M Popović1, A Matana1, V Torlak2, T Boutin3, D Brdar2, I Gunjača1, D Kaličanin1, I Kolčić4, V Boraska Perica1, A Punda2, O Polašek4, M Barbalić1, C Hayward3, T Zemunik5. 1. Department of Medical Biology, University of Split, School of Medicine, Šoltanska 2, Split, Croatia. 2. Department of Nuclear Medicine, University Hospital Split, Spinčićeva 1, Split, Croatia. 3. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, United Kingdom. 4. Department of Public Health, University of Split, School of Medicine Split, Šoltanska 2, Split, Croatia. 5. Department of Medical Biology, University of Split, School of Medicine, Šoltanska 2, Split, Croatia. tzemunik@mefst.hr.
Abstract
PURPOSE: Thyroid hormones are essential for the normal function of almost all human tissues, and have critical roles in metabolism, differentiation and growth. Free triiodothyronine (fT3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels are under strong genetic influence; however, most of the heritability is yet unexplained. METHODS: In order to identify novel loci associated with fT3, fT4 and TSH serum levels we performed a genome-wide meta-analysis of 7 411 206 polymorphisms in up to 1731 euthyroid individuals from three Croatian cohorts from Dalmatia region: two genetically isolated island populations and one mainland population. Additionally, we also performed a bivariate analysis of fT3 and fT4 levels. RESULTS: The EPHB2 gene variant rs67142165 reached genome-wide significance for association with fT3 plasma levels (P = 9.27 × 10-9) and its significance was confirmed in bivariate analysis (P = 9.72 × 10-9). We also found a genome-wide significant association for variant rs13037502 upstream of the PTPN1 gene and TSH plasma levels (P = 1.67 × 10-8). CONCLUSION: We identified a first genome-wide significant variant associated with fT3 plasma levels, as well as a novel locus associated with TSH plasma levels. These findings are biologically relevant and enrich our knowledge about the genetic basis of pituitary-thyroid axis function.
PURPOSE: Thyroid hormones are essential for the normal function of almost all human tissues, and have critical roles in metabolism, differentiation and growth. Free triiodothyronine (fT3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels are under strong genetic influence; however, most of the heritability is yet unexplained. METHODS: In order to identify novel loci associated with fT3, fT4 and TSH serum levels we performed a genome-wide meta-analysis of 7 411 206 polymorphisms in up to 1731 euthyroid individuals from three Croatian cohorts from Dalmatia region: two genetically isolated island populations and one mainland population. Additionally, we also performed a bivariate analysis of fT3 and fT4 levels. RESULTS: The EPHB2 gene variant rs67142165 reached genome-wide significance for association with fT3 plasma levels (P = 9.27 × 10-9) and its significance was confirmed in bivariate analysis (P = 9.72 × 10-9). We also found a genome-wide significant association for variant rs13037502 upstream of the PTPN1 gene and TSH plasma levels (P = 1.67 × 10-8). CONCLUSION: We identified a first genome-wide significant variant associated with fT3 plasma levels, as well as a novel locus associated with TSH plasma levels. These findings are biologically relevant and enrich our knowledge about the genetic basis of pituitary-thyroid axis function.
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