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

Zhou, Wei; Brumpton, Ben; Kabil, Omer; Gudmundsson, Julius; Thorleifsson, Gudmar; Weinstock, Josh; Zawistowski, Matthew; Nielsen, Jonas B.; Chaker, Layal; Medici, Marco; Teumer, Alexander; Naitza, Silvia; Sanna, Serena; Schultheiss, Ulla T.; Cappola, Anne; Karjalainen, Juha; Kurki, Mitja; Oneka, Morgan; Taylor, Peter; Fritsche, Lars G.; Graham, Sarah E.; Wolford, Brooke N.; Overton, William; Rasheed, Humaira; Haug, Eirin B.; Gabrielsen, Maiken E.; Skogholt, Anne Heidi; Surakka, Ida; Davey Smith, George; Pandit, Anita; Roychowdhury, Tanmoy; Hornsby, Whitney E.; Jonasson, Jon G.; Senter, Leigha; Liyanarachchi, Sandya; Ringel, Matthew D.; Xu, Li; Kiemeney, Lambertus A.; He, Huiling; Netea-Maier, Romana T.; Mayordomo, Jose I.; Plantinga, Theo S.; Hrafnkelsson, Jon; Hjartarson, Hannes; Sturgis, Erich M.; Palotie, Aarno; Daly, Mark; Citterio, Cintia E.; Arvan, Peter; Brummett, Chad M.; Boehnke, Michael; de la Chapelle, Albert; Stefansson, Kari; Hveem, Kristian; Willer, Cristen J.; Åsvold, Bjørn Olav

Opin vísindi
→
Háskóli Íslands
→
Greinar- HÍ
→
Skoða verk

dc.contributor	Háskóli Íslands
dc.contributor	University of Iceland
dc.contributor.author	Zhou, Wei
dc.contributor.author	Brumpton, Ben
dc.contributor.author	Kabil, Omer
dc.contributor.author	orcid.org/0000-0003-2517-4763 Gudmundsson, Julius
dc.contributor.author	orcid.org/0000-0003-4623-9087 Thorleifsson, Gudmar
dc.contributor.author	Weinstock, Josh
dc.contributor.author	Zawistowski, Matthew
dc.contributor.author	Nielsen, Jonas B.
dc.contributor.author	Chaker, Layal
dc.contributor.author	Medici, Marco
dc.contributor.author	Teumer, Alexander
dc.contributor.author	Naitza, Silvia
dc.contributor.author	Sanna, Serena
dc.contributor.author	Schultheiss, Ulla T.
dc.contributor.author	Cappola, Anne
dc.contributor.author	Karjalainen, Juha
dc.contributor.author	Kurki, Mitja
dc.contributor.author	Oneka, Morgan
dc.contributor.author	Taylor, Peter
dc.contributor.author	Fritsche, Lars G.
dc.contributor.author	Graham, Sarah E.
dc.contributor.author	Wolford, Brooke N.
dc.contributor.author	Overton, William
dc.contributor.author	Rasheed, Humaira
dc.contributor.author	Haug, Eirin B.
dc.contributor.author	Gabrielsen, Maiken E.
dc.contributor.author	Skogholt, Anne Heidi
dc.contributor.author	Surakka, Ida
dc.contributor.author	Davey Smith, George
dc.contributor.author	Pandit, Anita
dc.contributor.author	Roychowdhury, Tanmoy
dc.contributor.author	Hornsby, Whitney E.
dc.contributor.author	Jonasson, Jon G.
dc.contributor.author	Senter, Leigha
dc.contributor.author	Liyanarachchi, Sandya
dc.contributor.author	Ringel, Matthew D.
dc.contributor.author	Xu, Li
dc.contributor.author	Kiemeney, Lambertus A.
dc.contributor.author	He, Huiling
dc.contributor.author	Netea-Maier, Romana T.
dc.contributor.author	Mayordomo, Jose I.
dc.contributor.author	Plantinga, Theo S.
dc.contributor.author	Hrafnkelsson, Jon
dc.contributor.author	Hjartarson, Hannes
dc.contributor.author	Sturgis, Erich M.
dc.contributor.author	Palotie, Aarno
dc.contributor.author	Daly, Mark
dc.contributor.author	Citterio, Cintia E.
dc.contributor.author	Arvan, Peter
dc.contributor.author	Brummett, Chad M.
dc.contributor.author	Boehnke, Michael
dc.contributor.author	de la Chapelle, Albert
dc.contributor.author	orcid.org/0000-0003-1676-864X Stefansson, Kari
dc.contributor.author	Hveem, Kristian
dc.contributor.author	Willer, Cristen J.
dc.contributor.author	Åsvold, Bjørn Olav
dc.date.accessioned	2020-10-23T10:36:57Z
dc.date.available	2020-10-23T10:36:57Z
dc.date.issued	2020-08-07
dc.identifier.citation	Zhou, W., Brumpton, B., Kabil, O. et al. GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer. Nature Communications 11, 3981 (2020). https://doi.org/10.1038/s41467-020-17718-z
dc.identifier.issn	2041-1723
dc.identifier.uri	https://hdl.handle.net/20.500.11815/2135
dc.description	Publsiher's version (útgefin grein)
dc.description.abstract	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.
dc.description.sponsorship	We acknowledge the University of Michigan Precision Health Initiative and Medical School Central Biorepository for providing biospecimen storage, management, processing, and distribution services, and the Center for Statistical Genetics in the Department of Biostatistics at the School of Public Health for genotype data curation, imputation, and management in support of this research (for MGI cohort). The biochemical work at the University of Michigan was done with funding from NIH R01 DK-40344. This research has been conducted using the UK Biobank Resource under application number 24460. The HUNT Study is a collaboration between the HUNT Research Centre (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research and Innovation in Central Norway; and the Joint Research Committee between St Olav’s Hospital and the Faculty of Medicine and Health Sciences, NTNU. We thank Sean Caron for web development for data sharing. Support for this research was provided by NIH grant DK062370 (M.B.). Ohio State Cohort was supported by NIH P50CA168505 SPORE (M.D.R. and A.d.l.C.). Support for the HUNT and MGI analysis was additionally provided by R35HL135824 (C.J.W.) and R01HL109946 (C.J.W.). W.Z. was supported by the National Human Genome Research Institute of the National Institutes of Health under award number T32HG010464. G.D.S., B.B., H.R. and E.B.H. work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol MC_UU_00011/1.
dc.format.extent	3981
dc.language.iso	en
dc.publisher	Springer Science and Business Media LLC
dc.relation.ispartofseries	Nature Communications;11(1)
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	Thyroid stimulating hormone
dc.subject	Development
dc.subject	Metabolism
dc.subject	GWAS meta-analysis
dc.subject	Genetic analysis
dc.subject	Erfðarannsóknir
dc.subject	Efnaskipti
dc.subject	Hormónar
dc.title	GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer
dc.type	info:eu-repo/semantics/article
dcterms.license	Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
dc.description.version	Peer Reviewed
dc.identifier.journal	Nature Communications
dc.identifier.doi	10.1038/s41467-020-17718-z
dc.relation.url	https://www.nature.com/articles/s41467-020-17718-z#Abs1
dc.contributor.department	Læknadeild (HÍ)
dc.contributor.department	Faculty of Medicine (UI)
dc.contributor.school	Heilbrigðisvísindasvið (HÍ)
dc.contributor.school	School of Health Sciences (UI)