Little is known regarding the shared genetic architecture or causality underlying the phenotypic association observed for uterine leiomyoma (UL) and breast cancer (BC). Leveraging summary statistics from the hitherto largest genome-wide association study (GWAS) conducted in each trait, we investigated the genetic overlap and causal associations of UL with BC overall, as well as with its subtypes defined by the status of estrogen receptor (ER). We observed a positive genetic correlation between UL and BC overall (rg = 0.09, p = 6.00 × 10-3), which was consistent in ER+ subtype (rg = 0.06, p = 0.01) but not in ER- subtype (rg = 0.06, p = 0.08). Partitioning the whole genome into 1,703 independent regions, local genetic correlation was identified at 22q13.1 for UL with BC overall and with ER+ subtype. Significant genetic correlation was further discovered in 9 out of 14 functional categories, with the highest estimates observed in coding, H3K9ac, and repressed regions. Cross-trait meta-analysis identified 9 novel loci shared between UL and BC. Mendelian randomization demonstrated a significantly increased risk of BC overall (OR = 1.09, 95% CI = 1.01-1.18) and ER+ subtype (OR = 1.09, 95% CI = 1.01-1.17) for genetic liability to UL. No reverse causality was found. Our comprehensive genome-wide cross-trait analysis demonstrates a shared genetic basis, pleiotropic loci, as well as a putative causal relationship between UL and BC, highlighting an intrinsic link underlying these two complex female diseases.
Keywords: breast cancer; causal inference; genetic correlation; pleiotropic loci; uterine leiomyoma.
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