Whole-genome sequence-based analysis of thyroid function.
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.
Thyroid Research Group, Institute of Molecular &Experimental Medicine, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
Peter N
PN
Taylor
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.
Eleonora
E
Porcu
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
Shelby
S
Chew
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
Purdey J
PJ
Campbell
Division of Genetics and Cell Biology, San Raffaele Research Institute, Milano, Italy.
Michela
M
Traglia
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
Suzanne J
SJ
Brown
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.
Benjamin H
BH
Mullin
MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Bristol, UK.
Hashem A
HA
Shihab
MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Bristol, UK.
Josine
J
Min
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
Klaudia
K
Walter
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
Yasin
Y
Memari
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
Jie
J
Huang
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
Michael R
0000000190977381
MR
Barnes
1] Pathwest Laboratory Medicine WA, Nedlands, Western Australia, Australia [2] School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
John P
JP
Beilby
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.
Pimphen
P
Charoen
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
Petr
P
Danecek
Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.
Frank
F
Dudbridge
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.
Vincenzo
V
Forgetta
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.
Celia
C
Greenwood
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.
Elin
E
Grundberg
MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Box 285, Cambridge, UK.
Andrew D
AD
Johnson
1] Pathwest Laboratory Medicine WA, Nedlands, Western Australia, Australia [2] School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Western Australia, Australia.
Jennie
J
Hui
1] Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia [2] Pathwest Laboratory Medicine WA, Nedlands, Western Australia, Australia.
Ee M
EM
Lim
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
Shane
S
McCarthy
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
Dawn
D
Muddyman
Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
Vijay
0000000315518411
V
Panicker
1] Department of Twin Research and Genetic Epidemiology, King's College London, London, UK [2] Laboratory of Genetics, NIA, Baltimore, Maryland 21224, USA.
John R B
JR
Perry
Laboratory of Genetics, NIA, Baltimore, Maryland 21224, USA.
Jordana T
JT
Bell
Laboratory of Genetics, NIA, Baltimore, Maryland 21224, USA.
Wei
W
Yuan
MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Bristol, UK.
Caroline
C
Relton
MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Bristol, UK.
Tom
T
Gaunt
Facharzt für Laboratoriumsmedizin, Geschäftsführer amedes Ost, Halle/Leipzig GmbH, Leipziger Chaussee 191f, 06112 Halle (Saale), Germany.
David
D
Schlessinger
Center for Statistical Genetics, Biostatistics Department, University of Michigan, Ann Arbor, Michigan, USA.
Goncalo
G
Abecasis
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.
Francesco
F
Cucca
Laboratory of Genetics, NIA, Baltimore, Maryland 21224, USA.
Gabriela L
GL
Surdulescu
Institute of Molecular Genetics-CNR, Pavia, Italy.
Wolfram
W
Woltersdorf
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
Eleftheria
E
Zeggini
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.
Hou-Feng
HF
Zheng
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.
Daniela
D
Toniolo
Thyroid Research Group, Institute of Molecular &Experimental Medicine, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
Colin M
CM
Dayan
Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.
Silvia
S
Naitza
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.
John P
JP
Walsh
Laboratory of Genetics, NIA, Baltimore, Maryland 21224, USA.
Tim
T
Spector
MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Bristol, UK.
George
G
Davey Smith
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
Richard
R
Durbin
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.
J Brent
JB
Richards
Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.
Serena
S
Sanna
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.
Nicole
0000000310953852
N
Soranzo
MRC Integrative Epidemiology Unit at the University of Bristol, University of Bristol, Bristol, UK.
Nicholas J
NJ
Timpson
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.
Scott G
SG
Wilson
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics; D056726:Genetic Association Studies; D023281:Genomics / Q000379:methods; D006801:Humans; D016704:Synapsins / Q000235:genetics / Q000378:metabolism*; D013961:Thyroid Gland / Q000378:metabolism / Q000502:physiology*; D013972:Thyrotropin / Q000235:genetics / Q000378:metabolism*; D013974:Thyroxine / Q000235:genetics / Q000378:metabolism*; D006113:United Kingdom
C000604872:SYN2 protein, human; D016704:Synapsins; D013972:Thyrotropin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C468781:PDE8B protein, human; D013974:Thyroxine