Genome-wide association analyses of autoimmune hypothyroidism reveal autoimmune and thyroid-specific contributions and an inverse relationship with cancer risk
: 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
: 2026
Nature Genetics
: 58
: 550
: 559
: 1061-4036
: 1546-1718
DOI: https://doi.org/10.1038/s41588-026-02521-1
: https://doi.org/10.1038/s41588-026-02521-1
: https://research.utu.fi/converis/portal/detail/Publication/515760705
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.
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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).
