GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer.

Genetic Loci Genetic Pleiotropy Genetic Predisposition to Disease Genome-Wide Association Study Goiter / genetics Humans Mendelian Randomization Analysis Multifactorial Inheritance / genetics Mutation, Missense / genetics Phenotype Physical Chromosome Mapping Prevalence Risk Factors Thyroglobulin / genetics Thyroid Neoplasms / epidemiology Thyrotropin / genetics

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
07 08 2020
Historique:
received: 07 11 2019
accepted: 08 07 2020
entrez: 10 8 2020
pubmed: 10 8 2020
medline: 10 9 2020
Statut: epublish

Résumé

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.

Identifiants

DOI: 10.1038/s41467-020-17718-z PMID: 32769997 PMC: PMC7414135
pubmed: 32769997
doi: 10.1038/s41467-020-17718-z
pii: 10.1038/s41467-020-17718-z
pmc: PMC7414135
doi:

Substances chimiques

Thyrotropin 9002-71-5
Thyroglobulin 9010-34-8

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

3981

Subventions

Organisme : NHLBI NIH HHS
ID : R01 HL109946
Pays : United States
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : T32 HG010464
Pays : United States
Organisme : NHGRI NIH HHS
ID : T32 HG000040
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM070449
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK040344
Pays : United States
Organisme : NIDDK NIH HHS
ID : U01 DK062370
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016058
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK020572
Pays : United States
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R56 DK062370
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA168505
Pays : United States
Organisme : Medical Research Council
ID : MC_UU_00011/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R35 HL135824
Pays : United States
Organisme : NIA NIH HHS
ID : K24 AG042765
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK062370
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL105756
Pays : United States

Commentaires et corrections

Type : ErratumIn

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Auteurs

Wei Zhou (W)

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA. wzhou@broadinstitute.org.
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA. wzhou@broadinstitute.org.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. wzhou@broadinstitute.org.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. wzhou@broadinstitute.org.
ORCID: 0000-0001-7719-0859

Ben Brumpton (B)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Department of Thoracic Medicine, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
ORCID: 0000-0002-3058-1059

Omer Kabil (O)

Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Division of Metabolism Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Julius Gudmundsson (J)

deCODE genetics/AMGEN, 101, Reykjavik, Iceland.

Gudmar Thorleifsson (G)

deCODE genetics/AMGEN, 101, Reykjavik, Iceland.

Josh Weinstock (J)

Center for Statistical Genetics and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
ORCID: 0000-0001-7013-1899

Matthew Zawistowski (M)

Center for Statistical Genetics and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
ORCID: 0000-0002-3005-083X

Jonas B Nielsen (JB)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Department of Epidemiology Research, Statens Serum Institute, Copenhagen, Denmark.
ORCID: 0000-0002-6654-2852

Layal Chaker (L)

Erasmus MC Academic Center for Thyroid Diseases, Rotterdam, The Netherlands.
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

Marco Medici (M)

Erasmus MC Academic Center for Thyroid Diseases, Rotterdam, The Netherlands.
Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, 6500HB, Nijmegen, The Netherlands.

Alexander Teumer (A)

Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany.
ORCID: 0000-0002-8309-094X

Silvia Naitza (S)

Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato, Monserrato, Italy.

Serena Sanna (S)

Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato, Monserrato, Italy.
Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
ORCID: 0000-0002-3768-1749

Ulla T Schultheiss (UT)

Faculty of Medicine and Medical Center, Institute of Genetic Epidemiology, University of Freiburg, Freiburg, Germany.
Faculty of Medicine and Medical Center, Department of Medicine IV-Nephrology and Primary Care, University of Freiburg, Freiburg, Germany.

Anne Cappola (A)

Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Juha Karjalainen (J)

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, Helsinki, 00014, Finland.

Mitja Kurki (M)

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, Helsinki, 00014, Finland.

Morgan Oneka (M)

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
ORCID: 0000-0002-9672-0445

Peter Taylor (P)

Thyroid Research Group, Systems Immunity Research Institute, Cardiff University School of Medicine, Cardiff, UK.

Lars G Fritsche (LG)

Center for Statistical Genetics and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
ORCID: 0000-0002-2110-1690

Sarah E Graham (SE)

Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
ORCID: 0000-0003-1271-2489

Brooke N Wolford (BN)

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
Center for Statistical Genetics and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
ORCID: 0000-0003-3153-1552

William Overton (W)

Center for Statistical Genetics and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

Humaira Rasheed (H)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
ORCID: 0000-0002-3331-5864

Eirin B Haug (EB)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Maiken E Gabrielsen (ME)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Faculty of Medicine and Health Sciences, Department of Public Health and Nursing, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.

Anne Heidi Skogholt (AH)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
Faculty of Medicine and Health Sciences, Department of Public Health and Nursing, Norwegian University of Science and Technology, NTNU, Trondheim, Norway.

Ida Surakka (I)

Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

George Davey Smith (G)

Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
ORCID: 0000-0002-1407-8314

Anita Pandit (A)

Center for Statistical Genetics and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.

Tanmoy Roychowdhury (T)

Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Whitney E Hornsby (WE)

Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Jon G Jonasson (JG)

Landspitali-University Hospital, 101, Reykjavik, Iceland.
Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland.
The Icelandic Cancer Registry, 105, Reykjavik, Iceland.

Leigha Senter (L)

Division of Human Genetics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, 43210, USA.

Sandya Liyanarachchi (S)

Department of Cancer Biology and Genetics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, 43210, USA.

Matthew D Ringel (MD)

Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University, Columbus, Ohio, 43210, USA.

Li Xu (L)

Department of Head and Neck Surgery, and Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA.

Lambertus A Kiemeney (LA)

Radboud University Medical Centre, Radboud Institute for Health Sciences, 6500HB, Nijmegen, The Netherlands.
ORCID: 0000-0002-2368-1326

Huiling He (H)

Department of Cancer Biology and Genetics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, 43210, USA.

Romana T Netea-Maier (RT)

Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Centre, Radboud Institute for Molecular Life Sciences, 6500HB, Nijmegen, The Netherlands.
ORCID: 0000-0002-9603-0460

Jose I Mayordomo (JI)

University of Colorado Hospital, Aurora, Colorado, 80045, USA.

Theo S Plantinga (TS)

Department of Pathology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500HB, Nijmegen, The Netherlands.
ORCID: 0000-0003-4990-6084

Jon Hrafnkelsson (J)

Landspitali-University Hospital, 101, Reykjavik, Iceland.

Hannes Hjartarson (H)

Landspitali-University Hospital, 101, Reykjavik, Iceland.

Erich M Sturgis (EM)

Department of Head and Neck Surgery, and Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 77030, USA.

Aarno Palotie (A)

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, Helsinki, 00014, Finland.

Mark Daly (M)

Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Institute for Molecular Medicine Finland, Helsinki Institute of Life Sciences, University of Helsinki, Helsinki, 00014, Finland.

Cintia E Citterio (CE)

Division of Metabolism Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología y Biotecnología/Cátedra de Genética, Buenos Aires, C1113AAD, Argentina.
CONICET-Universidad de Buenos Aires, Instituto de Inmunología, Genética y Metabolismo (INIGEM), C1120AAR, Buenos Aires, Argentina.
ORCID: 0000-0002-3547-5458

Peter Arvan (P)

Division of Metabolism Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Chad M Brummett (CM)

Division of Pain Medicine, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Michael Boehnke (M)

Center for Statistical Genetics and Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
ORCID: 0000-0002-6442-7754

Albert de la Chapelle (A)

Department of Cancer Biology and Genetics, Ohio State University Comprehensive Cancer Center, Columbus, Ohio, 43210, USA.
ORCID: 0000-0001-9345-9248

Kari Stefansson (K)

deCODE genetics/AMGEN, 101, Reykjavik, Iceland.
Faculty of Medicine, University of Iceland, 101, Reykjavik, Iceland.
ORCID: 0000-0003-1676-864X

Kristian Hveem (K)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway.
HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, 7600, Norway.
Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, 7600, Norway.

Cristen J Willer (CJ)

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA.
Department of Internal Medicine, Division of Cardiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
ORCID: 0000-0001-5645-4966

Bjørn Olav Åsvold (BO)

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Trondheim, Norway. bjorn.o.asvold@ntnu.no.
HUNT Research Centre, Department of Public Health and Nursing, NTNU, Norwegian University of Science and Technology, Levanger, 7600, Norway. bjorn.o.asvold@ntnu.no.
Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway. bjorn.o.asvold@ntnu.no.
ORCID: 0000-0003-3837-2101

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Pléiotropie › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Maladies endocriniennes › Maladies de la thyroïde › Goitre › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Techniques d'investigation › Analyse de randomisation mendélienne › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Phénomènes génétiques › Modes de transmission héréditaire › Hérédité multifactorielle › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation faux-sens › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Cartographie chromosomique › Cartographie physique de chromosome › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Collecte de données › Registre civil › Morbidité › Prévalence › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Facteurs de risque › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Iodoprotéines › Thyroglobuline › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Maladies endocriniennes › Maladies de la thyroïde › Tumeurs de la thyroïde › GWAS of thyroid stimulating hormone highlights...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Hormones peptidiques › Hormones hypophysaires › Hormones antéhypophysaires › Thyréostimuline › GWAS of thyroid stimulating hormone highlights...