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Nat Commun. 2015 Mar 6;6:5681. doi: 10.1038/ncomms6681.

Whole-genome sequence-based analysis of thyroid function.

Collaborators (172)

Al Turki S, 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, Day-Williams A, Day IN, Down T, Du Y, 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, Kolb-Kokocinski A, Lachance G, Langford C, Lawson D, Lee I, Lek M, Liang J, Lin H, Li R, Li Y, Liu R, Lönnqvist J, Lopes M, Iotchkova 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 M, Raymond L, Rehnström K, Richards B, Ring S, Ritchie GR, 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, Spasic-Boskovic O, St Clair D, Stalker J, Stevens E, St Pourcian B, Sun J, Suvisaari J, Tachmazidou I, Tobin MD, Valdes A, Van Kogelenberg M, Vijayarangakannan P, Visscher PM, Wain LV, Walters JT, Wang G, Wang J, Wang Y, Ward K, Wheeler E, Whyte T, Williams H, Williamson KA, Wilson C, Wong K, Xu C, Yang J, Zhang F, Zhang P.

Author information

1
Thyroid Research Group, Institute of Molecular &Experimental Medicine, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
2
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.
3
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
4
Division of Genetics and Cell Biology, San Raffaele Research Institute, Milano, Italy.
5
1] Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia [2] School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.
6
MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Bristol, UK.
7
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
8
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
9
1] Pathwest Laboratory Medicine WA, Nedlands, Western Australia, Australia [2] School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
10
1] Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK [2] Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
11
Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.
12
1] Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada [2] Department of Oncology, Department of Epidemiology, Biostatistics and Occupational Health, Jewish General Hospital, Lady Davis Institute, McGill University, Montréal, Québec, Canada.
13
1] Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada [2] Department of Oncology, Department of Epidemiology, Biostatistics and Occupational Health, Jewish General Hospital, Lady Davis Institute, McGill University, Montréal, Québec, Canada [3] Department of Human Genetics, McGill University, Montreal, Québec, Canada H3A1A5.
14
1] McGill University and Genome Quebec Innovation Centre, Montreal, Québec, Canada H3A1A5 [2] Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung and Blood Institute, Bethesda, Maryland, USA.
15
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Box 285, Cambridge, UK.
16
1] Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia [2] Pathwest Laboratory Medicine WA, Nedlands, Western Australia, Australia.
17
1] Department of Twin Research and Genetic Epidemiology, King's College London, London, UK [2] Laboratory of Genetics, NIA, Baltimore, Maryland 21224, USA.
18
Laboratory of Genetics, NIA, Baltimore, Maryland 21224, USA.
19
Facharzt für Laboratoriumsmedizin, Geschäftsführer amedes Ost, Halle/Leipzig GmbH, Leipziger Chaussee 191f, 06112 Halle (Saale), Germany.
20
Center for Statistical Genetics, Biostatistics Department, University of Michigan, Ann Arbor, Michigan, USA.
21
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.
22
Institute of Molecular Genetics-CNR, Pavia, Italy.
23
1] Department of Oncology, Department of Epidemiology, Biostatistics and Occupational Health, Jewish General Hospital, Lady Davis Institute, McGill University, Montréal, Québec, Canada [2] Department of Pathology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
24
1] Division of Genetics and Cell Biology, San Raffaele Research Institute, Milano, Italy [2] Department of Psychiatry, Trinity Centre for Health Sciences, St James Hospital, James's Street, Dublin 8, Ireland.
25
Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.
26
1] Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada [2] Department of Oncology, Department of Epidemiology, Biostatistics and Occupational Health, Jewish General Hospital, Lady Davis Institute, McGill University, Montréal, Québec, Canada [3] Laboratory of Genetics, NIA, Baltimore, Maryland 21224, USA [4] Department of Pathology, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
27
1] Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia [2] School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia [3] Laboratory of Genetics, NIA, Baltimore, Maryland 21224, USA.

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.

PMID:
25743335
PMCID:
PMC4366514
DOI:
10.1038/ncomms6681
[Indexed for MEDLINE]
Free PMC Article

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