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

## TL;DR

This study identifies 418 genetic signals linked to autoimmune hypothyroidism and classifies them into general autoimmunity and thyroid-specific categories, revealing a protective effect against skin cancer.

## Contribution

The study introduces a Bayesian classification method to distinguish systemic autoimmunity and thyroid-specific loci in autoimmune hypothyroidism.

## Key findings

- 418 independent genetic signals were identified for autoimmune hypothyroidism.
- 38% of loci are involved in general autoimmunity, while 20% are thyroid-specific.
- 10% of AIHT loci show a protective effect against skin cancer.

## 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.

Genome-wide analyses identify 418 independent associations with autoimmune hypothyroidism and classify risk loci into distinct groupings related to systemic autoimmunity and thyroid-specific dysfunction.