Taylor Peter N, Porcu Eleonora, Chew Shelby, Campbell Purdey J, Traglia Michela, Brown Suzanne J, Mullin Benjamin H, Shihab Hashem A, Min Josine, Walter Klaudia, Memari Yasin, Huang Jie, Barnes Michael R, Beilby John P, Charoen Pimphen, Danecek Petr, Dudbridge Frank, Forgetta Vincenzo, Greenwood Celia, Grundberg Elin, Johnson Andrew D, Hui Jennie, Lim Ee M, McCarthy Shane, Muddyman Dawn, Panicker Vijay, Perry John R B, Bell Jordana T, Yuan Wei, Relton Caroline, Gaunt Tom, Schlessinger David, Abecasis Goncalo, Cucca Francesco, Surdulescu Gabriela L, Woltersdorf Wolfram, Zeggini Eleftheria, Zheng Hou-Feng, Toniolo Daniela, Dayan Colin M, Naitza Silvia, Walsh John P, Spector Tim, Davey Smith George, Durbin Richard, Richards J Brent, Sanna Serena, Soranzo Nicole, Timpson Nicholas J, Wilson Scott G
Thyroid Research Group, Institute of Molecular &Experimental Medicine, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
1] Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy [2] Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy [3] Center for Statistical Genetics, Biostatistics Department, University of Michigan, Ann Arbor, Michigan, USA.
Nat Commun. 2015 Mar 6;6:5681. doi: 10.1038/ncomms6681.
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.
正常的甲状腺功能对健康至关重要，但其遗传结构仍知之甚少。在此，对于可遗传的甲状腺性状促甲状腺激素（TSH）和游离甲状腺素（FT4），我们分析了来自UK10K项目（N = 2287）的全基因组序列数据。使用额外的全基因组序列和深度推测数据集，我们报告了与TSH和FT4相关的常见变异（MAF≥1%）的荟萃分析结果（N = 16335）。对于TSH，我们在SYN2中鉴定出一个新变异（MAF = 23.5%，P = 6.15×10⁻⁹），在PDE8B中鉴定出一个新的独立变异（MAF = 10.4%，P = 5.94×10⁻¹⁴）。对于FT4，我们报告了B4GALT6/SLC25A52附近的一个低频变异（MAF = 3.2%，P = 1.27×10⁻⁹），该变异标记了一个罕见的TTR变异（MAF = 0.4%，P = 2.14×10⁻¹¹）。所有常见变异解释了TSH和FT4中≥20%的变异。使用序列核关联测试对罕见变异（MAF<1%）进行分析，揭示了NRG1中与FT4的新关联。我们的结果表明，全基因组序列关联研究中增加的覆盖范围鉴定出了与甲状腺功能相关的新变异。
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