Endocrine Abstracts

Autoimmune hypothyroidism, also known as Hashimoto’s thyroiditis (HT), is a common autoimmune thyroid disorder with a prevalence of 3-5% in the United States and Europe. Despite its high prevalence and high heritability (~70%), very little is known about the genetic basis of autoimmune hypothyroidism. To improve our understanding of the genetic signatures associated with HT development, we conducted a genome-wide association studies (GWAS) and follow-up analyses using ten cohorts encompassing multiple ethnicities. The GWAS and subsequent meta-analysis included 43,113 cases and 1,196,957 controls. Cases were defined as individuals with an ICD9/10 code for autoimmune thyroiditis or unspecified hypothyroidism. Individuals free of thyroid disease were included as controls. The association analyses were adjusted for age, sex, population structure, and relatedness. Secondary analyses included colocalization with mRNA levels in tissues of the hypothalamus-pituitary-thyroid axis using the GTEx and DICE datasets, pathway and functional enrichment analyses including single-cell data, pheWAS, genetic correlations, and two-sample Mendelian randomization to assess causal effects of HT. In the ancestry-combined HT GWAS, we identified 155 significant (P < 5e-8) independent genetic associations, of which 58 variants in 28 loci represent novel associations. Six loci were specific for European ancestry individuals. We identified 149 colocalizations (posterior probability > 0.85) in protein coding genes from whole blood, thyroid, pituitary, and hypothalamus tissue, and 161 colocalizations in the immune cells, predominantly in different types of T-cells. These colocalizations encompassed several genes integral to the thyroid hormone production and regulation like TG and PDE8B, and immune regulatory genes including VAV3 and IRF5. Pathway analyses revealed an enrichment of HT associated genes involved in the immune system, encompassing besides immune cells also the spleen, and highlighting the importance of T-cells and natural killer cells in the HT process. Using single-cell sequencing data, we found a significant contribution of natural killer T-cells within the thyroid. PheWAS and genetic correlation results revealed pleiotropy with other autoimmune diseases, like rheumatoid arthritis, Sjogren syndrome, celiac disease, and thyroid related traits including thyroid hormone levels and Graves’ disease. Prevalent HT indicated causal effects on increased risk of myocardial infarction, reduced waist circumference, increased levels of TSH and reduced T3. Using a well-defined case definition, our analyses identified novel loci associated with HT and highlight potential shared mechanisms underlying HT with other autoimmune diseases and the variability in thyroid hormone measurements. These results improve our understanding of HT and provide insights into the genetic basis of the disease across ancestries.