Investigating the shared genetic architecture and causality of breast cancer and thyroid cancer: genome-wide cross...

An epidemiological association between breast cancer (BC) and thyroid cancer (TC) has been found in several observational studies, but whether they share common genetic factors remain unknown. Our research aimed to investigate the shared genetic architecture and potential causal link between BC, including estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) subtypes, and TC.

Using genome-wide association study (GWAS) summary statistics, we examined the genetic correlation of BC and TC through linkage disequilibrium score regression (LDSC), Heritability Estimation from Summary Statistics (ρ-HESS), and stratified LDSC (S-LDSC). Shared risk single-nucleotide polymorphisms (SNPs) were obtained using cross-trait meta-analysis with Multi-trait Analysis of GWAS (MTAG) and Cross Phenotype Association (CPASSOC). Co-localization analysis was used to identify shared causal genetic variants. Functional annotation and tissue-specific SNP heritability enrichment analysis was used to investigate SNP enrichment at the molecular and tissue levels. Causality was determined by bidirectional Mendelian randomization.

A significant, positive global genetic correlation between BC and TC was identified, and was also confirmed in the ER+ subtype. Local genetic correlation analysis identified strong signals in the 2q35 region encompassing rs13387042 (TNP1) and rs966423 (DIRC3). Cross-trait meta-analysis uncovered 23 risk SNPs. Co-localization analysis indicated shared causal variants with high posterior probabilities of shared causality. Gene Ontology enrichment analysis identified significant enrichment in cell cycle G1/S phase transition regulation and Wnt signaling pathway. Bidirectional Mendelian randomization suggested a significant association between BC genetic liability and increased TC risk, particularly in the ER+ subtype.

Our study identified a genetic correlation, shared risk genes, and potential causal connection between BC and TC. These findings offered perspectives on the possible mechanisms underlying their comorbidity and the future development of therapeutics.