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; David Westergaard; Thomas Werge; Unnur Thorsteinsdottir; Kari Steffanson; Bitten A. Jensen; Ole B. Pedersen; Erik Sørensen; Jonas Ghouse; DBDS Genomic Consortium; Estonian Biobank Research Team; 23andMe Research Team

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
, David Westergaard
, Thomas Werge
, Unnur Thorsteinsdottir

Kari Steffanson, Bitten A. Jensen, Ole B. Pedersen, Erik Sørensen, Jonas Ghouse^*, DBDS Genomic Consortium, Estonian Biobank Research Team, 23andMe Research Team

^*Corresponding author for this work

Department of Clinical Medicine - Department of Clinical Immunology

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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	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

Access to Document

10.1038/s41588-025-02410-zLicence: CC BY

Library access?

Check availability with the Royal Danish Library

Cite this

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., Westergaard, D., Werge, T., ... 23andMe Research Team (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

@article{7842d04d25af48769a36c3e751526dd7,

title = "Genome-wide association study and polygenic risk prediction of hypothyroidism",

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.",

author = "Rand, \{S{\o}ren A.\} and Gustav Ahlberg and Vinicius Tragante and Monfort, \{Laia M.\} and Chaoqun Zheng and Ulla Feldt-Rasmussen and Klose, \{Marianne C.\} and Maris Teder-Laving and Andres Metspalu and Poulsen, \{Henrik E.\} and Christina Ellervik and Birte Nygaard and Christian Erikstrup and Bruun, \{Mie T.\} and \{A. Jensen\}, Bitten and Henrik Ullum and S{\o}ren Brunak and David Westergaard and Thomas Werge and Unnur Thorsteinsdottir and Jacob Tr{\ae}holt and Hreinn Stefansson and Kari Steffanson and Schork, \{Andrew Joseph\} and Klaus Rostgaard and Rohde, \{Palle Duun\} and Thorunn Rafnar and Quinn, \{Liam James Elgaard\} and Pedersen, \{Frederikke Byron\} and Mette Nyegaard and Janna Nissen and Nielsen, \{Line Hjorth Sjernholm\} and Christina Mikkelsen and Susan Mikkelsen and Mette Kongstad and Lisette Kogelman and Kjerulff, \{Bertram Dalskov\} and Kathrine Kaspersen and \{A. Jensen\}, Bitten and \{von Stemann\}, \{Jakob Hjorth\} and Henrik Hjalgrim and Lotte Lindhede and Mikkelsen, \{Dorte Helenius\} and Hansen, \{Thomas Folkmann\} and Josephine Gladov and Dinh, \{Khoa Manh\} and Boldsen, \{Jens Kj{\ae}rgaard\} and Pedersen, \{Ole B.\} and Erik S{\o}rensen and Jonas Ghouse and \{DBDS Genomic Consortium\} and \{Estonian Biobank Research Team\} and \{23andMe Research Team\}",

year = "2025",

month = dec,

doi = "10.1038/s41588-025-02410-z",

language = "English",

volume = "57",

pages = "3007--3015",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "12",

}

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, Westergaard, D, Werge, T, Thorsteinsdottir, U, Steffanson, K, A. Jensen, B, Pedersen, OB, Sørensen, E, Ghouse, J, DBDS Genomic Consortium, Estonian Biobank Research Team & 23andMe Research Team 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

TY - JOUR

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 - Westergaard, David

AU - Werge, Thomas

AU - Thorsteinsdottir, Unnur

AU - Træholt, Jacob

AU - Stefansson, Hreinn

AU - Steffanson, Kari

AU - Schork, Andrew Joseph

AU - Rostgaard, Klaus

AU - Rohde, Palle Duun

AU - Rafnar, Thorunn

AU - Quinn, Liam James Elgaard

AU - Pedersen, Frederikke Byron

AU - Nyegaard, Mette

AU - Nissen, Janna

AU - Nielsen, Line Hjorth Sjernholm

AU - Mikkelsen, Christina

AU - Mikkelsen, Susan

AU - Kongstad, Mette

AU - Kogelman, Lisette

AU - Kjerulff, Bertram Dalskov

AU - Kaspersen, Kathrine

AU - A. Jensen, Bitten

AU - von Stemann, Jakob Hjorth

AU - Hjalgrim, Henrik

AU - Lindhede, Lotte

AU - Mikkelsen, Dorte Helenius

AU - Hansen, Thomas Folkmann

AU - Gladov, Josephine

AU - Dinh, Khoa Manh

AU - Boldsen, Jens Kjærgaard

AU - Pedersen, Ole B.

AU - Sørensen, Erik

AU - Ghouse, Jonas

AU - DBDS Genomic Consortium

AU - Estonian Biobank Research Team

AU - 23andMe Research Team

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.

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

AN - SCOPUS:105022468888

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

Abstract

Access to Document

Library access?

Other files and links

Fingerprint

Cite this