Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function

Abstract

Thyroid-stimulating hormone (TSH) controls thyroid growth and hormone secretion through binding to its G protein-coupled receptor (TSHR) and production of cyclic AMP (cAMP). Serum TSH is a sensitive indicator of thyroid function, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over a life span. By genotyping 362,129 SNPs in 4,300 Sardinians, we identified a strong association (p = 1.3 x 10(-11)) between alleles of rs4704397 and circulating TSH levels; each additional copy of the minor A allele was associated with an increase of 0.13 muIU/ml in TSH. The single-nucleotide polymorphism (SNP) is located in intron 1 of PDE8B, encoding a high-affinity cAMP-specific phosphodiesterase. The association was replicated in 4,158 individuals, including additional Sardinians and two genetically distant cohorts from Tuscany and the Old Order Amish (overall p value = 1.9 x 10(-20)). In addition to association of TSH levels with SNPs in PDE8B, our genome scan provided evidence for association with PDE10A and several biologically interesting candidates in a focused analysis of 24 genes. In particular, we found evidence for association of TSH levels with SNPs in the THRB (rs1505287, p = 7.3 x 10(-5)), GNAQ (rs10512065, p = 2.0 x 10(-4)), TG (rs2252696, p = 2.2 x 10(-3)), POU1F1 (rs1976324, p = 3.9 x 10(-3)), PDE4D (rs27178, p = 8.3 x 10(-3)), and TSHR (rs4903957, p = 8.6 x 10(-3)) loci. Overall, the results suggest a primary effect of PDE8B variants on cAMP levels in the thyroid. This would affect production of T4 and T3 and feedback to alter TSH release by the pituitary. PDE8B may thus provide a candidate target for the treatment of thyroid dysfunction.

Figure 1

Results of Genome-wide Association Scan for TSH Levels For each marker, the −log₁₀ of the p value resulting from an association test that evaluates its additive effect on the phenotype is plotted. The position of PDE8B is annotated.

Figure 2

Association with TSH Levels and Linkage-Disequilibrium Patterns in the Region Surrounding PDE8B (A) The top panel summarizes association between the SNPs and TSH levels in each individual (−log₁₀ of the p value). The SNP showing strongest association (rs4704397) is highlighted and indicated with a red square. Other SNPs are colored according to their degree of disequilibrium with rs4704397, ranging from high (red) to intermediate (green) to low (blue). r² values of rs4704397 with rs6885099 and rs2046045 (red dots) are r² = 0.98 and r² = 0.97, respectively. The transcript for all genes in the region is indicated in the next panel, with an arrow indicating transcript direction. (B) The two panels summarize the patterns of disequilibrium in SardiNIA and in the CEPH from Utah (CEU; Utah residents with ancestry from northern and western Europe) HapMap populations. r² values are colored as in (A) with GOLD, which schematically draws the LD plot according to the physical position of markers, resulting in a line divided according to marker-marker distance. The gray bar marks the region of association and facilitates comparisons between the panels. (C) The bottom panel summarizes the results of the fine mapping in the PDE8B gene. The association results are for all SNPs in the SardiNIA sample genotyped with either the 500K or 10K Mapping Array Set or the ParAllele custom chip. The top three markers, all in intron 1, are highlighted. The transcripts for all the PDE8B isoforms are indicated at the bottom.

Figure 3

Quantile-Quantile Plot of SNPs Associated with TSH Level in the SardiNIA Study Red dots represent all the 362,129 SNPs analyzed in the GWAS. Blue dots represent all analyzed SNPs not located within the PDE8B gene. The gray area corresponds to the 90% confidence region from a null distribution of p values generated from 100 simulations.