Constructing shared genetic architecture between bioavailable testosterone and luminal A breast cancer in female.

Background: Observational studies have showed a strong association between bioavailable testosterone (BT) and breast cancer. However, the role of genetic factors in their comorbidity remains unknown.

Methods: Using large genome-wide association study (GWAS) data, we employed linkage disequilibrium score regression (LDSC) to identify the breast cancer subtype most genetically correlated with BT. We then constructed the shared genetic architecture between BT and this subtype by: (1) applied Heritability Estimation from Summary Statistics for local genetic correlations and stratified-LDSC for partitioned heritability; (2) performed a cross-trait GWAS meta-analysis to find novel single-nucleotide polymorphism (SNP) and validated through colocalization; (3) conducted both cross-tissue and single-tissue transcriptome-wide association studies (TWAS) and validated the candidate genes through Mendelian randomization (MR); (4) investigated SNP-heritability enrichment at the gene set, tissue, and cell levels using Multi-marker Analysis of GenoMic Annotation.

Results: Luminal A breast cancer (Luminal ABC) was selected as it is a common subtype of breast cancer and demonstrates a superior genetic correlation with BT. We identified strong local correlations in 132 distinct genomic regions and confirmed shared SNPs including rs1432679 and rs7175852. TWAS highlighted two pleiotropic genes, MICALL1 and TRIOBP, with TRIOBP validated by MR. We also found six shared pathways and luminal cells in mammary gland pregnancy shared between BT and Luminal ABC. For tissue-specific enrichment, BT was mainly found in the liver and adrenal gland, whereas Luminal ABC was found in the minor salivary gland.

Conclusions: This study sheds light on the genetic architecture of BT and Luminal ABC and suggests new avenues for research and therapy.