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

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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 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

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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

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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 = "Springer Nature",

}

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

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