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

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

Tekijät: 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

Kustantaja: Springer Nature

Julkaisuvuosi: 2026

Lehti: Nature Genetics

Vuosikerta: 58

Aloitussivu: 550

Lopetussivu: 559

ISSN: 1061-4036

eISSN: 1546-1718

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

Julkaisun avoimuus kirjaamishetkellä: Avoimesti saatavilla

Julkaisukanavan avoimuus : Osittain avoin julkaisukanava

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

Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/515760705

Rinnakkaistallenteen lisenssi: CC BY

Rinnakkaistallennetun julkaisun versio: Kustantajan versio

Tiivistelmä

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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s41588-026-02521-1.pdf

Julkaisussa olevat rahoitustiedot:
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).