Whole-genome sequence-based analysis of thyroid function

Peter N Taylor; Eleonora Porcu; Shelby Chew; Purdey J Campbell; Michela Traglia; Suzanne J Brown; Benjamin H Mullin; Hashem A Shihab; Josine Min; Klaudia Walter; Yasin Memari; Jie Huang; Michael R Barnes; John P Beilby; Pimphen Charoen; Petr Danecek; Frank Dudbridge; Vincenzo Forgetta; Celia Greenwood; Elin Grundberg; Andrew D Johnson; Jennie Hui; Ee M Lim; Shane McCarthy; Dawn Muddyman; Vijay Panicker; John R B Perry; Jordana T Bell; Wei Yuan; Caroline Relton; Tom Gaunt; David Schlessinger; Goncalo Abecasis; Francesco Cucca; Gabriela L Surdulescu; Wolfram Woltersdorf; Eleftheria Zeggini; Hou-Feng Zheng; Daniela Toniolo; Colin M Dayan; Silvia Naitza; John P Walsh; Tim Spector; George Davey Smith; Richard Durbin; J Brent Richards; Serena Sanna; Nicole Soranzo; Nicholas J Timpson; Scott G Wilson; UK0K Consortium

doi:10.1038/ncomms6681

Whole-genome sequence-based analysis of thyroid function

Peter N Taylor, Eleonora Porcu, Shelby Chew, Purdey J Campbell, Michela Traglia, Suzanne J Brown, Benjamin H Mullin, Hashem A Shihab, Josine Min, Klaudia Walter, Yasin Memari, Jie Huang, Michael R Barnes, John P Beilby, Pimphen Charoen, Petr Danecek, Frank Dudbridge, Vincenzo Forgetta, Celia Greenwood, Elin GrundbergAndrew D Johnson, Jennie Hui, Ee M Lim, Shane McCarthy, Dawn Muddyman, Vijay Panicker, John R B Perry, Jordana T Bell, Wei Yuan, Caroline Relton, Tom Gaunt, David Schlessinger, Goncalo Abecasis, Francesco Cucca, Gabriela L Surdulescu, Wolfram Woltersdorf, Eleftheria Zeggini, Hou-Feng Zheng, Daniela Toniolo, Colin M Dayan, Silvia Naitza, John P Walsh, Tim Spector, George Davey Smith, Richard Durbin, J Brent Richards, Serena Sanna, Nicole Soranzo, Nicholas J Timpson, Scott G Wilson, UK0K Consortium

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Abstract

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 language	English
Article number	5681 (2015)
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms6681
Publication status	Published - 6 Mar 2015

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MRC UoB UNITE Unit - programme 3
Timpson, N. J. & Timpson, N. J.
1/06/13 → 31/03/18
Project: Research
MRC UoB UNITE Unit - Programme 2
Relton, C. L. & Relton, C. L.
1/06/13 → 31/03/18
Project: Research
IEU Theme 2
Flach, P. A., Gaunt, T. R. & Gaunt, T. R.
1/06/13 → 31/03/18
Project: Research

Professor Nicholas John Timpson
- N.J.Timpsonbristol.acuk
- Bristol Medical School (PHS) - Professor of Genetic Epidemiology
- Bristol Population Health Science Institute
- MRC Integrative Epidemiology Unit
- Cancer
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Taylor, P. N., Porcu, E., Chew, S., Campbell, P. J., Traglia, M., Brown, S. J., Mullin, B. H., Shihab, H. A., Min, J., Walter, K., Memari, Y., Huang, J., Barnes, M. R., Beilby, J. P., Charoen, P., Danecek, P., Dudbridge, F., Forgetta, V., Greenwood, C., ... UK0K Consortium (2015). Whole-genome sequence-based analysis of thyroid function. Nature Communications, 6, [5681 (2015)]. https://doi.org/10.1038/ncomms6681

@article{928cad37bacf4fa5ae41bc508b922054,

title = "Whole-genome sequence-based analysis of thyroid function",

abstract = "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 = "Taylor, {Peter N} and Eleonora Porcu and Shelby Chew and Campbell, {Purdey J} and Michela Traglia and Brown, {Suzanne J} and Mullin, {Benjamin H} and Shihab, {Hashem A} and Josine Min and Klaudia Walter and Yasin Memari and Jie Huang and Barnes, {Michael R} and Beilby, {John P} and Pimphen Charoen and Petr Danecek and Frank Dudbridge and Vincenzo Forgetta and Celia Greenwood and Elin Grundberg and Johnson, {Andrew D} and Jennie Hui and Lim, {Ee M} and Shane McCarthy and Dawn Muddyman and Vijay Panicker and Perry, {John R B} and Bell, {Jordana T} and Wei Yuan and Caroline Relton and Tom Gaunt and David Schlessinger and Goncalo Abecasis and Francesco Cucca and Surdulescu, {Gabriela L} and Wolfram Woltersdorf and Eleftheria Zeggini and Hou-Feng Zheng and Daniela Toniolo and Dayan, {Colin M} and Silvia Naitza and Walsh, {John P} and Tim Spector and {Davey Smith}, George and Richard Durbin and {Brent Richards}, J and Serena Sanna and Nicole Soranzo and Timpson, {Nicholas J} and Wilson, {Scott G} and {UK0K Consortium}",

year = "2015",

month = mar,

day = "6",

doi = "10.1038/ncomms6681",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

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}

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, JRB, Bell, JT, Yuan, W, Relton, C , Gaunt, T, Schlessinger, D, Abecasis, G, Cucca, F, Surdulescu, GL, Woltersdorf, W, Zeggini, E, Zheng, H-F, Toniolo, D, Dayan, CM, Naitza, S, Walsh, JP, Spector, T, Davey Smith, G, Durbin, R, Brent Richards, J, Sanna, S, Soranzo, N, Timpson, NJ, Wilson, SG & UK0K Consortium 2015, 'Whole-genome sequence-based analysis of thyroid function', Nature Communications, vol. 6, 5681 (2015). https://doi.org/10.1038/ncomms6681

TY - JOUR

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

AU - Taylor, Peter N

AU - Porcu, Eleonora

AU - Chew, Shelby

AU - Campbell, Purdey J

AU - Traglia, Michela

AU - Brown, Suzanne J

AU - Mullin, Benjamin H

AU - Shihab, Hashem A

AU - Min, Josine

AU - Walter, Klaudia

AU - Memari, Yasin

AU - Huang, Jie

AU - Barnes, Michael R

AU - Beilby, John P

AU - Charoen, Pimphen

AU - Danecek, Petr

AU - Dudbridge, Frank

AU - Forgetta, Vincenzo

AU - Greenwood, Celia

AU - Grundberg, Elin

AU - Johnson, Andrew D

AU - Hui, Jennie

AU - Lim, Ee M

AU - McCarthy, Shane

AU - Muddyman, Dawn

AU - Panicker, Vijay

AU - Perry, John R B

AU - Bell, Jordana T

AU - Yuan, Wei

AU - Relton, Caroline

AU - Gaunt, Tom

AU - Schlessinger, David

AU - Abecasis, Goncalo

AU - Cucca, Francesco

AU - Surdulescu, Gabriela L

AU - Woltersdorf, Wolfram

AU - Zeggini, Eleftheria

AU - Zheng, Hou-Feng

AU - Toniolo, Daniela

AU - Dayan, Colin M

AU - Naitza, Silvia

AU - Walsh, John P

AU - Spector, Tim

AU - Davey Smith, George

AU - Durbin, Richard

AU - Brent Richards, J

AU - Sanna, Serena

AU - Soranzo, Nicole

AU - Timpson, Nicholas J

AU - Wilson, Scott G

AU - UK0K Consortium

PY - 2015/3/6

Y1 - 2015/3/6

N2 - 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 - 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 (Academic Journal)

C2 - 25743335

VL - 6

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 5681 (2015)

ER -

Whole-genome sequence-based analysis of thyroid function

Abstract

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MRC UoB UNITE Unit - Programme 2

IEU Theme 2

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