Genome-wide association study and polygenic risk prediction of hypothyroidism
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.
Authors
- Mie Topholm Bruun (ORCID: https://orcid.org/0000-0002-8819-5388)
- Laia M. Monfort (ORCID: https://orcid.org/0000-0002-7170-481X)
- Henrik Enghusen Poulsen (ORCID: https://orcid.org/0000-0003-4242-9924)
- Christina Mikkelsen (ORCID: https://orcid.org/0000-0002-2945-6197)
- Bitten Aagaard Jensen
- Tōnu Esko (ORCID: https://orcid.org/0000-0003-1982-6569)
- Mette Kongstad
- Andrea Barghetti (ORCID: https://orcid.org/0000-0002-5805-9289)
- Thomas Folkmann Hansen (ORCID: https://orcid.org/0000-0001-6703-7762)
- Hreinn Stefánsson (ORCID: https://orcid.org/0000-0002-9331-6666)
- Anjali J. Shastri
- Søren Brunak (ORCID: https://orcid.org/0000-0003-0316-5866)
- Mari Nelis (ORCID: https://orcid.org/0000-0001-9748-1020)
- Søren A Rand (ORCID: https://orcid.org/0000-0002-1892-1911)
- David Westergaard (ORCID: https://orcid.org/0000-0003-0128-8432)
- Mait Metspalu (ORCID: https://orcid.org/0000-0003-3099-9161)
- Lea Arregui Nordahl Christoffersen (ORCID: https://orcid.org/0000-0002-5816-6324)
- Henrik Ullum (ORCID: https://orcid.org/0000-0001-7306-9058)
- Erik Sørensen (ORCID: https://orcid.org/0000-0002-5002-9077)
- Shubham Saini (ORCID: https://orcid.org/0000-0002-1900-0284)
- Maria Didriksen (ORCID: https://orcid.org/0000-0002-4856-496X)
- Christina Ellervik (ORCID: https://orcid.org/0000-0002-3088-4375)
- Guðmar Þorleifsson (ORCID: https://orcid.org/0000-0003-4623-9087)
- Liam Quinn (ORCID: https://orcid.org/0000-0002-3597-2948)
- Ulla Feldt-Rasmussen
- Saedís Saevarsdóttir (ORCID: https://orcid.org/0000-0001-9392-6184)
- Andrew J. Schork (ORCID: https://orcid.org/0000-0003-4164-9335)
- Lili Milani (ORCID: https://orcid.org/0000-0002-5323-3102)
- Josephine Gladov (ORCID: https://orcid.org/0000-0001-9233-3117)
- Stella Aslibekyan
- Jakob Hjorth von Stemann (ORCID: https://orcid.org/0000-0002-4591-3052)
- Joseph Dowsett (ORCID: https://orcid.org/0000-0001-5381-2633)
- Jingchunzi Shi (ORCID: https://orcid.org/0000-0002-9671-2568)
- Jens Kjærgaard Boldsen (ORCID: https://orcid.org/0000-0002-8139-1642)
- Daníel F. Guðbjartsson (ORCID: https://orcid.org/0000-0002-5222-9857)
- Nanna Brøns (ORCID: https://orcid.org/0000-0001-9912-2806)
- Lisette J. A. Kogelman (ORCID: https://orcid.org/0000-0001-9782-7810)
- Georgi Hudjashov (ORCID: https://orcid.org/0000-0002-7536-9086)
- Gustav Ahlberg (ORCID: https://orcid.org/0000-0003-0066-2779)
- Michael Schwinn (ORCID: https://orcid.org/0000-0002-6151-369X)
- Maris Teder‐Laving (ORCID: https://orcid.org/0000-0002-5872-1850)
- Alfonso Buil (ORCID: https://orcid.org/0000-0002-3097-1014)
- Line Nielsen (ORCID: https://orcid.org/0000-0002-4127-4361)
- Jakob Thaning Bay (ORCID: https://orcid.org/0000-0003-1159-4003)
- Mette Nyegaard (ORCID: https://orcid.org/0000-0003-4973-8543)
- Ingileif Jónsdóttir (ORCID: https://orcid.org/0000-0001-8339-150X)
- Sarah L. Elson (ORCID: https://orcid.org/0000-0002-3211-3750)
- Julie M. Granka (ORCID: https://orcid.org/0000-0001-7571-9050)
- Sayantan Das (ORCID: https://orcid.org/0000-0002-9251-1320)
- Henning Bundgaard (ORCID: https://orcid.org/0000-0002-0563-7049)
- Johan Skov Bundgaard (ORCID: https://orcid.org/0000-0003-2069-9034)
- Ole Birger Pedersen (ORCID: https://orcid.org/0000-0003-2312-5976)
- Chris Eijsbouts (ORCID: https://orcid.org/0000-0001-5179-0653)
- Chris German (ORCID: https://orcid.org/0000-0002-2717-5316)
- Jonas Ghouse (ORCID: https://orcid.org/0000-0002-9634-5964)
- Birte Nygaard (ORCID: https://orcid.org/0000-0002-9540-4950)
- Alan Kwong (ORCID: https://orcid.org/0000-0002-0779-7126)
- Sisse Rye Ostrowski (ORCID: https://orcid.org/0000-0001-5288-3851)
- Kathrine Agergård Kaspersen (ORCID: https://orcid.org/0000-0002-7973-3623)
- Bertram Kjerulff (ORCID: https://orcid.org/0000-0001-9953-9521)
- K. Brito (ORCID: https://orcid.org/0009-0009-6589-7262)
- Karina Banasik (ORCID: https://orcid.org/0000-0003-2489-2499)
- Þórunn Rafnar (ORCID: https://orcid.org/0000-0003-0491-7046)
- Marianne Klose (ORCID: https://orcid.org/0000-0001-6075-0821)
- Reedik Mägi (ORCID: https://orcid.org/0000-0002-2964-6011)
- Janna Nissen (ORCID: https://orcid.org/0000-0002-8891-8451)
- Christian Erikstrup (ORCID: https://orcid.org/0000-0001-6551-6647)
- Morten S. Olesen (ORCID: https://orcid.org/0000-0001-9477-5322)
- Catherine H. Weldon
- Vinicius Tragante (ORCID: https://orcid.org/0000-0002-8223-8957)
- Andres Metspalu (ORCID: https://orcid.org/0000-0002-3718-796X)
- Yanyu Liang (ORCID: https://orcid.org/0000-0001-8893-6505)
- Qiaojuan Jane Su
- Hilma Hólm (ORCID: https://orcid.org/0000-0002-9517-6636)
- Palle Duun Rohde (ORCID: https://orcid.org/0000-0003-4347-8656)
- Klaus Rostgaard (ORCID: https://orcid.org/0000-0001-6220-9414)
- Emily DelloRusso
- Wanwan Xu
- Vinh Tran (ORCID: https://orcid.org/0000-0001-6772-7595)
- Chaoqun Zheng (ORCID: https://orcid.org/0000-0002-3248-8560)
- Frederikke Byron Pedersen (ORCID: https://orcid.org/0000-0002-4433-7268)
- Joyce Y. Tung
- Dorte Helenius Mikkelsen (ORCID: https://orcid.org/0000-0002-7360-4812)
- Adam Auton
- Thomas Werge
- Unnur Thorsteinsdottir
- Robert K. Bell
- Henrik Hjalgrim
- Keng-Han Lin
- K. Bond
- Matthew H. McIntyre
- Jacob Træholt
- Zayn Cochinwala
- Mette Skou Bendtsen
- Kari Steffanson
- Lotte Lindhede
- Suyash Shingrapure
Institutions
- Statens Serum Institut (DK)
- University of Copenhagen (DK)
- Boston Children's Hospital (US)
- deCODE Genetics (Iceland) (IS)
- Harvard University (US)
- University of Iceland (IS)
- Aarhus University (DK)
- Aalborg University Hospital (DK)
- Novo Nordisk Foundation (DK)
- Frederiksberg Hospital (DK)
- Odense University Hospital (DK)
- Herlev Hospital (DK)
- Hvidovre Hospital (DK)
- Aarhus University Hospital (DK)
- Copenhagen University Hospital (DK)
- Gentofte Hospital (DK)
- Rigshospitalet (DK)
- Zealand University Hospital (DK)
- 23andMe (United States) (US)
- Danish Cancer Society (DK)
- Zealand University Hospital Køge (DK)
- University of Tartu (EE)
- Aalborg University (DK)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-11-14
- DOI
- https://doi.org/10.1038/s41588-025-02410-z
- Citations
- 1
- Primary Topic
- Thyroid Disorders and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.29
Funders
- Sundhedsstyrelsen
- Novo Nordisk Fonden