rs116340633 (TG): Thyroid Hormone Genetics Variant

Key takeaways

• Genetics explains an estimated 53% of thyroid cancer susceptibility and 75% of autoimmune thyroid disease risk based on family studies, making the thyroid hormone pathway one of the most genetically influenced systems studied.
• A scan of approximately 2.9 million genomes across 19 global biobanks found 570 previously unknown genetic locations tied to five thyroid diseases, including thyroid cancer, benign nodular goiter, and autoimmune conditions.
• The TG gene (thyroglobulin) encodes the primary scaffold protein for thyroid hormone production in the thyroid gland and is a central focus of thyroid disease genetics research.
• Polygenic risk scores built from thyroid-associated genetic variants can flag features of aggressive thyroid cancer including tumor size, multifocality, lymph node spread, and extranodal extension.
• Thyroid cancer, benign thyroid nodules, and autoimmune thyroid diseases share substantial genetic overlap, with genetic correlation coefficients ranging from 0.16 to 0.97.

What the research says A genome-wide association study (GWAS) of thyroid-stimulating hormone (TSH) levels in 247,107 participants identified 260 independent genetic variants meeting genome-wide significance (P < 5 x 10-8) at 156 unique genomic loci, implicating 112 putative causal genes of which 76 had not previously been linked to TSH. A separate multi-ancestry meta-analysis of approximately 2.9 million genomes from 19 biobanks identified 313 known and 570 new independent loci linked to five thyroid diseases: thyroid cancer, benign nodular goiter, Graves' disease, lymphocytic thyroiditis, and primary hypothyroidism. Genetic correlation analysis in that meta-analysis found shared genetic architecture across these conditions, with correlation coefficients (rg) between thyroid cancer, benign nodular goiter, and autoimmune thyroid diseases ranging from 0.16 to 0.97.

Reported associations

• Thyroid-stimulating hormone (TSH) levels: A 247,107-participant GWAS doubled the known number of genetic associations with TSH from 99 to 260 independent sentinel variants, implicating 112 putative causal genes across thyroid hormone pathways.
• Hypothyroidism: A polygenic score (PGS) derived from TSH-associated variants was linked to hypothyroidism susceptibility and age of onset in European ancestry populations and to hypothyroidism and other thyroid disease in South Asian ancestry populations.
• Hyperthyroidism: The same TSH polygenic score was associated with age of onset of hyperthyroidism in European ancestry populations.
• Thyroid cancer: A multi-biobank meta-analysis of approximately 2.9 million genomes identified loci associated with thyroid cancer, and polygenic risk scores derived from these variants were associated with structural disease recurrence, tumor size, multifocality (cancer present in multiple locations), lymph node metastases, and extranodal extension (spread beyond the thyroid capsule).
• Benign nodular goiter: The multi-ancestry thyroid disease meta-analysis identified genetic loci associated with benign nodular goiter, which showed genetic correlation (rg = 0.16 to 0.97) with thyroid cancer and autoimmune thyroid diseases.
• Graves' disease: Included among the five conditions studied in the multi-biobank meta-analysis, with shared genetic architecture identified between Graves' disease, other autoimmune thyroid diseases, and thyroid cancer.
• Lymphocytic thyroiditis: Also studied in the multi-biobank meta-analysis and found to share genetic overlap with the other thyroid conditions analyzed.
• Primary hypothyroidism: Among the five conditions covered in the approximately 2.9 million genome meta-analysis, with telomere maintenance genes identified as contributors to both benign and malignant thyroid nodular disease risk alongside primary hypothyroidism.

Evidence quality The TSH GWAS (247,107 participants) used a two-stage design, with Stage 1 discovery in European ancestry participants followed by replication in the Estonian Biobank (63,326 European ancestry) and Genes & Health (33,171 South Asian ancestry), applying a genome-wide significance threshold of P < 5 x 10-8. The thyroid disease meta-analysis (approximately 2.9 million genomes across 19 biobanks) is among the largest thyroid GWAS efforts conducted to date, with replication across diverse ancestry groups and polygenic risk score validation in independent clinical cohorts. Both studies report findings at the level of genome-wide significant loci and gene regions. Specific per-variant effect sizes (odds ratios or beta coefficients) and p-values for rs116340633 individually are not reported in the source material provided, so variant-level quantitative data for this SNP requires review of the original study supplementary tables. The evidence base for the locus broadly is robust, but variant-specific statistics are not available from the excerpts studied.

Lifestyle considerations No lifestyle considerations on file for this variant.