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

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dc.contributorHáskóli Íslandsen_US
dc.contributorUniversity of Icelanden_US
dc.contributor.authorZhou, Wei
dc.contributor.authorBrumpton, Ben
dc.contributor.authorKabil, Omer
dc.contributor.authorGudmundsson, Julius
dc.contributor.authorThorleifsson, Gudmar
dc.contributor.authorWeinstock, Josh
dc.contributor.authorZawistowski, Matthew
dc.contributor.authorNielsen, Jonas B.
dc.contributor.authorChaker, Layal
dc.contributor.authorMedici, Marco
dc.contributor.authorTeumer, Alexander
dc.contributor.authorNaitza, Silvia
dc.contributor.authorSanna, Serena
dc.contributor.authorSchultheiss, Ulla T.
dc.contributor.authorCappola, Anne
dc.contributor.authorKarjalainen, Juha
dc.contributor.authorKurki, Mitja
dc.contributor.authorOneka, Morgan
dc.contributor.authorTaylor, Peter
dc.contributor.authorFritsche, Lars G.
dc.contributor.authorGraham, Sarah E.
dc.contributor.authorWolford, Brooke N.
dc.contributor.authorOverton, William
dc.contributor.authorRasheed, Humaira
dc.contributor.authorHaug, Eirin B.
dc.contributor.authorGabrielsen, Maiken E.
dc.contributor.authorSkogholt, Anne Heidi
dc.contributor.authorSurakka, Ida
dc.contributor.authorDavey Smith, George
dc.contributor.authorPandit, Anita
dc.contributor.authorRoychowdhury, Tanmoy
dc.contributor.authorHornsby, Whitney E.
dc.contributor.authorJonasson, Jon G.
dc.contributor.authorSenter, Leigha
dc.contributor.authorLiyanarachchi, Sandya
dc.contributor.authorRingel, Matthew D.
dc.contributor.authorXu, Li
dc.contributor.authorKiemeney, Lambertus A.
dc.contributor.authorHe, Huiling
dc.contributor.authorNetea-Maier, Romana T.
dc.contributor.authorMayordomo, Jose I.
dc.contributor.authorPlantinga, Theo S.
dc.contributor.authorHrafnkelsson, Jon
dc.contributor.authorHjartarson, Hannes
dc.contributor.authorSturgis, Erich M.
dc.contributor.authorPalotie, Aarno
dc.contributor.authorDaly, Mark
dc.contributor.authorCitterio, Cintia E.
dc.contributor.authorArvan, Peter
dc.contributor.authorBrummett, Chad M.
dc.contributor.authorBoehnke, Michael
dc.contributor.authorde la Chapelle, Albert
dc.contributor.authorStefansson, Kari
dc.contributor.authorHveem, Kristian
dc.contributor.authorWiller, Cristen J.
dc.contributor.authorÅsvold, Bjørn Olav
dc.contributor.departmentLæknadeild (HÍ)en_US
dc.contributor.departmentFaculty of Medicine (UI)en_US
dc.contributor.schoolHeilbrigðisvísindasvið (HÍ)en_US
dc.contributor.schoolSchool of Health Sciences (UI)en_US
dc.date.accessioned2020-10-23T10:36:57Z
dc.date.available2020-10-23T10:36:57Z
dc.date.issued2020-08-07
dc.descriptionPublsiher's version (útgefin grein)en_US
dc.description.abstractThyroid 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.en_US
dc.description.sponsorshipWe 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.en_US
dc.description.versionPeer Revieweden_US
dc.format.extent3981en_US
dc.identifier.citationZhou, 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-zen_US
dc.identifier.doi10.1038/s41467-020-17718-z
dc.identifier.issn2041-1723
dc.identifier.journalNature Communicationsen_US
dc.identifier.urihttps://hdl.handle.net/20.500.11815/2135
dc.language.isoenen_US
dc.publisherSpringer Science and Business Media LLCen_US
dc.relation.ispartofseriesNature Communications;11(1)
dc.relation.urlhttps://www.nature.com/articles/s41467-020-17718-z#Abs1en_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectThyroid stimulating hormoneen_US
dc.subjectDevelopmenten_US
dc.subjectMetabolismen_US
dc.subjectGWAS meta-analysisen_US
dc.subjectGenetic analysisen_US
dc.subjectErfðarannsókniren_US
dc.subjectEfnaskiptien_US
dc.subjectHormónaren_US
dc.titleGWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid canceren_US
dc.typeinfo:eu-repo/semantics/articleen_US
dcterms.licenseOpen 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/.en_US

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