Genome-wide association study identifies four genetic loci associated with thyroid volume and goiter risk

Abstract

Thyroid disorders such as goiters represent important diseases, especially in iodine-deficient areas. Sibling studies have demonstrated that genetic factors substantially contribute to the interindividual variation of thyroid volume. We performed a genome-wide association study of this phenotype by analyzing a discovery cohort consisting of 3620 participants of the Study of Health in Pomerania (SHIP). Four genetic loci were associated with thyroid volume on a genome-wide level of significance. Of these, two independent loci are located upstream of and within CAPZB, which encodes the β subunit of the barbed-end F-actin binding protein that modulates actin polymerization, a process crucial in the colloid engulfment during thyroglobulin mobilization in the thyroid. The third locus marks FGF7, which encodes fibroblast growth factor 7. Members of this protein family have been discussed as putative signal molecules involved in the regulation of thyroid development. The fourth locus represents a "gene desert" on chromosome 16q23, located directly downstream of the predicted coding sequence LOC440389, which, however, had already been removed from the NCBI database as a result of the standard genome annotation processing at the time that this study was initiated. Experimental proof of the formerly predicted mature mRNA, however, demonstrates that LOC440389 indeed represents a real gene. All four associations were replicated in an independent sample of 1290 participants of the KORA study. These results increase the knowledge about genetic factors and physiological mechanisms influencing thyroid volume.

Figure 1

Manhattan Plots Showing the Significance of Association of All SNPs in the Meta-Analysis with the Phenotypes (A and B) “Thyroid volume” (A) and “goiter” (B). SNPs are plotted on the x axis according to their position on each chromosome against association with the respective phenotype on the y axis (shown as −log10 p value). SNPs were filtered by minor allele frequency of 1%. The black horizontal line indicates the threshold for genome-wide significance.

Figure 2

Regional Association Plots Showing the Association Signals in the Regions of the Four Loci Associated with the “Thyroid Volume” Phenotype on the −log10 Scale as a Function of Chromosome Position in the Meta-Analysis (A–D) The region upstream of CAPZB on chromosome 1 (A), the genic region within CAPZB on chromosome 1 (B), the FGF7 region on chromosome 15 (C), and the “gene desert” on chromosome 16 (D). Large diamonds in red indicate the lead SNPs exhibiting the lowest p values for association with the “thyroid volume” phenotype. The correlations (r²) between each of the surrounding SNPs and the respective lead SNP are indicated by red shading. Genes and nonsynonymous SNPs are labeled in blue. Lead SNPs that are located within genes are indicated by red letters. The left y axis indicates the p values for the association with “thyroid volume,” and the right y axis indicates the estimated recombination rates (HapMap Phase III), shown in light blue. Genes and the direction of transcription (NCBI) are displayed by green bars.

Figure 3

Immunohistochemical Detection of FGF7 Immunohistochemical detection of FGF7 in thyroid follicle epithelial cells (arrows). Colloid within the follicles is unstained (asterisks). Endothelial cells also react positively (dotted arrows). The lower edge of the panel measures 250 μm.

Figure 4

Northern Analysis Demonstrating the Presence of an LOC440389-Specific mRNA of around 0.8 kb in Skeletal Muscle Tissue and Thyroid Tissue SM, skeletal muscle tissue; Thy, thyroid tissue. The first two lanes (SM and Thy) contained 5 μg of total tissue-specific RNA each. The right lane (MW) represents the RNA molecular weight standard. Total RNA was separated by electrophoresis in a 1.2% gel, and, after blotting, the nylon membrane was hybridized with a LOC440389-specific RNA probe.