Whole-genome sequence-based analysis of thyroid function.
Taylor PN., Porcu E., Chew S., Campbell PJ., Traglia M., Brown SJ., Mullin BH., Shihab HA., Min J., Walter K., Memari Y., Huang J., Barnes MR., Beilby JP., Charoen P., Danecek P., Dudbridge F., Forgetta V., Greenwood C., Grundberg E., Johnson AD., Hui J., Lim EM., McCarthy S., Muddyman D., Panicker V., Perry JR., Bell JT., Yuan W., Relton C., Gaunt T., Schlessinger D., Abecasis G., Cucca F., Surdulescu GL., Woltersdorf W., Zeggini E., Zheng HF., Toniolo D., Dayan CM., Naitza S., Walsh JP., Spector T., Davey Smith G., Durbin R., Richards JB., Sanna S., Soranzo N., Timpson NJ., Wilson SG., UK0K Consortium None.
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.