Genome-wide association study and polygenic risk prediction of hypothyroidism

Søren A Rand; Gustav Ahlberg; Vinicius Tragante; Laia M Monfort; Chaoqun Zheng; Ulla Feldt-Rasmussen; Marianne C Klose; Maris Teder-Laving; Andres Metspalu; Henrik E Poulsen; Christina Ellervik; Birte Nygaard; Christian Erikstrup; Mie T Bruun; Bitten A Jensen; Henrik Ullum; Søren Brunak; Michael Schwinn; Sisse R Ostrowski; Ole B Pedersen; Erik Sørensen; Ingileif Jonsdottir; Daniel F Gudbjartsson; Gudmar Thorleifsson; Hilma Holm; Saedis Saevarsdottir; Kari Stefansson; Morten Salling Olesen; Henning Bundgaard; DBDS Genomic Consortium; Jonas Ghouse

doi:10.1038/s41588-025-02410-z

Genome-wide association study and polygenic risk prediction of hypothyroidism

Søren A Rand^*, Gustav Ahlberg, Vinicius Tragante, Laia M Monfort, Chaoqun Zheng, Ulla Feldt-Rasmussen, Marianne C Klose, Maris Teder-Laving, Andres Metspalu, Henrik E Poulsen, Christina Ellervik, Birte Nygaard, Christian Erikstrup, Mie T Bruun, Bitten A Jensen, Henrik Ullum, Søren Brunak, Michael Schwinn, Sisse R Ostrowski, Ole B PedersenErik Sørensen, Ingileif Jonsdottir, Daniel F Gudbjartsson, Gudmar Thorleifsson, Hilma Holm, Saedis Saevarsdottir, Kari Stefansson, Morten Salling Olesen, Henning Bundgaard, DBDS Genomic Consortium, Jonas Ghouse

^*Corresponding author for this work

Abstract

We performed a genome-wide meta-analysis of hypothyroidism (113,393 cases and 1,065,268 controls), free thyroxine (191,449 individuals) and thyroid-stimulating hormone (482,873 individuals). We identified 350 loci associated with hypothyroidism, including 179 not previously reported, 29 of which were linked through thyroid-stimulating hormone. We found that many hypothyroidism risk loci regulate blood cell counts and the circulating inflammasome, and through multiple gene-mapping strategies, we prioritized 259 putative causal genes enriched in immune-related functions. We developed a polygenic risk score (PRS) based on more than 115,000 hypothyroidism cases to address diagnostic challenges in individuals with or at risk of thyroid hormone deficiency. We show that the highest predictive accuracy for hypothyroidism was achieved when combining the PRS with thyroid hormones and thyroid-peroxidase autoantibodies, and that the PRS was able to stratify risk of progression among individuals with subclinical hypothyroidism. These findings demonstrate the potential for a hypothyroidism PRS to support the prediction of disease progression and onset in thyroid hormone deficiency.

Original language	English
Journal	Nature Genetics
Volume	57
Issue number	12
Pages (from-to)	3007-3015
Number of pages	9
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-025-02410-z
Publication status	Published - Dec 2025

Keywords

Case-Control Studies
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Hypothyroidism/genetics
Male
Multifactorial Inheritance/genetics
Polymorphism, Single Nucleotide
Risk Factors
Thyrotropin/blood
Thyroxine/blood

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Rand, S. A., Ahlberg, G., Tragante, V., Monfort, L. M., Zheng, C., Feldt-Rasmussen, U., Klose, M. C., Teder-Laving, M., Metspalu, A., Poulsen, H. E., Ellervik, C., Nygaard, B., Erikstrup, C., Bruun, M. T., A Jensen, B., Ullum, H., Brunak, S., Schwinn, M., Ostrowski, S. R., ... Ghouse, J. (2025). Genome-wide association study and polygenic risk prediction of hypothyroidism. Nature Genetics, 57(12), 3007-3015. https://doi.org/10.1038/s41588-025-02410-z

Rand, SA , Ahlberg, G, Tragante, V, Monfort, LM , Zheng, C , Feldt-Rasmussen, U , Klose, MC, Teder-Laving, M, Metspalu, A, Poulsen, HE, Ellervik, C, Nygaard, B, Erikstrup, C, Bruun, MT, A Jensen, B, Ullum, H, Brunak, S, Schwinn, M , Ostrowski, SR, Pedersen, OB, Sørensen, E, Jonsdottir, I, Gudbjartsson, DF, Thorleifsson, G, Holm, H, Saevarsdottir, S, Stefansson, K, Salling Olesen, M, Bundgaard, H, DBDS Genomic Consortium & Ghouse, J 2025, 'Genome-wide association study and polygenic risk prediction of hypothyroidism', Nature Genetics, vol. 57, no. 12, pp. 3007-3015. https://doi.org/10.1038/s41588-025-02410-z

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abstract = "We performed a genome-wide meta-analysis of hypothyroidism (113,393 cases and 1,065,268 controls), free thyroxine (191,449 individuals) and thyroid-stimulating hormone (482,873 individuals). We identified 350 loci associated with hypothyroidism, including 179 not previously reported, 29 of which were linked through thyroid-stimulating hormone. We found that many hypothyroidism risk loci regulate blood cell counts and the circulating inflammasome, and through multiple gene-mapping strategies, we prioritized 259 putative causal genes enriched in immune-related functions. We developed a polygenic risk score (PRS) based on more than 115,000 hypothyroidism cases to address diagnostic challenges in individuals with or at risk of thyroid hormone deficiency. We show that the highest predictive accuracy for hypothyroidism was achieved when combining the PRS with thyroid hormones and thyroid-peroxidase autoantibodies, and that the PRS was able to stratify risk of progression among individuals with subclinical hypothyroidism. These findings demonstrate the potential for a hypothyroidism PRS to support the prediction of disease progression and onset in thyroid hormone deficiency.",

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T1 - Genome-wide association study and polygenic risk prediction of hypothyroidism

AU - Rand, Søren A

AU - Ahlberg, Gustav

AU - Tragante, Vinicius

AU - Monfort, Laia M

AU - Zheng, Chaoqun

AU - Feldt-Rasmussen, Ulla

AU - Klose, Marianne C

AU - Teder-Laving, Maris

AU - Metspalu, Andres

AU - Poulsen, Henrik E

AU - Ellervik, Christina

AU - Nygaard, Birte

AU - Erikstrup, Christian

AU - Bruun, Mie T

AU - A Jensen, Bitten

AU - Ullum, Henrik

AU - Brunak, Søren

AU - Schwinn, Michael

AU - Ostrowski, Sisse R

AU - Pedersen, Ole B

AU - Sørensen, Erik

AU - Jonsdottir, Ingileif

AU - Gudbjartsson, Daniel F

AU - Thorleifsson, Gudmar

AU - Holm, Hilma

AU - Saevarsdottir, Saedis

AU - Stefansson, Kari

AU - Salling Olesen, Morten

AU - Bundgaard, Henning

AU - DBDS Genomic Consortium

AU - Ghouse, Jonas

A2 - Werge, Thomas Mears

PY - 2025/12

Y1 - 2025/12

N2 - We performed a genome-wide meta-analysis of hypothyroidism (113,393 cases and 1,065,268 controls), free thyroxine (191,449 individuals) and thyroid-stimulating hormone (482,873 individuals). We identified 350 loci associated with hypothyroidism, including 179 not previously reported, 29 of which were linked through thyroid-stimulating hormone. We found that many hypothyroidism risk loci regulate blood cell counts and the circulating inflammasome, and through multiple gene-mapping strategies, we prioritized 259 putative causal genes enriched in immune-related functions. We developed a polygenic risk score (PRS) based on more than 115,000 hypothyroidism cases to address diagnostic challenges in individuals with or at risk of thyroid hormone deficiency. We show that the highest predictive accuracy for hypothyroidism was achieved when combining the PRS with thyroid hormones and thyroid-peroxidase autoantibodies, and that the PRS was able to stratify risk of progression among individuals with subclinical hypothyroidism. These findings demonstrate the potential for a hypothyroidism PRS to support the prediction of disease progression and onset in thyroid hormone deficiency.

AB - We performed a genome-wide meta-analysis of hypothyroidism (113,393 cases and 1,065,268 controls), free thyroxine (191,449 individuals) and thyroid-stimulating hormone (482,873 individuals). We identified 350 loci associated with hypothyroidism, including 179 not previously reported, 29 of which were linked through thyroid-stimulating hormone. We found that many hypothyroidism risk loci regulate blood cell counts and the circulating inflammasome, and through multiple gene-mapping strategies, we prioritized 259 putative causal genes enriched in immune-related functions. We developed a polygenic risk score (PRS) based on more than 115,000 hypothyroidism cases to address diagnostic challenges in individuals with or at risk of thyroid hormone deficiency. We show that the highest predictive accuracy for hypothyroidism was achieved when combining the PRS with thyroid hormones and thyroid-peroxidase autoantibodies, and that the PRS was able to stratify risk of progression among individuals with subclinical hypothyroidism. These findings demonstrate the potential for a hypothyroidism PRS to support the prediction of disease progression and onset in thyroid hormone deficiency.

KW - Case-Control Studies

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Hypothyroidism/genetics

KW - Male

KW - Multifactorial Inheritance/genetics

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

KW - Thyrotropin/blood

KW - Thyroxine/blood

UR - https://www.scopus.com/pages/publications/105022468888

U2 - 10.1038/s41588-025-02410-z

DO - 10.1038/s41588-025-02410-z

M3 - Journal article

C2 - 41238958

SN - 1061-4036

VL - 57

SP - 3007

EP - 3015

JO - Nature Genetics

JF - Nature Genetics

IS - 12

ER -

Genome-wide association study and polygenic risk prediction of hypothyroidism

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Keywords

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