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 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; Bjorn Olav Asvold

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 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, Bjorn Olav Asvold

Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

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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.

Originele taal-2	English
Artikelnummer	3981
Aantal pagina's	13
Tijdschrift	Nature Communications
Volume	11
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1038/s41467-020-17718-z
Status	Published - 7-aug.-2020

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Author Correction: GWAS of thyroid stimulating hormone highlights the pleiotropic effects and inverse association with thyroid cancer
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. & Fritsche, L. G. & 36 anderen, Graham, S. E., Wolford, B. N., Overton, W., Rasheed, H., Haug, E. B., Gabrielsen, M. E., Skogholt, A. H., Surakka, I., Davey Smith, G., Pandit, A., Roychowdhury, T., Hornsby, W. E., Jonasson, J. G., Senter, L., Liyanarachchi, S., Ringel, M. D., Xu, L., Kiemeney, L. A., He, H., Netea-Maier, R. T., Mayordomo, J. I., Plantinga, T. S., Hrafnkelsson, J., Hjartarson, H., Sturgis, E. M., Palotie, A., Daly, M., Citterio, C. E., Arvan, P., Brummett, C. M., Boehnke, M., de la Chapelle, A., Stefansson, K., Hveem, K., Willer, C. J. & Åsvold, B. O., 16-dec.-2021, In: Nature Communications. 12, 1, blz. 7354 7354.
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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., ... Asvold, B. O. (2020). GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer. Nature Communications, 11(1), Artikel 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 = "ENDOGENOUS SUBCLINICAL HYPERTHYROIDISM, SERUM THYROTROPIN CONCENTRATION, GENOME-WIDE ASSOCIATION, CONGENITAL HYPOTHYROIDISM, COMMON VARIANTS, TSH, RECEPTOR, THYROGLOBULIN, HYPERTENSION, MALIGNANCY",

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 Smith, {George Davey} 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 Jose Mayordomo 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 Asvold, {Bjorn Olav}",

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 Publishing Group",

number = "1",

}

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, Smith, GD, Pandit, A, Roychowdhury, T, Hornsby, WE, Jonasson, JG, Senter, L, Liyanarachchi, S, Ringel, MD, Xu, L, Kiemeney, LA, He, H, Netea-Maier, RT, Mayordomo, J, 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 & Asvold, BO 2020, 'GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer', Nature Communications, vol. 11, nr. 1, 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 - Smith, George Davey

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

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 - Asvold, Bjorn 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 - ENDOGENOUS SUBCLINICAL HYPERTHYROIDISM

KW - SERUM THYROTROPIN CONCENTRATION

KW - GENOME-WIDE ASSOCIATION

KW - CONGENITAL HYPOTHYROIDISM

KW - COMMON VARIANTS

KW - TSH

KW - RECEPTOR

KW - THYROGLOBULIN

KW - HYPERTENSION

KW - MALIGNANCY

U2 - 10.1038/s41467-020-17718-z

DO - 10.1038/s41467-020-17718-z

M3 - Article

C2 - 32769997

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3981

ER -

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

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