A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function

Abstract

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

GENETICS IN ENDOCRINOLOGY: Genetic variation in deiodinases: a systematic review of potential clinical effects in humans

“…Recent evidence supports a strong correlation between fT 4 levels and D1-rs2235544 polymorphism in a large meta-analysis (nO40 000 subjects; PZ7.87!10 K32 ) (26). These findings might point toward an increased D1 activity of the T-allele.…”

The Phosphodiesterase 8B Gene rs4704397 is Associated with Thyroid Function, Risk of Myocardial Infarction, and Body Height: The Tromsø Study

“…However, the association was weak and not significant after inclusion of BMI in the analysis. Similarly, in the two large studies by Gudmundsson et al (11) and by Porcu et al (12), this reciprocal relation was not statistically significant.…”

“…However, nature has, in a way, already performed its own ''RCT'' just waiting to be analyzed. Thus, the free thyroxine (fT4), free triiodothyroinine (fT3), and TSH levels are, in part, genetically determined, as demonstrated in several genome wide association studies (GWAS) where single nucleotide polymorphisms (SNPs) related to thyroid function have been identified (10)(11)(12). In particular, the rs4704397 SNP in the phosphodiesterase 8B (PDE8B) gene appears to be one of the SNPs most strongly associated with the serum TSH level (13)(14)(15), and one copy of the rare A allele confers a mean increase of 0.13 mIU/L TSH (13) resulting in a difference between the major and minor homozygote subjects of *0.25 mIU/L TSH.…”

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

“…Several of the genes have previous associations to vascular disease (PHACTR1, 29,30 TGFBR2, 31 [43][44][45] and coronary artery calcification 46 and rs11624776 at ITPK1 with thyroid hormone levels 47 ). Six of the loci harbor genes that are involved in nitric oxide signaling and oxidative stress (REST 48 , GJA1 49 , YAP1 50 , PRDM16 51 , LRP1 52 , and MRVI1 53 ).…”