Autoimmune hypothyroidism GWAS reveals independent autoimmune and thyroid-specific contributions and an inverse relation with cancer risk

Abstract

The high prevalence of autoimmune hypothyroidism (AIHT) - more than 5% in human populations - provides a unique opportunity to unlock the most complete picture to date of genetic loci that underlie systemic and organ-specific autoimmunity. Using a meta-analysis of 81,718 AIHT cases in FinnGen and the UK Biobank, we dissect associations along axes of thyroid dysfunction and autoimmunity. This largest-to-date scan of hypothyroidism identifies 418 independent associations (p < 5×10^{- 8}), more than half of which have not previously been documented in thyroid disease. In 48 of these, a protein-coding variant is the lead SNP or is highly correlated (r² > 0.95) with the lead SNP at the locus, including low-frequency coding variants at LAG3, ZAP70, TG, TNFSF11, IRF3, S1PR4, HABP2, ZNF429 as well as established variants at ADCY7, IFIH1 and TYK2. The variants at LAG3 (P67T), ZAP70 (T155M), and TG (Q655X) are highly enriched in Finland and functional experiments in T-cells demonstrate that the ZAP70:T155M allele reduces T-cell activation. By employing a large-scale scan of non-thyroid autoimmunity and a published meta-analysis of TSH levels, we use a Bayesian classifier to dissect the associated loci into distinct groupings and from this estimate, a significant proportion are involved in systemic (i.e., general to multiple autoimmune conditions) autoimmunity (34%) and another subset in thyroid-specific dysfunction (17%). By comparing these association results further to other common disease endpoints, we identify a noteworthy overlap with skin cancer, with 10% of AIHT loci showing a consistent but opposite pattern of association where alleles that increase the risk of hypothyroidism have protective effects for skin cancer. The association results, including genes encoding checkpoint inhibitors and other genes affecting protein levels of PD1, bolster the causal role of natural variation in autoimmunity influencing cancer outcomes.

Figure 1.. Impaired T cell activation in ZAP70 T155M variant T cell line in response to TCR stimulation.

ZAP70-deficient Jurkat cells (P116 clone) were reconstituted with either ZAP70 or variants and stimulated with anti-CD3 and anti-CD28 (1ug/ml). Cells were then stained for detection of CD69 (A) or ZAP70, phospho-SLP76 (B) prior to FACS analysis. Control: ZAP70 deficient cells infected with control virus; WT ZAP70: ZAP70 deficient cells reconstituted with wide-type ZAP70; T155M: ZAP70 deficient cells expressing ZAP70 T155M; Y315A&Y319A: ZAP70 deficient cells expressing an inactive mutant ZAP70 Y315A&Y319A.

Figure 2

Scatter plots of effect sizes from AIHT-associated variant effect sizes compared with effect sizes from A. non-thyroid autoimmune diseases from FinnGen+UKBB, B. TSH levels from (Zhou et al.), and C. skin cancer from FinnGen+UKBB. Optimal two-group fit of Bayesian linemodels (Pirinen et al.) (run with parameters scale=0.6 and correlation=0.99) displayed with red indicating association to AIHT and blue indicating association to both AIHT and the query phenotype. Data points are colored if linemodels assignment with greater than 80% probability. Data points displayed (n=202) represent AIHT-independent index variants with p<1×10⁻¹¹. (Full data and assignment probabilities listed in Supplementary Table 3)