Abstract
BackgroundHypothyroidism 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.ObjectiveThis 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.MethodsGenome-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.ResultsNo 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.ConclusionIn 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.
Highlights
Thyroid hormone concentrations exhibit a physiological narrow variability within the individual, but exhibit a considerable inter-individual variability [1]
Four loci previously associated with thyroid stimulating hormone (TSH) in adults were confirmed in this study population (PDE10A, FOXE1, NR3C2, p = 2.4 Á 10−11), VEGFA)
Effect sizes of variants known to associate with TSH or free T4 (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
Summary
Thyroid hormone concentrations exhibit a physiological narrow variability within the individual, but exhibit a considerable inter-individual variability [1]. The age-dependent effects of genetic variations on TSH and fT4 were illustrated in a recent study, in which a gene risk score (GRS) based on studies in adults explained considerably less of the variation in TSH and fT4 in newborns compared to children at six years of age (TSH 0.8−1.0%, fT4 0.2−0.3% vs TSH 5.3−5.5%, fT4 1.9−3.6%) [19]. This difference may be biased by the maternal thyroid concentrations, which are known to pass the placental barrier. 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
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