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<p>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.</p>

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Genome-wide association study and polygenic risk prediction of hypothyroidism

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月14日

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  • 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,
  • Karina Banasik,
  • Jakob Bay,
  • Andrea Barghetti,
  • Mette Skou Bendtsen,
  • Jens Kjærgaard Boldsen,
  • Nanna Brøns,
  • Alfonso Buil Demur,
  • Johan Skov Bundgaard,
  • Lea Arregui Nordahl Christoffersen,
  • Maria Didriksen,
  • Khoa Manh Dinh,
  • Joseph Dowsett,
  • Josephine Gladov,
  • Thomas Folkmann Hansen,
  • Dorte Helenius Mikkelsen,
  • Lotte Lindhede,
  • Henrik Hjalgrim,
  • Jakob Hjorth von Stemann,
  • Bitten Aagaard Jensen,
  • Kathrine Kaspersen,
  • Bertram Dalskov Kjerulff,
  • Lisette Kogelman,
  • Mette Kongstad,
  • Susan Mikkelsen,
  • Christina Mikkelsen,
  • Line Hjorth Sjernholm Nielsen,
  • Janna Nissen,
  • Mette Nyegaard,
  • Frederikke Byron Pedersen,
  • Liam James Elgaard Quinn,
  • Thorunn Rafnar,
  • Palle Duun Rohde,
  • Klaus Rostgaard,
  • Andrew Joseph Schork,
  • Kari Steffanson,
  • Hreinn Stefansson,
  • Jacob Træholt,
  • Unnur Thorsteinsdottir,
  • Thomas Werge,
  • David Westergaard,
  • Lili Milani,
  • Tony Esko,
  • Reedik Magi,
  • Mait Metspalu,
  • Mari Nelis,
  • Georgi Hudjashov,
  • Stella Aslibekyan,
  • Adam Auton,
  • Robert K. Bell,
  • Katelyn Kukar Bond,
  • Zayn Cochinwala,
  • Sayantan Das,
  • Kahsaia de Brito,
  • Emily DelloRusso,
  • Chris Eijsbouts,
  • Sarah L. Elson,
  • Chris German,
  • Julie M. Granka,
  • Alan Kwong,
  • Yanyu Liang,
  • Keng-Han Lin,
  • Matthew H. McIntyre,
  • Shubham Saini,
  • Anjali J. Shastri,
  • Jingchunzi Shi,
  • Suyash Shingrapure,
  • Qiaojuan Jane Su,
  • Vinh Tran,
  • Joyce Y. Tung,
  • Catherine H. Weldon,
  • Wanwan Xu,
  • 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,
  • Jonas Ghouse

摘要

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.