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 (r_g = 0.09, p = 6.00 × 10⁻³), which was consistent in ER+ subtype (r_g = 0.06, p = 0.01) but not in ER− subtype (r_g = 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.

关于子宫肌瘤 (UL) 和乳腺癌 (BC) 所观察到的表型关联背后的共同遗传结构或因果关系知之甚少。利用迄今最大的全基因组关联研究 (GWAS) 对每个性状进行的汇总统计数据，我们研究了 UL 与 BC 的遗传重叠和因果关系，以及与由雌激素受体 (ER) 状态定义的其亚型的关系。我们观察到 UL 和 BC 之间总体上存在正向遗传相关性（r _g  = 0.09，p = 6.00 × 10 ^{−3 ），这在 ER+ 亚型（} r _g = 0.06，p = 0.01）中一致， 但在 ER− 亚型（r _g  = 0.06，p = 0.08）。将整个基因组划分为 1,703 个独立区域，在 22q13.1 处确定了 UL 与 BC 整体和 ER+ 亚型的局部遗传相关性。在 14 个功能类别中的 9 个中进一步发现了显着的遗传相关性，其中在编码、H3K9ac 和抑制区域中观察到的估计值最高。跨性状荟萃分析确定了 UL 和 BC 之间共有的 9 个新基因座。孟德尔随机化显示 BC 总体风险（OR = 1.09，95% CI = 1.01–1.18）和 ER+ 亚型（OR = 1.09，95% CI = 1.01–1.17）对 UL 遗传易感性的风险显着增加。没有发现反向因果关系。我们全面的全基因组跨性状分析证明了 UL 和 BC 之间共有的遗传基础、多效性基因座以及假定的因果关系，强调了这两种复杂女性疾病背后的内在联系。