Ohrt Johanne Dam, Dahl Maria, Fonvig Cilius Esmann, Hollensted Mette, Have Christian Theil, Kadarmideen Haja N, Pedersen Oluf, Hansen Torben, Holm Jens-Christian, Grarup Niels
机构信息
The Children's Obesity Clinic, Department of Pediatrics, Copenhagen University Hospital Holbæk, Holbæk, Denmark.
The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
出版信息
PLoS One. 2017 Mar 23;12(3):e0174204. doi: 10.1371/journal.pone.0174204. eCollection 2017.
BACKGROUND
Hypothyroidism is associated with obesity, and thyroid hormones are involved in the regulation of body composition, including fat mass. Genome-wide association studies (GWAS) in adults have identified 19 and 6 loci associated with plasma concentrations of thyroid stimulating hormone (TSH) and free thyroxine (fT4), respectively.
OBJECTIVE
This study aimed to identify and characterize genetic variants associated with circulating TSH and fT4 in Danish children and adolescents and to examine whether these variants associate with obesity.
METHODS
Genome-wide association analyses of imputed genotype data with fasting plasma concentrations of TSH and fT4 from a population-based sample of Danish children, adolescents, and young adults, and a group of children, adolescents, and young adults with overweight and obesity were performed (N = 1,764, mean age = 12.0 years [range 2.5-24.7]). Replication was performed in additional comparable samples (N = 2,097, mean age = 11.8 years [1.2-22.8]). Meta-analyses, using linear additive fixed-effect models, were performed on the results of the discovery and replication analyses.
RESULTS
No novel loci associated with TSH or fT4 were identified. Four loci previously associated with TSH in adults were confirmed in this study population (PDE10A (rs2983511: β = 0.112SD, p = 4.8 ∙ 10-16), FOXE1 (rs7847663: β = 0.223SD, p = 1.5 ∙ 10-20), NR3C2 (rs9968300: β = 0.194SD), p = 2.4 ∙ 10-11), VEGFA (rs2396083: β = 0.088SD, p = 2.2 ∙ 10-10)). Effect sizes of variants known to associate with TSH or fT4 in adults showed a similar direction of effect in our cohort of children and adolescents, 11 of which were associated with TSH or fT4 in our study (p<0.0002). None of the TSH or fT4 associated SNPs were associated with obesity in our cohort, indicating no pleiotropic effects of these variants on obesity.
CONCLUSION
In a group of Danish children and adolescents, four loci previously associated with plasma TSH concentrations in adults, were associated with plasma TSH concentrations in children, suggesting comparable genetic determinants of thyroid function in adults and children.
背景
甲状腺功能减退与肥胖有关，甲状腺激素参与身体成分的调节，包括脂肪量。全基因组关联研究（GWAS）在成年人中已分别鉴定出19个和6个与促甲状腺激素（TSH）和游离甲状腺素（fT4）血浆浓度相关的基因座。
目的
本研究旨在鉴定和表征丹麦儿童和青少年中与循环TSH和fT4相关的基因变异，并研究这些变异是否与肥胖相关。
方法
对来自丹麦儿童、青少年和青年成年人的基于人群样本以及一组超重和肥胖的儿童、青少年和青年成年人的推算基因型数据与空腹血浆TSH和fT4浓度进行全基因组关联分析（N = 1764，平均年龄 = 12.0岁[范围2.5 - 24.7]）。在另外的可比样本中进行重复验证（N = 2097，平均年龄 = 11.8岁[1.2 - 22.8]）。使用线性加性固定效应模型对发现和重复分析的结果进行荟萃分析。
结果
未鉴定出与TSH或fT4相关的新基因座。在本研究人群中确认了四个先前在成年人中与TSH相关的基因座（PDE10A（rs2983511：β = 0.112SD，p = 4.8 ∙ 10 - 16），FOXE1（rs7847663：β = 0.223SD，p = 1.5 ∙ 10 - 20），NR3C2（rs9968300：β = 0.194SD），p = 2.4 ∙ 10 - 11），VEGFA（rs2396083：β = 0.088SD，p = 2.2 ∙ 10 - 10））。在成年人中已知与TSH或fT4相关的变异的效应大小在我们的儿童和青少年队列中显示出相似的效应方向，其中11个在我们的研究中与TSH或fT4相关（p < 0.0002）。在我们的队列中，没有一个与TSH或fT4相关的单核苷酸多态性（SNP）与肥胖相关，表明这些变异对肥胖没有多效性影响。
结论
在一组丹麦儿童和青少年中，四个先前在成年人中与血浆TSH浓度相关的基因座与儿童血浆TSH浓度相关，表明成年人和儿童甲状腺功能的遗传决定因素具有可比性。
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