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; +41 more...Memari, Y; Huang, J; Barnes, MR; Beilby, JP; Charoen, P; Danecek, P; Dudbridge, FORCID logo; 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, CORCID logo; Gaunt, T; Schlessinger, D; Abecasis, G; Cucca, F; Surdulescu, GL; Woltersdorf, W; Zeggini, E; Zheng, H; 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 and (2014) Whole-genome sequence-based analysis of thyroid function. Nature communications, 6 (1). 5681-. ISSN 2041-1723 DOI: 10.1038/ncomms6681
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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.


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