Whole-genome sequence-based analysis of thyroid function

UK10K consortium

doi:10.1038/ncomms6681

Whole-genome sequence-based analysis of thyroid function

UK10K consortium

Research output: Contribution to journal › Article › peer-review

81 Citations (Scopus)

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
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms6681
Publication status	Published - Mar 2015
Externally published	Yes

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@article{acaeba12ca5b4b7ab68073745c51a2ea,

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 = "{UK10K consortium} and 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 Zheng, {Hou Feng} and Daniela Toniolo and Dayan, {Colin M.} and Silvia Naitza and Walsh, {John P.} and Tim Spector and Smith, {George Davey} and Richard Durbin and Richards, {J. Brent} and Serena Sanna and Nicole Soranzo and Timpson, {Nicholas J.} and Jackson, {David K.}",

year = "2015",

month = mar,

doi = "10.1038/ncomms6681",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

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AU - UK10K consortium

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 - Smith, George Davey

AU - Durbin, Richard

AU - Richards, J. Brent

AU - Sanna, Serena

AU - Soranzo, Nicole

AU - Timpson, Nicholas J.

AU - Jackson, David K.

PY - 2015/3

Y1 - 2015/3

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.

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U2 - 10.1038/ncomms6681

DO - 10.1038/ncomms6681

M3 - Article

C2 - 25743335

AN - SCOPUS:84924347503

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 5681

ER -

Whole-genome sequence-based analysis of thyroid function

Abstract

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