A genome-wide association study of thyroid stimulating hormone and free thyroxine in Danish children and adolescents

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Tenna Ruest Haarmark Nielsen, Emil Vincent Rosenbaum Appel, Mathilde Svendstrup, Johanne Dam Ohrt, Maria Dahl, Cilius Esmann Fonvig, Mette Hollensted, Christian Theil Have, Haja N Kadarmideen, Oluf Pedersen, Torben Hansen, Jens-Christian Holm, Niels Grarup

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.

Original languageEnglish
Article numbere0174204
JournalPloS one
Volume12
Issue number3
Number of pages16
ISSN1932-6203
DOIs
Publication statusPublished - 2017

    Research areas

  • Adolescent, Adult, Age Factors, Body Mass Index, Child, Child, Preschool, Denmark, Female, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Humans, Male, Pediatric Obesity, Polymorphism, Single Nucleotide, Thyrotropin, Thyroxine, Young Adult, Journal Article

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