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; Jrb, Perry; 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; Smith, Gd; Durbin, R; Richards, Jb; Sanna, S; Soranzo, N; Timpson, Nj; Wilson, Sg; Turki, Sa; Anderson, C; Anney, R; Antony, D; Artigas, Ms; Ayub, M; Balasubramaniam, S; Barrett, Jc; Barroso, I; Beales, P; Bentham, J; Bhattacharya, S; Birney, E; Blackwood, D; Bobrow, M; Bochukova, E; Bolton, P; Bounds, R; Boustred, C; Breen, G; Calissano, M; Carss, K; Chatterjee, K; Chen, L; Ciampi, A; Cirak, S; Clapham, P; Clement, G; Coates, G; Collier, D; Cosgrove, C; Cox, T; Craddock, N; Crooks, L; Curran, S; Curtis, D; Daly, A; Daywilliams, A; Inm, Day; Down, T; Y, Du; Dunham, I; Edkins, S; Ellis, P; Evans, D; Faroogi, S; Fatemifar, G; Fitzpatrick, Dr; Flicek, P; Flyod, J; Foley, Ar; Franklin, Cs; Futema, M; Gallagher, L; Geihs, M; Geschwind, D; Griffin, H; Grozeva, D; Guo, X; Guo, X; Gurling, H; Hart, D; Hendricks, A; Holmans, P; Howie, B; Huang, L; Hubbard, T; Humphries, Se; Hurles, Me; Hysi, P; Jackson, Dk; Jamshidi, Y; Jing, T; Joyce, C; Kaye, J; Keane, T; Keogh, J; Kemp, J; Kennedy, K; Kolbkokocinski, A; Lachance, G; Langford, C; Lawson, D; Lee, I; Lek, M; Liang, J; Lin, H; R, Li; Y, Li; Liu, R; Lonnqvist, J; Lopes, M; Lotchkova, V; Macarthur, D; Marchini, J; Maslen, J; Massimo, M; Mathieson, I; Marenne, G; Mcguffin, P; Mcintosh, A; Mckechanie, Ag; Mcquillin, A; Metrustry, S; Mitchison, H; Moayyeri, A; Morris, J; Muntoni, F; Northstone, K; O'Donnovan, M; Onoufriadis, A; O'Rahilly, S; Oualkacha, K; Owen, Mj; Palotie, A; Panoutsopoulou, K; Parker, V; Parr, Jr; Paternoster, L; Paunio, T; Payne, F; Pietilainen, O; Plagnol, V; Quaye, L; Quail, Ma; Raymond, L; Rehnstrom, K; Richards, B; Ring, S; Grs, Ritchie; Roberts, N; Savage, Db; Scambler, P; Schiffels, S; Schmidts, M; Schoenmakers, N; Semple, Rk; Serra, E; Sharp, Si; Shin, Sy; Skuse, D; Small, K; Southam, L; Spasicboskovic, O; Clair, Ds; Stalker, J; Stevens, E; Pourcian, Bs; Sun, J; Suvisaari, J; Tachmazidou, I; Tobin, Md; Valdes, A; Van Kogelenberg, M; Vijayarangakannan, P; Visscher, Pm; Wain, Lv; Jtr, Walters; Wang, G; Wang, J; Wang, Y; Ward, K; Wheeler, E; Whyte, T; Williams, H; Williamson, Ka; Wilson, C; Wong, K; Cj, Xu; Yang, J; Zhang, F; Zhang, P

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.