Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China.
National Cancer Institute, Rockville, Maryland, United States of America.
PLoS Genet. 2024 May 3;20(5):e1011268. doi: 10.1371/journal.pgen.1011268. eCollection 2024 May.
Age at first sexual intercourse (AFS) and lifetime number of sexual partners (NSP) may influence the pathogenesis of uterine leiomyoma (UL) through their associations with hormonal concentrations and uterine infections. Leveraging summary statistics from large-scale genome-wide association studies conducted in European ancestry for each trait (NAFS = 214,547; NNSP = 370,711; NUL = 302,979), we observed a significant negative genomic correlation for UL with AFS (rg = -0.11, P = 7.83×10-4), but not with NSP (rg = 0.01, P = 0.62). Four specific genomic regions were identified as contributing significant local genetic correlations to AFS and UL, including one genomic region further identified for NSP and UL. Partitioning SNP-heritability with cell-type-specific annotations, a close clustering of UL with both AFS and NSP was identified in immune and blood-related components. Cross-trait meta-analysis revealed 15 loci shared between AFS/NSP and UL, including 7 novel SNPs. Univariable two-sample Mendelian randomization (MR) analysis suggested no evidence for a causal association between genetically predicted AFS/NSP and risk of UL, nor vice versa. Multivariable MR adjusting for age at menarche or/and age at natural menopause revealed a significant causal effect of genetically predicted higher AFS on a lower risk of UL. Such effect attenuated to null when age at first birth was further included. Utilizing participant-level data from the UK Biobank, one-sample MR based on genetic risk scores yielded consistent null findings among both pre-menopausal and post-menopausal females. From a genetic perspective, our study demonstrates an intrinsic link underlying sexual factors (AFS and NSP) and UL, highlighting shared biological mechanisms rather than direct causal effects. Future studies are needed to elucidate the specific mechanisms involved in the shared genetic influences and their potential impact on UL development.
初次性行为年龄（AFS）和终生性伴侣数（NSP）可能通过与激素浓度和子宫感染的关联影响子宫肌瘤（UL）的发病机制。利用在欧洲血统人群中进行的大规模全基因组关联研究的汇总统计数据，针对每种特征（NAFS = 214,547；NNSP = 370,711；NUL = 302,979），我们观察到 UL 与 AFS 之间存在显著的负基因组相关性（rg = -0.11，P = 7.83×10-4），但与 NSP 无关（rg = 0.01，P = 0.62）。确定了四个特定的基因组区域，这些区域对 AFS 和 UL 有显著的局部遗传相关性，包括一个对 NSP 和 UL 有贡献的基因组区域。通过与细胞类型特异性注释的 SNP 遗传力进行分区，在免疫和血液相关成分中，UL 与 AFS 和 NSP 紧密聚类。跨特征荟萃分析揭示了 AFS/NSP 和 UL 之间共享的 15 个基因座，包括 7 个新的 SNP。单变量两样本孟德尔随机化（MR）分析表明，遗传预测的 AFS/NSP 与 UL 风险之间没有因果关系，反之亦然。多变量 MR 调整初潮年龄或/和自然绝经年龄后，发现遗传预测的 AFS 升高与 UL 风险降低之间存在显著的因果关系。当进一步纳入首次生育年龄时，这种影响减弱为零。利用英国生物库的参与者水平数据，基于遗传风险评分的单样本 MR 在绝经前和绝经后女性中均得出一致的无效结果。从遗传角度来看，我们的研究表明性因素（AFS 和 NSP）与 UL 之间存在内在联系，突出了共同的生物学机制，而不是直接的因果关系。需要进一步的研究来阐明共同遗传影响所涉及的具体机制及其对 UL 发展的潜在影响。
