Genome-wide association analyses of autoimmune hypothyroidism reveal autoimmune and thyroid-specific contributions and an inverse relationship with cancer risk - UTU Research Portal

A1 Refereed original research article in a scientific journal

Genome-wide association analyses of autoimmune hypothyroidism reveal autoimmune and thyroid-specific contributions and an inverse relationship with cancer risk

Authors: Reeve, Mary Pat; Kanai, Masahiro; Graham, Daniel B.; Karjalainen, Juha; Luo, Shuang; Kolosov, Nikita; Adams, Cameron; Ritari, Jarmo; Karczewski, Konrad J.; Kiiskinen, Tuomo; Jiang, Yu; Fuller, Zachary; Mehtonen, Juha; Kurki, Mitja I.; Khan, Zia; Daly, Mark J.; Partanen, Jukka; McCarthy, Mark I.; Artomov, Mykyta; Palotie, Aarno; Tuomi, Tiinamaija; Pirinen, Matti; Kero, Jukka; Xavier, Ramnik J.; Ripatti, Samuli

Publisher: Springer Nature

Publication year: 2026

Journal: Nature Genetics

Volume: 58

First page : 550

Last page: 559

ISSN: 1061-4036

eISSN: 1546-1718

DOI: https://doi.org/10.1038/s41588-026-02521-1

Publication's open availability at the time of reporting: Open Access

Publication channel's open availability : Partially Open Access publication channel

Web address : https://doi.org/10.1038/s41588-026-02521-1

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/515760705

Self-archived copy's licence: CC BY

Self-archived copy's version: Publisher`s PDF

Abstract

The high prevalence (>5%) of autoimmune hypothyroidism (AIHT) provides a unique opportunity to dissect genetic contributions to systemic and organ-specific autoimmunity. Here we performed a genome-wide association meta-analysis of 81,718 AIHT cases in FinnGen and the UK Biobank, identifying 418 independent signals (P < 5 × 10^-8). At 48 of these loci, a protein-coding variant is, or is highly correlated (r² > 0.95) with, the lead variant, including Finnish-enriched coding variants in LAG3, ZAP70 and TG. We demonstrated that ZAP70:T155M reduces T cell activation and broadly compare large-scale scans of nonthyroid autoimmunity and thyroid-stimulating hormone levels with a Bayesian classifier to assign loci into distinct groupings, estimating that 38% are involved in general autoimmunity whereas 20% are thyroid specific. We further identified substantial antagonistic pleiotropy, with 10% of AIHT loci showing a consistent protective effect against skin cancer. The AIHT results, including numerous genes encoding checkpoint proteins, support the causal role of natural immune variation influencing cancer outcomes.

Downloadable publication

This is an electronic reprint of the original article.
This reprint may differ from the original in pagination and typographic detail. Please cite the original version.

s41588-026-02521-1.pdf

Funding information in the publication:
N.K. and M.A. were supported by the Aging Biology Foundation (to M.A.). R.J.X. and D.B.G. were supported by the National Institutes of Health (grant nos. DK43351 and DK135492). J. Kero was supported by Sigrid Juselius Foundation Finland (grant no. 1062). S.R. was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (grant no. 312062). T.T. was supported by the Academy of Finland, University of Helsinki.
Open Access funding provided by University of Helsinki (including Helsinki University Central Hospital).