| Title: | Genome-wide association analyses of autoimmune hypothyroidism reveal autoimmune and thyroid-specific contributions and an inverse relationship with cancer risk |
| Journal: | Nature Genetics |
| Published: | 26 Feb 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41748903/ |
| DOI: | https://doi.org/10.1038/s41588-026-02521-1 |
Publication 17616
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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.</p>
12 Keywords
- Autoimmune Diseases
- Autoimmunity
- Female
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Hashimoto Disease
- Humans
- Male
- Neoplasms
- Polymorphism, Single Nucleotide
- Thyroid Gland
- Thyroiditis, Autoimmune
25 Authors
- Mary Pat Reeve
- Masahiro Kanai
- Daniel B. Graham
- Juha Karjalainen
- Shuang Luo
- Nikita Kolosov
- Cameron Adams
- Jarmo Ritari
- Konrad J. Karczewski
- Tuomo Kiiskinen
- Yu Jiang
- Zachary Fuller
- Juha Mehtonen
- Mitja I. Kurki
- Zia Khan
- Jukka Partanen
- Mark I. McCarthy
- Mykyta Artomov
- Aarno Palotie
- Tiinamaija Tuomi
- Matti Pirinen
- Jukka Kero
- Ramnik J. Xavier
- Mark J. Daly
- Samuli Ripatti
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