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.

Figure 1. Regional association plots showing genome-wide significant loci for serum TSH.

In each panel (A–F), the most significant SNP is indicated (purple circle). In panel F, an independent signal at the associated locus is indicated with an arrow. The SNPs surrounding the most significant SNP are color-coded to reflect their LD with this SNP as in the inset (taken from pairwise r² values from the HapMap CEU database build 36/hg18). Symbols reflect genomic functional annotation, as indicated in the legend . Genes and the position of exons, as well as the direction of transcription, are noted in lower boxes. In each panel the scale bar on the Y-axis changes according to the strength of the association.

Figure 2. Regional association plots showing genome-wide significant loci for serum TSH.

In each panel (A–F), the most significant SNP is indicated (purple circle). The SNPs surrounding the most significant SNP are color-coded to reflect their LD with this SNP as in the inset (taken from pairwise r² values from the HapMap CEU database build 36/hg18). Symbols reflect genomic functional annotation, as indicated in the legend . Genes and the position of exons, as well as the direction of transcription, are noted in lower boxes. In each panel the scale bar on the Y-axis changes according to the strength of the association.

Figure 3. Regional association plots showing genome-wide significant loci for serum TSH.

In each panel (A–F), the most significant SNP is indicated (purple circle). The SNPs surrounding the most significant SNP are color-coded to reflect their LD with this SNP as in the inset (taken from pairwise r² values from the HapMap CEU database build 36/hg18). Symbols reflect genomic functional annotation, as indicated in the legend . Genes and the position of exons, as well as the direction of transcription, are noted in lower boxes. In each panel the scale bar on the Y-axis changes according to the strength of the association.

Figure 4. Regional association plots showing genome-wide significant loci for serum TSH.

In the upper panel, the most significant SNP is indicated (purple circle). The SNPs surrounding the most significant SNP are color-coded to reflect their LD with this SNP as in the inset (taken from pairwise r² values from the HapMap CEU database build 36/hg18). Symbols reflect genomic functional annotation, as indicated in the legend . Genes and the position of exons, as well as the direction of transcription, are noted in the lower box. The scale bar on the Y-axis changes according to the strength of the association.

Figure 5. Regional association plots showing genome-wide significant loci for serum FT4.

In each panel (A–F), the most significant SNP is indicated (purple circle). The SNPs surrounding the most significant SNP are color-coded to reflect their LD with this SNP as in the inset (taken from pairwise r² values from the HapMap CEU database build 36/hg18). Symbols reflect genomic functional annotation, as indicated in the legend . Genes and the position of exons, as well as the direction of transcription, are noted in lower boxes. In each panel the scale bar on the Y-axis changes according to the strength of the association.

Figure 6. Forest plot of SNPs with gender-specific effects.

Squares represent the estimated per-allele beta-estimate for individual studies (a) and in males and females separately (b). The area of the square is inversely proportional to the variance of the estimate. Diamonds represent the summary beta estimates for the subgroups indicated. Horizontal lines represent 95% confidence intervals. In b, red and blue dotted lines represent, respectively, females and males.