Whole-genome sequence-based analysis of thyroid function

P.N. Taylor, E. Porcu, S. Chew, P.J. Campbell, M. Traglia, S.J. Brown, Benjamin Mullin, H.A. Shihab, J. Min, K.K.H. Walter, Y. Memari, J. Huang, M.R. Barnes, John Beilby, P. Charoen, P. Danecek, F. Dudbridge, V. Forgetta, C. Greenwood, E. Grundberg & 201 others A.D. Johnson, Jennie Hui, E.M. Lim, S. Mccarthy, D. Muddyman, V. Panicker, J.R.B. Perry, J.T. Bell, W. Yuan, C.L. Relton, T.R. Gaunt, D. Schlessinger, G.R. Abecasis, F. Cucca, G.L. Surdulescu, W. Woltersdorf, E. Zeggini, H. Zheng, D. Toniolo, C.M. Dayan, S. Naitza, John Walsh, T.D. Spector, G.D. Smith, R.M. Durbin, J.B. Richards, S. Sanna, N. Soranzo, N.J. Timpson, Scott Wilson, S.A. Turki, C.A. Anderson, R.J.L. Anney, D. Antony, M.S. Artigas, M.K. Ayub, S. Balasubramaniam, J.C. Barrett, I. Barroso, P.L. Beales, J.R. Bentham, S. Bhattacharya, E. Birney, D.H.R. Blackwood, M.N. Bobrow, E.G. Bochukova, P.A. Bolton, R. Bounds, C.R. Boustred, G. Breen, M. Calissano, K.J. Carss, K. Chatterjee, L. Chen, A. Ciampi, S. Cirak, P. Clapham, G. Clement, G. Coates, D.A. Collier, C.L. Cosgrove, T.V. Cox, N.J. Craddock, L. Crooks, S.R. Curran, D. Curtis, A. Daly, A.G. Day-Williams, I.N.M. Day, T.A. Down, Y. Du, I. Dunham, S.J. Edkins, P.D. Ellis, D.M.D. Evans, S. Faroogi, G. Fatemifar, D.R. Fitzpatrick, P. Flicek, J. Flyod, A.R. Foley, C.S. Franklin, M. Futema, L. Gallagher, M. Geihs, D.H. Geschwind, H. Griffin, D. Grozeva, X. Guo, H.M.D. Gurling, D.J. Hart, A.E. Hendricks, P.A. Holmans, B.N. Howie, L. Huang, T.J.P. Hubbard, S.E. Humphries, M.E. Hurles, P.G. Hysi, D.K. Jackson, Y. Jamshidi, T. Jing, C. Joyce, J. Kaye, T.M. Keane, J.M. Keogh, J.P. Kemp, K.L. Kennedy, A. Kolb-Kokocinski, G. Lachance, C. Langford, D.J. Lawson, I. Lee, M. Lek, J. Liang, H. Lin, R. Li, Y. Li, R. Liu, J. Lönnqvist, M.C. Lopes, V. Lotchkova, D.G. Macarthur, J.L. Marchini, J. Maslen, M. Massimo, I. Mathieson, G. Marenne, P.W. Mcguffin, A.M. Mcintosh, A.G. Mckechanie, A. Mcquillin, S.J. Metrustry, H.M. Mitchison, A. Moayyeri, J.A. Morris, F.M. Muntoni, K. Northstone, M. O'Donnovan, A. Onoufriadis, S.P. O'Rahilly, K. Oualkacha, M.J. Owen, A. Palotie, K. Panoutsopoulou, V. Parker, J.R. Parr, L. Paternoster, T. Paunio, F. Payne, O.P.H. Pietiläinen, V. Plagnol, L. Quaye, M.A. Quail, L.F. Raymond, K. Rehnström, B. Richards, S.M. Ring, G.R.S. Ritchie, N.Y. Roberts, D.B. Savage, P.J. Scambler, S. Schiffels, M. Schmidts, N.A. Schoenmakers, R.K. Semple, E. Serra, S.I. Sharp, S. Shin, D.H. Skuse, K.S. Small, L. Southam, O. Spasić-Bǒsković, D.S. Clair, J.W. Stalker, E. Stevens, B.S. Pourcian, J. Sun, J.M. Suvisaari, I. Tachmazidou, M.D. Tobin, A.A. Valdes, M. Van Kogelenberg, P. Vijayarangakannan, P.M. Visscher, L.V. Wain, J.T.R. Walters, G. Wang, J. Wang, Y. Wang, K.J. Ward, E. Wheeler, T. Whyte, H. Williams, K.A. Williamson, C. Wilson, K. Wong, C. Xu, J. Yang, F. Zhang, P. Zhang

Research output: Contribution to journalArticle

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Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. 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.
Original languageEnglish
Pages (from-to)1-11
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 2015

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genome
Thyrotropin
Sequence Analysis
Thyroid Gland
Genes
Genome
thyroxine
marking
health
Genome-Wide Association Study
Thyroxine
low frequencies
Meta-Analysis
Health
Testing

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Taylor, P. N., Porcu, E., Chew, S., Campbell, P. J., Traglia, M., Brown, S. J., ... Zhang, P. (2015). Whole-genome sequence-based analysis of thyroid function. Nature Communications, 6, 1-11. https://doi.org/10.1038/ncomms6681
Taylor, P.N. ; Porcu, E. ; Chew, S. ; Campbell, P.J. ; Traglia, M. ; Brown, S.J. ; Mullin, Benjamin ; Shihab, H.A. ; Min, J. ; Walter, K.K.H. ; Memari, Y. ; Huang, J. ; Barnes, M.R. ; Beilby, John ; Charoen, P. ; Danecek, P. ; Dudbridge, F. ; Forgetta, V. ; Greenwood, C. ; Grundberg, E. ; Johnson, A.D. ; Hui, Jennie ; Lim, E.M. ; Mccarthy, S. ; Muddyman, D. ; Panicker, V. ; Perry, J.R.B. ; Bell, J.T. ; Yuan, W. ; Relton, C.L. ; Gaunt, T.R. ; Schlessinger, D. ; Abecasis, G.R. ; Cucca, F. ; Surdulescu, G.L. ; Woltersdorf, W. ; Zeggini, E. ; Zheng, H. ; Toniolo, D. ; Dayan, C.M. ; Naitza, S. ; Walsh, John ; Spector, T.D. ; Smith, G.D. ; Durbin, R.M. ; Richards, J.B. ; Sanna, S. ; Soranzo, N. ; Timpson, N.J. ; Wilson, Scott ; Turki, S.A. ; Anderson, C.A. ; Anney, R.J.L. ; Antony, D. ; Artigas, M.S. ; Ayub, M.K. ; Balasubramaniam, S. ; Barrett, J.C. ; Barroso, I. ; Beales, P.L. ; Bentham, J.R. ; Bhattacharya, S. ; Birney, E. ; Blackwood, D.H.R. ; Bobrow, M.N. ; Bochukova, E.G. ; Bolton, P.A. ; Bounds, R. ; Boustred, C.R. ; Breen, G. ; Calissano, M. ; Carss, K.J. ; Chatterjee, K. ; Chen, L. ; Ciampi, A. ; Cirak, S. ; Clapham, P. ; Clement, G. ; Coates, G. ; Collier, D.A. ; Cosgrove, C.L. ; Cox, T.V. ; Craddock, N.J. ; Crooks, L. ; Curran, S.R. ; Curtis, D. ; Daly, A. ; Day-Williams, A.G. ; Day, I.N.M. ; Down, T.A. ; Du, Y. ; Dunham, I. ; Edkins, S.J. ; Ellis, P.D. ; Evans, D.M.D. ; Faroogi, S. ; Fatemifar, G. ; Fitzpatrick, D.R. ; Flicek, P. ; Flyod, J. ; Foley, A.R. ; Franklin, C.S. ; Futema, M. ; Gallagher, L. ; Geihs, M. ; Geschwind, D.H. ; Griffin, H. ; Grozeva, D. ; Guo, X. ; Gurling, H.M.D. ; Hart, D.J. ; Hendricks, A.E. ; Holmans, P.A. ; Howie, B.N. ; Huang, L. ; Hubbard, T.J.P. ; Humphries, S.E. ; Hurles, M.E. ; Hysi, P.G. ; Jackson, D.K. ; Jamshidi, Y. ; Jing, T. ; Joyce, C. ; Kaye, J. ; Keane, T.M. ; Keogh, J.M. ; Kemp, J.P. ; Kennedy, K.L. ; Kolb-Kokocinski, A. ; Lachance, G. ; Langford, C. ; Lawson, D.J. ; Lee, I. ; Lek, M. ; Liang, J. ; Lin, H. ; Li, R. ; Li, Y. ; Liu, R. ; Lönnqvist, J. ; Lopes, M.C. ; Lotchkova, V. ; Macarthur, D.G. ; Marchini, J.L. ; Maslen, J. ; Massimo, M. ; Mathieson, I. ; Marenne, G. ; Mcguffin, P.W. ; Mcintosh, A.M. ; Mckechanie, A.G. ; Mcquillin, A. ; Metrustry, S.J. ; Mitchison, H.M. ; Moayyeri, A. ; Morris, J.A. ; Muntoni, F.M. ; Northstone, K. ; O'Donnovan, M. ; Onoufriadis, A. ; O'Rahilly, S.P. ; Oualkacha, K. ; Owen, M.J. ; Palotie, A. ; Panoutsopoulou, K. ; Parker, V. ; Parr, J.R. ; Paternoster, L. ; Paunio, T. ; Payne, F. ; Pietiläinen, O.P.H. ; Plagnol, V. ; Quaye, L. ; Quail, M.A. ; Raymond, L.F. ; Rehnström, K. ; Richards, B. ; Ring, S.M. ; Ritchie, G.R.S. ; Roberts, N.Y. ; Savage, D.B. ; Scambler, P.J. ; Schiffels, S. ; Schmidts, M. ; Schoenmakers, N.A. ; Semple, R.K. ; Serra, E. ; Sharp, S.I. ; Shin, S. ; Skuse, D.H. ; Small, K.S. ; Southam, L. ; Spasić-Bǒsković, O. ; Clair, D.S. ; Stalker, J.W. ; Stevens, E. ; Pourcian, B.S. ; Sun, J. ; Suvisaari, J.M. ; Tachmazidou, I. ; Tobin, M.D. ; Valdes, A.A. ; Van Kogelenberg, M. ; Vijayarangakannan, P. ; Visscher, P.M. ; Wain, L.V. ; Walters, J.T.R. ; Wang, G. ; Wang, J. ; Wang, Y. ; Ward, K.J. ; Wheeler, E. ; Whyte, T. ; Williams, H. ; Williamson, K.A. ; Wilson, C. ; Wong, K. ; Xu, C. ; Yang, J. ; Zhang, F. ; Zhang, P. / Whole-genome sequence-based analysis of thyroid function. In: Nature Communications. 2015 ; Vol. 6. pp. 1-11.
@article{2d45f07a1f6040899ec0b46496fc7d06,
title = "Whole-genome sequence-based analysis of thyroid function",
abstract = "{\circledC} 2015 Macmillan Publishers Limited. All rights reserved. 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.",
author = "P.N. Taylor and E. Porcu and S. Chew and P.J. Campbell and M. Traglia and S.J. Brown and Benjamin Mullin and H.A. Shihab and J. Min and K.K.H. Walter and Y. Memari and J. Huang and M.R. Barnes and John Beilby and P. Charoen and P. Danecek and F. Dudbridge and V. Forgetta and C. Greenwood and E. Grundberg and A.D. Johnson and Jennie Hui and E.M. Lim and S. Mccarthy and D. Muddyman and V. Panicker and J.R.B. Perry and J.T. Bell and W. Yuan and C.L. Relton and T.R. Gaunt and D. Schlessinger and G.R. Abecasis and F. Cucca and G.L. Surdulescu and W. Woltersdorf and E. Zeggini and H. Zheng and D. Toniolo and C.M. Dayan and S. Naitza and John Walsh and T.D. Spector and G.D. Smith and R.M. Durbin and J.B. Richards and S. Sanna and N. Soranzo and N.J. Timpson and Scott Wilson and S.A. Turki and C.A. Anderson and R.J.L. Anney and D. Antony and M.S. Artigas and M.K. Ayub and S. Balasubramaniam and J.C. Barrett and I. Barroso and P.L. Beales and J.R. Bentham and S. Bhattacharya and E. Birney and D.H.R. Blackwood and M.N. Bobrow and E.G. Bochukova and P.A. Bolton and R. Bounds and C.R. Boustred and G. Breen and M. Calissano and K.J. Carss and K. Chatterjee and L. Chen and A. Ciampi and S. Cirak and P. Clapham and G. Clement and G. Coates and D.A. Collier and C.L. Cosgrove and T.V. Cox and N.J. Craddock and L. Crooks and S.R. Curran and D. Curtis and A. Daly and A.G. Day-Williams and I.N.M. Day and T.A. Down and Y. Du and I. Dunham and S.J. Edkins and P.D. Ellis and D.M.D. Evans and S. Faroogi and G. Fatemifar and D.R. Fitzpatrick and P. Flicek and J. Flyod and A.R. Foley and C.S. Franklin and M. Futema and L. Gallagher and M. Geihs and D.H. Geschwind and H. Griffin and D. Grozeva and X. Guo and H.M.D. Gurling and D.J. Hart and A.E. Hendricks and P.A. Holmans and B.N. Howie and L. Huang and T.J.P. Hubbard and S.E. Humphries and M.E. Hurles and P.G. Hysi and D.K. Jackson and Y. Jamshidi and T. Jing and C. Joyce and J. Kaye and T.M. Keane and J.M. Keogh and J.P. Kemp and K.L. Kennedy and A. Kolb-Kokocinski and G. Lachance and C. Langford and D.J. Lawson and I. Lee and M. Lek and J. Liang and H. Lin and R. Li and Y. Li and R. Liu and J. L{\"o}nnqvist and M.C. Lopes and V. Lotchkova and D.G. Macarthur and J.L. Marchini and J. Maslen and M. Massimo and I. Mathieson and G. Marenne and P.W. Mcguffin and A.M. Mcintosh and A.G. Mckechanie and A. Mcquillin and S.J. Metrustry and H.M. Mitchison and A. Moayyeri and J.A. Morris and F.M. Muntoni and K. Northstone and M. O'Donnovan and A. Onoufriadis and S.P. O'Rahilly and K. Oualkacha and M.J. Owen and A. Palotie and K. Panoutsopoulou and V. Parker and J.R. Parr and L. Paternoster and T. Paunio and F. Payne and O.P.H. Pietil{\"a}inen and V. Plagnol and L. Quaye and M.A. Quail and L.F. Raymond and K. Rehnstr{\"o}m and B. Richards and S.M. Ring and G.R.S. Ritchie and N.Y. Roberts and D.B. Savage and P.J. Scambler and S. Schiffels and M. Schmidts and N.A. Schoenmakers and R.K. Semple and E. Serra and S.I. Sharp and S. Shin and D.H. Skuse and K.S. Small and L. Southam and O. Spasić-Bǒsković and D.S. Clair and J.W. Stalker and E. Stevens and B.S. Pourcian and J. Sun and J.M. Suvisaari and I. Tachmazidou and M.D. Tobin and A.A. Valdes and {Van Kogelenberg}, M. and P. Vijayarangakannan and P.M. Visscher and L.V. Wain and J.T.R. Walters and G. Wang and J. Wang and Y. Wang and K.J. Ward and E. Wheeler and T. Whyte and H. Williams and K.A. Williamson and C. Wilson and K. Wong and C. Xu and J. Yang and F. Zhang and P. Zhang",
year = "2015",
doi = "10.1038/ncomms6681",
language = "English",
volume = "6",
pages = "1--11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group - Macmillan Publishers",

}

Taylor, PN, Porcu, E, Chew, S, Campbell, PJ, Traglia, M, Brown, SJ, Mullin, B, Shihab, HA, Min, J, Walter, KKH, Memari, Y, Huang, J, Barnes, MR, Beilby, J, 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, JRB, Bell, JT, Yuan, W, Relton, CL, Gaunt, TR, Schlessinger, D, Abecasis, GR, Cucca, F, Surdulescu, GL, Woltersdorf, W, Zeggini, E, Zheng, H, Toniolo, D, Dayan, CM, Naitza, S, Walsh, J, Spector, TD, Smith, GD, Durbin, RM, Richards, JB, Sanna, S, Soranzo, N, Timpson, NJ, Wilson, S, Turki, SA, Anderson, CA, Anney, RJL, Antony, D, Artigas, MS, Ayub, MK, Balasubramaniam, S, Barrett, JC, Barroso, I, Beales, PL, Bentham, JR, Bhattacharya, S, Birney, E, Blackwood, DHR, Bobrow, MN, Bochukova, EG, Bolton, PA, Bounds, R, Boustred, CR, Breen, G, Calissano, M, Carss, KJ, Chatterjee, K, Chen, L, Ciampi, A, Cirak, S, Clapham, P, Clement, G, Coates, G, Collier, DA, Cosgrove, CL, Cox, TV, Craddock, NJ, Crooks, L, Curran, SR, Curtis, D, Daly, A, Day-Williams, AG, Day, INM, Down, TA, Du, Y, Dunham, I, Edkins, SJ, Ellis, PD, Evans, DMD, Faroogi, S, Fatemifar, G, Fitzpatrick, DR, Flicek, P, Flyod, J, Foley, AR, Franklin, CS, Futema, M, Gallagher, L, Geihs, M, Geschwind, DH, Griffin, H, Grozeva, D, Guo, X, Gurling, HMD, Hart, DJ, Hendricks, AE, Holmans, PA, Howie, BN, Huang, L, Hubbard, TJP, Humphries, SE, Hurles, ME, Hysi, PG, Jackson, DK, Jamshidi, Y, Jing, T, Joyce, C, Kaye, J, Keane, TM, Keogh, JM, Kemp, JP, Kennedy, KL, Kolb-Kokocinski, A, Lachance, G, Langford, C, Lawson, DJ, Lee, I, Lek, M, Liang, J, Lin, H, Li, R, Li, Y, Liu, R, Lönnqvist, J, Lopes, MC, Lotchkova, V, Macarthur, DG, Marchini, JL, Maslen, J, Massimo, M, Mathieson, I, Marenne, G, Mcguffin, PW, Mcintosh, AM, Mckechanie, AG, Mcquillin, A, Metrustry, SJ, Mitchison, HM, Moayyeri, A, Morris, JA, Muntoni, FM, Northstone, K, O'Donnovan, M, Onoufriadis, A, O'Rahilly, SP, Oualkacha, K, Owen, MJ, Palotie, A, Panoutsopoulou, K, Parker, V, Parr, JR, Paternoster, L, Paunio, T, Payne, F, Pietiläinen, OPH, Plagnol, V, Quaye, L, Quail, MA, Raymond, LF, Rehnström, K, Richards, B, Ring, SM, Ritchie, GRS, Roberts, NY, Savage, DB, Scambler, PJ, Schiffels, S, Schmidts, M, Schoenmakers, NA, Semple, RK, Serra, E, Sharp, SI, Shin, S, Skuse, DH, Small, KS, Southam, L, Spasić-Bǒsković, O, Clair, DS, Stalker, JW, Stevens, E, Pourcian, BS, Sun, J, Suvisaari, JM, Tachmazidou, I, Tobin, MD, Valdes, AA, Van Kogelenberg, M, Vijayarangakannan, P, Visscher, PM, Wain, LV, Walters, JTR, Wang, G, Wang, J, Wang, Y, Ward, KJ, Wheeler, E, Whyte, T, Williams, H, Williamson, KA, Wilson, C, Wong, K, Xu, C, Yang, J, Zhang, F & Zhang, P 2015, 'Whole-genome sequence-based analysis of thyroid function' Nature Communications, vol. 6, pp. 1-11. https://doi.org/10.1038/ncomms6681

Whole-genome sequence-based analysis of thyroid function. / Taylor, P.N.; Porcu, E.; Chew, S.; Campbell, P.J.; Traglia, M.; Brown, S.J.; Mullin, Benjamin; Shihab, H.A.; Min, J.; Walter, K.K.H.; Memari, Y.; Huang, J.; Barnes, M.R.; Beilby, John; Charoen, P.; Danecek, P.; Dudbridge, F.; Forgetta, V.; Greenwood, C.; Grundberg, E.; Johnson, A.D.; Hui, Jennie; Lim, E.M.; Mccarthy, S.; Muddyman, D.; Panicker, V.; Perry, J.R.B.; Bell, J.T.; Yuan, W.; Relton, C.L.; Gaunt, T.R.; Schlessinger, D.; Abecasis, G.R.; Cucca, F.; Surdulescu, G.L.; Woltersdorf, W.; Zeggini, E.; Zheng, H.; Toniolo, D.; Dayan, C.M.; Naitza, S.; Walsh, John; Spector, T.D.; Smith, G.D.; Durbin, R.M.; Richards, J.B.; Sanna, S.; Soranzo, N.; Timpson, N.J.; Wilson, Scott; Turki, S.A.; Anderson, C.A.; Anney, R.J.L.; Antony, D.; Artigas, M.S.; Ayub, M.K.; Balasubramaniam, S.; Barrett, J.C.; Barroso, I.; Beales, P.L.; Bentham, J.R.; Bhattacharya, S.; Birney, E.; Blackwood, D.H.R.; Bobrow, M.N.; Bochukova, E.G.; Bolton, P.A.; Bounds, R.; Boustred, C.R.; Breen, G.; Calissano, M.; Carss, K.J.; Chatterjee, K.; Chen, L.; Ciampi, A.; Cirak, S.; Clapham, P.; Clement, G.; Coates, G.; Collier, D.A.; Cosgrove, C.L.; Cox, T.V.; Craddock, N.J.; Crooks, L.; Curran, S.R.; Curtis, D.; Daly, A.; Day-Williams, A.G.; Day, I.N.M.; Down, T.A.; Du, Y.; Dunham, I.; Edkins, S.J.; Ellis, P.D.; Evans, D.M.D.; Faroogi, S.; Fatemifar, G.; Fitzpatrick, D.R.; Flicek, P.; Flyod, J.; Foley, A.R.; Franklin, C.S.; Futema, M.; Gallagher, L.; Geihs, M.; Geschwind, D.H.; Griffin, H.; Grozeva, D.; Guo, X.; Gurling, H.M.D.; Hart, D.J.; Hendricks, A.E.; Holmans, P.A.; Howie, B.N.; Huang, L.; Hubbard, T.J.P.; Humphries, S.E.; Hurles, M.E.; Hysi, P.G.; Jackson, D.K.; Jamshidi, Y.; Jing, T.; Joyce, C.; Kaye, J.; Keane, T.M.; Keogh, J.M.; Kemp, J.P.; Kennedy, K.L.; Kolb-Kokocinski, A.; Lachance, G.; Langford, C.; Lawson, D.J.; Lee, I.; Lek, M.; Liang, J.; Lin, H.; Li, R.; Li, Y.; Liu, R.; Lönnqvist, J.; Lopes, M.C.; Lotchkova, V.; Macarthur, D.G.; Marchini, J.L.; Maslen, J.; Massimo, M.; Mathieson, I.; Marenne, G.; Mcguffin, P.W.; Mcintosh, A.M.; Mckechanie, A.G.; Mcquillin, A.; Metrustry, S.J.; Mitchison, H.M.; Moayyeri, A.; Morris, J.A.; Muntoni, F.M.; Northstone, K.; O'Donnovan, M.; Onoufriadis, A.; O'Rahilly, S.P.; Oualkacha, K.; Owen, M.J.; Palotie, A.; Panoutsopoulou, K.; Parker, V.; Parr, J.R.; Paternoster, L.; Paunio, T.; Payne, F.; Pietiläinen, O.P.H.; Plagnol, V.; Quaye, L.; Quail, M.A.; Raymond, L.F.; Rehnström, K.; Richards, B.; Ring, S.M.; Ritchie, G.R.S.; Roberts, N.Y.; Savage, D.B.; Scambler, P.J.; Schiffels, S.; Schmidts, M.; Schoenmakers, N.A.; Semple, R.K.; Serra, E.; Sharp, S.I.; Shin, S.; Skuse, D.H.; Small, K.S.; Southam, L.; Spasić-Bǒsković, O.; Clair, D.S.; Stalker, J.W.; Stevens, E.; Pourcian, B.S.; Sun, J.; Suvisaari, J.M.; Tachmazidou, I.; Tobin, M.D.; Valdes, A.A.; Van Kogelenberg, M.; Vijayarangakannan, P.; Visscher, P.M.; Wain, L.V.; Walters, J.T.R.; Wang, G.; Wang, J.; Wang, Y.; Ward, K.J.; Wheeler, E.; Whyte, T.; Williams, H.; Williamson, K.A.; Wilson, C.; Wong, K.; Xu, C.; Yang, J.; Zhang, F.; Zhang, P.

In: Nature Communications, Vol. 6, 2015, p. 1-11.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Whole-genome sequence-based analysis of thyroid function

AU - Taylor, P.N.

AU - Porcu, E.

AU - Chew, S.

AU - Campbell, P.J.

AU - Traglia, M.

AU - Brown, S.J.

AU - Mullin, Benjamin

AU - Shihab, H.A.

AU - Min, J.

AU - Walter, K.K.H.

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PY - 2015

Y1 - 2015

N2 - © 2015 Macmillan Publishers Limited. All rights reserved. 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.

AB - © 2015 Macmillan Publishers Limited. All rights reserved. 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.

U2 - 10.1038/ncomms6681

DO - 10.1038/ncomms6681

M3 - Article

VL - 6

SP - 1

EP - 11

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

ER -

Taylor PN, Porcu E, Chew S, Campbell PJ, Traglia M, Brown SJ et al. Whole-genome sequence-based analysis of thyroid function. Nature Communications. 2015;6:1-11. https://doi.org/10.1038/ncomms6681