Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

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. and Kiiskinen, Tuomo , et al. (2026) In Nature Genetics 58(3). p.550-559
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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
author collaboration
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Genetics
volume
58
issue
3
pages
10 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:105031946764
  • pmid:41748903
ISSN
1061-4036
DOI
10.1038/s41588-026-02521-1
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2026.
id
26289a3b-36a8-49d0-8870-d65cacc3c804
date added to LUP
2026-05-06 13:44:35
date last changed
2026-05-08 07:52:13
@article{26289a3b-36a8-49d0-8870-d65cacc3c804,
  abstract     = {{<p>The high prevalence (&gt;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 &lt; 5 × 10<sup>−8</sup>). At 48 of these loci, a protein-coding variant is, or is highly correlated (r<sup>2</sup> &gt; 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>}},
  author       = {{Reeve, Mary Pat and Kanai, Masahiro and Graham, Daniel B. and Karjalainen, Juha and Luo, Shuang and Kolosov, Nikita and Adams, Cameron and Ritari, Jarmo and Karczewski, Konrad J. and Kiiskinen, Tuomo and Jiang, Yu and Fuller, Zachary and Mehtonen, Juha and Kurki, Mitja I. and Khan, Zia and Partanen, Jukka and McCarthy, Mark I. and Artomov, Mykyta and Palotie, Aarno and Tuomi, Tiinamaija and Pirinen, Matti and Kero, Jukka and Xavier, Ramnik J. and Daly, Mark J. and Ripatti, Samuli}},
  issn         = {{1061-4036}},
  language     = {{eng}},
  number       = {{3}},
  pages        = {{550--559}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Genetics}},
  title        = {{Genome-wide association analyses of autoimmune hypothyroidism reveal autoimmune and thyroid-specific contributions and an inverse relationship with cancer risk}},
  url          = {{http://dx.doi.org/10.1038/s41588-026-02521-1}},
  doi          = {{10.1038/s41588-026-02521-1}},
  volume       = {{58}},
  year         = {{2026}},
}