Genetic drivers of etiologic heterogeneity in thyroid cancer

Abstract

Thyroid cancer is the most common endocrine malignancy, yet its biological underpinnings remain incompletely understood. We conducted a multi-ancestry genome-wide association study meta-analysis of thyroid cancer (16,167 cases and 2,430,374 controls), identifying 51 independent loci, including 21 novel signals. We analyzed the associations of thyroid cancer risk alleles with 151 other thyroid-cancer-related traits. These pleiotropic relationships reveal mechanistic clusters linked to thyroid function, oncogenic pathways, and mixed physiological function. Two thyroid-specific clusters associated with thyroid stimulating hormone, influencing thyroid growth and function and were enriched in thyroid tissues. Oncogenic clusters included DNA repair (ATM, CHEK2, TP53) and telomere maintenance (TERT) genes, implicating shared cancer mechanisms. Cluster-specific polygenic scores were associated with thyroid disease, cancer, and metabolic traits across ancestry groups, suggesting distinct genetic subtypes of thyroid cancer risk. These results demonstrate the utility of pleiotropy-based approaches in uncovering thyroid cancer mechanisms and advancing genetically informed risk stratification.