engleski

Genome-wide meta-analysis identifies novel loci associated with free triiodothyronine and thyroid-stimulating hormone

Background: Thyroid hormones are essential for the normal function of almost all human tissues, and have critical roles in metabolism, differentiation and growth. Although twin and family studies have estimated that up to 65% of serum free triiodothyronine (fT3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) variation is genetically determined, most of the heritability is yet unexplained. Moreover, no genome-wide significant signals have been identified for an association with fT3 levels so far. Methods: We performed a genome-wide meta- analysis in up to 1731 euthyroid individuals originating from three Croatian cohorts: City of Split and the Islands of Korčula and Vis. Euthyroid participants were selected based on detailed thyroid status that includes biochemical measurements of thyroid function (including measurements of fT3, fT4, TSH, TgAb and TPOAb) and anamnestic data. A total of 7 411 206 variants, imputed using the 1000 Genomes reference panel, were analyzed for an association. Genome-wide association study (GWAS) within each data set was carried out under an additive model, controlling for age, gender and relatedness. Meta-analysis was performed using the inverse-variance fixed- effects method. Additionally, we also conducted multiple-trait GWAS to test the association between each variant and the two intermediately correlated traits fT3 and fT4 simultaneously. Results: The EPHB2 gene variant rs67142165 reached genome-wide significance for association with fT3 plasma levels (P=9.27x10- 9) and its significance was confirmed in the multiple-trait GWAS (P=9.72x10-9). We also found a genome-wide significant association for variant rs13037502 upstream of the PTPN1 gene and TSH serum levels (P=1.67x10-8). Conclusion: To the best of our knowledge, this is the first GWAS of these traits performed in minutely selected euthyroid subjects. We identified the first genome-wide significant association for fT3 level to date, as well as a novel association with TSH level. Furthermore, we carried out the first reported multiple- trait GWAS of fT3 and fT4, which resulted in identification of EPHB2 as a potential pleiotropic gene. These findings are biologically relevant and add new knowledge to the genetics of observed thyroid-related traits.

genome-wide association analysis ; thyroid hormones

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