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

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.

Fig. 1. Impaired T cell activation in the ZAP70 Thr155Met variant T cell line in response to TCR stimulation.

a,b, ZAP70-deficient Jurkat cells (P116 clone) reconstituted with either ZAP70 or variants and stimulated with anti-CD3 and anti-CD28 (1 μg ml⁻¹). Cells were then stained for detection of CD69 (a) or ZAP70, phospho-ZAP70 (pZAP70) and phospho-SLP76 (pSLP76) (b) before FACS analysis. Control, ZAP70-deficient cells infected with control virus; Thr155Met, ZAP70-deficient cells expressing ZAP70 Thr155Met; Try315Ala&Tyr319Ala, ZAP70-deficient cells expressing an inactive mutant ZAP70 Try315Ala&Tyr319Ala; WT ZAP70, ZAP70-deficient cells reconstituted with wild-type ZAP70.

Fig. 2. Analysis of shared effects using linemodels.

a–d, Scatter plots of effect sizes from AIHT-associated variant effect sizes compared with effect sizes from nonthyroid autoimmune diseases from FinnGen + UKBB (a), TSH levels from FinnGen (b), skin cancer from FinnGen + UKBB (c) and Graves’ disease from FinnGen + UKBB (d). Optimal two-group fit of Bayesian linemodels run with scale and correlation parameters were fixed and displayed with red indicating an association to AIHT only and blue to both AIHT and the query phenotype. As recommended, β and s.e. were transformed into √(heritability) scale by multiplying both by √(2× MAF × (1 − MAF)). Data points are colored when linemodels group assignments are >95% probability. (Full data and assignment probabilities are listed in Supplementary Table 3.) cors, correlations.