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<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 (<i>P</i> &lt; 5 × 10<sup>−8</sup>). At 48 of these loci, a protein-coding variant is, or is highly correlated (<i>r</i><sup>2</sup> &gt; 0.95) with, the lead variant, including Finnish-enriched coding variants in <i>LAG3</i>, <i>ZAP70</i> and <i>TG</i>. We demonstrated that <i>ZAP70</i>: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>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月26日

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  • 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,
  • Mark J. Daly,
  • Jukka Partanen,
  • Mark I. McCarthy,
  • Mykyta Artomov,
  • Aarno Palotie,
  • Tiinamaija Tuomi,
  • Matti Pirinen,
  • Jukka Kero,
  • Ramnik J. Xavier,
  • Mark J. Daly,
  • Samuli Ripatti

摘要

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.