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

Wei Zhou; Ben M 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  Schultheiss; Anne Cappola; Juha Karjalainen; Mitja I. Kurki; Morgan Oneka; Peter Taylor; Lars G Fritsche; Sarah Graham; Brooke Wolford; William Overton; Humaira Rasheed; Eirin B Haug; Maiken Gabrielsen; Anne Heidi Skogholt; Ida Surakka; George Davey Smith; Anita Pandit; Tanmoy Roychowdhury; Whitney Hornsby; Jon G. Jonasson; Leigha Senter; Sandya  Liyanarachchi; Matthew Ringel; LI Xu; Lambertus A Kiemeney; Huiling He; Romana Netea-Maier; José I. Mayordomo; Theo Plantinga; Jon Hrafnkelsson; Hannes Hjartarson; Erich Sturgis; Aarno Palotie; Mark Daly; Cintia Citterio; Peter Arvan; Chad M Brummett; Michael Boehnke; Albert de la Chapelle; Kari Stefansson; Kristian Hveem; Cristen J Willer; Bjorn O Asvold

doi:10.1038/s41467-020-17718-z

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

Wei Zhou^*, Ben M 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 Schultheiss, Anne Cappola, Juha Karjalainen, Mitja I. Kurki, Morgan Oneka, Peter Taylor, Lars G FritscheSarah Graham, Brooke Wolford, William Overton, Humaira Rasheed, Eirin B Haug, Maiken Gabrielsen, Anne Heidi Skogholt, Ida Surakka, George Davey Smith, Anita Pandit, Tanmoy Roychowdhury, Whitney Hornsby, Jon G. Jonasson, Leigha Senter, Sandya Liyanarachchi, Matthew Ringel, LI Xu, Lambertus A Kiemeney, Huiling He, Romana Netea-Maier, José I. Mayordomo, Theo Plantinga, Jon Hrafnkelsson, Hannes Hjartarson, Erich Sturgis, Aarno Palotie, Mark Daly, Cintia Citterio, Peter Arvan, Chad M Brummett, Michael Boehnke, Albert de la Chapelle, Kari Stefansson, Kristian Hveem, Cristen J Willer, Bjorn O Asvold^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

114 Citations (Scopus)

121 Downloads (Pure)

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 novel. 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 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
Article number	3981
Number of pages	13
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-020-17718-z
Publication status	Published - 7 Aug 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Access to Document

10.1038/s41467-020-17718-z

Full-text PDF (final published version)
This is the final published version of the article (version of record). It first appeared online via Nature Research at https://doi.org/10.1038/s41467-020-17718-z . Please refer to any applicable terms of use of the publisher.
Final published version, 1.22 MBLicence: CC BY

Handle.net

Persistent link

Embargoed Document

Full-text PDF (author accepted manuscript)
Accepted author manuscript, 1.31 MB

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal
Gaunt, L. F. (Principal Investigator) & Davey Smith, G. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research

Cite this

Zhou, W., Brumpton, B. M., 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., Cappola, A., Karjalainen, J., Kurki, M. I., Oneka, M., Taylor, P., ... Asvold, B. O. (2020). GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse genetic association with thyroid cancer. Nature Communications, 11, Article 3981. https://doi.org/10.1038/s41467-020-17718-z

@article{98bb11fe9c154e5dbfdc12393139c686,

title = "GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse genetic 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 novel. 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 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.",

author = "Wei Zhou and Brumpton, \{Ben M\} 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 Ulla Schultheiss and Anne Cappola and Juha Karjalainen and Kurki, \{Mitja I.\} and Morgan Oneka and Peter Taylor and Fritsche, \{Lars G\} and Sarah Graham and Brooke Wolford and William Overton and Humaira Rasheed and Haug, \{Eirin B\} and Maiken Gabrielsen and Skogholt, \{Anne Heidi\} and Ida Surakka and \{Davey Smith\}, George and Anita Pandit and Tanmoy Roychowdhury and Whitney Hornsby and Jonasson, \{Jon G.\} and Leigha Senter and Sandya Liyanarachchi and Matthew Ringel and LI Xu and Kiemeney, \{Lambertus A\} and Huiling He and Romana Netea-Maier and Mayordomo, \{Jos{\'e} I.\} and Theo Plantinga and Jon Hrafnkelsson and Hannes Hjartarson and Erich Sturgis and Aarno Palotie and Mark Daly and Cintia Citterio and Peter Arvan and Brummett, \{Chad M\} and Michael Boehnke and Chapelle, \{Albert de la\} and Kari Stefansson and Kristian Hveem and Willer, \{Cristen J\} and Asvold, \{Bjorn O\}",

year = "2020",

month = aug,

day = "7",

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

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Zhou, W, Brumpton, BM, Kabil, O, Gudmundsson, J, Thorleifsson, G, Weinstock, J, Zawistowski, M, Nielsen, JB, Chaker, L, Medici, M, Teumer, A, Naitza, S, Sanna, S, Schultheiss, U, Cappola, A, Karjalainen, J, Kurki, MI, Oneka, M, Taylor, P, Fritsche, LG, Graham, S, Wolford, B, Overton, W, Rasheed, H, Haug, EB, Gabrielsen, M, Skogholt, AH, Surakka, I, Davey Smith, G, Pandit, A, Roychowdhury, T, Hornsby, W, Jonasson, JG, Senter, L, Liyanarachchi, S, Ringel, M, Xu, LI, Kiemeney, LA, He, H, Netea-Maier, R, Mayordomo, JI, Plantinga, T, Hrafnkelsson, J, Hjartarson, H, Sturgis, E, Palotie, A, Daly, M, Citterio, C, Arvan, P, Brummett, CM, Boehnke, M, Chapelle, ADL, Stefansson, K, Hveem, K, Willer, CJ & Asvold, BO 2020, 'GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse genetic association with thyroid cancer', Nature Communications, vol. 11, 3981. https://doi.org/10.1038/s41467-020-17718-z

TY - JOUR

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

AU - Zhou, Wei

AU - Brumpton, Ben M

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

AU - Cappola, Anne

AU - Karjalainen, Juha

AU - Kurki, Mitja I.

AU - Oneka, Morgan

AU - Taylor, Peter

AU - Fritsche, Lars G

AU - Graham, Sarah

AU - Wolford, Brooke

AU - Overton, William

AU - Rasheed, Humaira

AU - Haug, Eirin B

AU - Gabrielsen, Maiken

AU - Skogholt, Anne Heidi

AU - Surakka, Ida

AU - Davey Smith, George

AU - Pandit, Anita

AU - Roychowdhury, Tanmoy

AU - Hornsby, Whitney

AU - Jonasson, Jon G.

AU - Senter, Leigha

AU - Liyanarachchi, Sandya

AU - Ringel, Matthew

AU - Xu, LI

AU - Kiemeney, Lambertus A

AU - He, Huiling

AU - Netea-Maier, Romana

AU - Mayordomo, José I.

AU - Plantinga, Theo

AU - Hrafnkelsson, Jon

AU - Hjartarson, Hannes

AU - Sturgis, Erich

AU - Palotie, Aarno

AU - Daly, Mark

AU - Citterio, Cintia

AU - Arvan, Peter

AU - Brummett, Chad M

AU - Boehnke, Michael

AU - Chapelle, Albert de la

AU - Stefansson, Kari

AU - Hveem, Kristian

AU - Willer, Cristen J

AU - Asvold, Bjorn O

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 novel. 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 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 novel. 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 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.

U2 - 10.1038/s41467-020-17718-z

DO - 10.1038/s41467-020-17718-z

M3 - Article (Academic Journal)

C2 - 32769997

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

M1 - 3981

ER -

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

Abstract

UN SDGs

Access to Document

Handle.net

Embargoed Document

Fingerprint

Projects

IEU: MRC Integrative Epidemiology Unit Quinquennial renewal

Cite this