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

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

doi:10.1038/s41467-020-17718-z

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

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

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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.

Original language	English
Pages (from-to)	3981
Number of pages	3981
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-17718-z
Publication status	Published - 7 Aug 2020

Other keywords

Thyroid stimulating hormone
Development
Metabolism
GWAS meta-analysis
Genetic analysis
Erfðarannsóknir
Efnaskipti
Hormónar
TSH
Thyroid cancer
Skjaldkirtilssjúkdómar
Skjaldkirtill
Thyrotropin
Thyroid Neoplasms

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10.1038/s41467-020-17718-z

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Zhou, W., Brumpton, B., Kabil, O., Gudmundsson, J., Thorleifsson, G., Weinstock, J., Zawistowski, M., Nielsen, J. B., Chaker, L., Medici, M., Teumer, A., Naitza, S., Sanna, S., Schultheiss, U. T., Cappola, A., Karjalainen, J., Kurki, M., Oneka, M., Taylor, P., ... Åsvold, B. O. (2020). GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer. Nature Communications, 11(1), 3981. https://doi.org/10.1038/s41467-020-17718-z

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title = "GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer",

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.",

keywords = "Thyroid stimulating hormone, Development, Metabolism, GWAS meta-analysis, Genetic analysis, Erf{\dh}aranns{\'o}knir, Efnaskipti, Horm{\'o}nar, TSH, Thyroid cancer, Skjaldkirtilssj{\'u}kd{\'o}mar, Skjaldkirtill, Thyrotropin, Thyroid Neoplasms, Thyroid stimulating hormone, Development, Metabolism, GWAS meta-analysis, Genetic analysis, Erf{\dh}aranns{\'o}knir, Efnaskipti, Horm{\'o}nar, TSH, Thyroid cancer, Skjaldkirtilssj{\'u}kd{\'o}mar, Skjaldkirtill, Thyrotropin, Thyroid Neoplasms",

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

year = "2020",

month = aug,

day = "7",

doi = "10.1038/s41467-020-17718-z",

language = "English",

volume = "11",

pages = "3981",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Zhou, W, Brumpton, B, Kabil, O, Gudmundsson, J, Thorleifsson, G, Weinstock, J, Zawistowski, M, Nielsen, JB, Chaker, L, Medici, M, Teumer, A, Naitza, S, Sanna, S, Schultheiss, UT, Cappola, A, Karjalainen, J, Kurki, M, Oneka, M, Taylor, P, Fritsche, LG, Graham, SE, Wolford, BN, Overton, W, Rasheed, H, Haug, EB, Gabrielsen, ME, Skogholt, AH, Surakka, I, Davey Smith, G, Pandit, A, Roychowdhury, T, Hornsby, WE, Jonasson, JG, Senter, L, Liyanarachchi, S, Ringel, MD, Xu, L, Kiemeney, LA, He, H, Netea-Maier, RT, Mayordomo, JI, Plantinga, TS, Hrafnkelsson, J, Hjartarson, H, Sturgis, EM, Palotie, A, Daly, M, Citterio, CE, Arvan, P, Brummett, CM, Boehnke, M, de la Chapelle, A, Stefansson, K, Hveem, K, Willer, CJ & Åsvold, BO 2020, 'GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer', Nature Communications, vol. 11, no. 1, pp. 3981. https://doi.org/10.1038/s41467-020-17718-z

TY - JOUR

T1 - GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

AU - Zhou, Wei

AU - Brumpton, Ben

AU - Kabil, Omer

AU - Gudmundsson, Julius

AU - Thorleifsson, Gudmar

AU - Weinstock, Josh

AU - Zawistowski, Matthew

AU - Nielsen, Jonas B.

AU - Chaker, Layal

AU - Medici, Marco

AU - Teumer, Alexander

AU - Naitza, Silvia

AU - Sanna, Serena

AU - Schultheiss, Ulla T.

AU - Cappola, Anne

AU - Karjalainen, Juha

AU - Kurki, Mitja

AU - Oneka, Morgan

AU - Taylor, Peter

AU - Fritsche, Lars G.

AU - Graham, Sarah E.

AU - Wolford, Brooke N.

AU - Overton, William

AU - Rasheed, Humaira

AU - Haug, Eirin B.

AU - Gabrielsen, Maiken E.

AU - Skogholt, Anne Heidi

AU - Surakka, Ida

AU - Davey Smith, George

AU - Pandit, Anita

AU - Roychowdhury, Tanmoy

AU - Hornsby, Whitney E.

AU - Jonasson, Jon G.

AU - Senter, Leigha

AU - Liyanarachchi, Sandya

AU - Ringel, Matthew D.

AU - Xu, Li

AU - Kiemeney, Lambertus A.

AU - He, Huiling

AU - Netea-Maier, Romana T.

AU - Mayordomo, Jose I.

AU - Plantinga, Theo S.

AU - Hrafnkelsson, Jon

AU - Hjartarson, Hannes

AU - Sturgis, Erich M.

AU - Palotie, Aarno

AU - Daly, Mark

AU - Citterio, Cintia E.

AU - Arvan, Peter

AU - Brummett, Chad M.

AU - Boehnke, Michael

AU - de la Chapelle, Albert

AU - Stefansson, Kari

AU - Hveem, Kristian

AU - Willer, Cristen J.

AU - Åsvold, Bjørn Olav

PY - 2020/8/7

Y1 - 2020/8/7

N2 - 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.

AB - 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.

KW - Thyroid stimulating hormone

KW - Development

KW - Metabolism

KW - GWAS meta-analysis

KW - Genetic analysis

KW - Erfðarannsóknir

KW - Efnaskipti

KW - Hormónar

KW - TSH

KW - Thyroid cancer

KW - Skjaldkirtilssjúkdómar

KW - Skjaldkirtill

KW - Thyrotropin

KW - Thyroid Neoplasms

KW - Thyroid stimulating hormone

KW - Development

KW - Metabolism

KW - GWAS meta-analysis

KW - Genetic analysis

KW - Erfðarannsóknir

KW - Efnaskipti

KW - Hormónar

KW - TSH

KW - Thyroid cancer

KW - Skjaldkirtilssjúkdómar

KW - Skjaldkirtill

KW - Thyrotropin

KW - Thyroid Neoplasms

U2 - 10.1038/s41467-020-17718-z

DO - 10.1038/s41467-020-17718-z

M3 - Article

C2 - 32769997

SN - 2041-1723

VL - 11

SP - 3981

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

Abstract

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