Large-scale association analysis identified novel differentiated thyroid carcinoma risk loci by integrating transcriptome and proteome

Differentiated thyroid cancer (DTC) is a prevalent malignancy with increasing global incidence, yet its genetic susceptibility remains poorly understood. Although previous genome-wide association studies (GWAS) have identified several susceptibility loci, the genetic, transcriptomic, and proteomic factors influencing DTC risk remain unclear. We conducted a large-scale GWAS of 7,681 cases and 963,550 controls of European ancestry. Transcriptome-wide association studies (TWAS) used the joint tissue imputation across thyroid, pituitary, blood, and hypothalamus tissues. Proteome-wide association studies (PWAS) integrated brain and plasma proteomic data to identify proteins influencing DTC risk. Mendelian randomization (MR) and Bayesian colocalization were conducted to infer causality. GWAS identified 18 novel loci associated with DTC risk, four of which were previously suggested and are now confirmed. TWAS identified 29 significant genes, including five genes ( LRRC34 , NRG1 , HEMGN , PTCSC3 , and SMAD3) located within known loci and three novel genes ( SAMD4A, RAD51-AS1, and MPHOSPH6 ) validated as causal through MR and Bayesian colocalization. PWAS identified seven significant proteins, with three ( MTHFR , KDELC2 , and SAMD4A ) confirmed as causal, further highlighting 15q15.1 as a novel risk locus consistently emerging across all omics layers. This integrated multi-omics approach reveals novel genetic and molecular mechanisms underlying DTC, linking genomic variation to gene expression and protein abundance.