Whole-genome sequence-based analysis of thyroid function

Abstract

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10(-11)). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF<1%) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.

Figure 1. Regional and genome-wide association plots for TSH.

(a) Regional association plot showing genome-wide significant locus for serum TSH at the SYN2, TIMP4 gene region. Inset is in vitro expression QTL data for the lead SNP rs310763 in adipose cells (A), lymphoblastoid cell lines (L), skin cells (S) and whole blood (W). Dotted line denotes genome-wide significance threshold. (b) Regional association plot after conditional analysis on rs2046045 in PDE8B showing our novel association with TSH at rs2928167 in PDE8B remained genome-wide significant. (c) Annotated Manhattan plot from the overall analysis for serum TSH levels. SNPs (MAF>1%) are plotted on the x axis according to their position on each chromosome against association with TSH on the y axis (shown as −log₁₀ (P value)). The loci are regarded as genome-wide significant at P<5 × 10⁻⁸. Variants with 1%<MAF<5% are shown as open diamond symbols. Common SNPs (MAF>5%) are shown as solid circles with those present in Hapmap II reference panels in grey and those derived from WGS or deeply imputed using WGS and 1000 genomes reference panels in blue. SNPs shown as a red asterisk represent novel genome-wide significant findings.

Figure 2. Regional and conditional plots for FT4.

(a) Regional association plot showing genome-wide significant locus for serum FT4 at the B4GALT6, SLC25A52 region (overall meta-analysis). ∇ shows the location of the Thr139Met substitution (rs28933981; MAF=0.4%) in TTR. Dotted red line denotes genome-wide significance threshold. (b) Forest plots of WGS association data for rs113107469 in the WGS discovery studies and meta-analysis, and below is the illustrating loss of signal on conditioning with rs28933981. Squares represent beta estimate and error bars represent 95% CI.

Figure 3. Overview of our findings of SNPs associated with TSH and FT4.

Blue coloured lines represent a novel signal identified in this meta-analysis. Red lines represent heterogeneity observed between the different cohorts in the association between the variant and TSH. - - - Indicates responsiveness observed to levothyroxine. — — Indicates observed eQTL or meQTL associations.

Figure 4. Plots showing NRG1 region with significant associations with FT4 from SKAT analysis.

Horizontal bar represents SKAT variant bins. (·)=single-point association data. Vertical lines in the bin (|) highlight rare variants that contribute to the association with a contribution proportional to the length of the line (that is, removal of the variant from the analysis causes the significance to fall to the level shown).