双样本孟德尔随机化法探究出生体重与乳腺癌的关系

Analysis of relationship between birth weight and breast cancer by two-sample Mendel randomization method

目的探究乳腺癌(breast cancer,BRCA)与出生体重是否存在关联。方法利用来自于出生体重和乳腺癌及其亚型的大型全基因组关联研究的汇总统计数据,将出生体重的总效应分解为胎儿和母亲两个成分,对样本进行连锁不平衡评分回归和孟德尔随机化分析(MR)。结果连锁不平衡评分未发现出生体重和乳腺癌间共有遗传基础,但发现出生体重胎儿效应与携带BRCA1基因的乳腺癌呈正相关(r_(g)=0.122,P=0.013)。孟德尔随机化分析未能确定出生体重和乳腺癌间因果关系(OR=0.99,95%CI:0.92~1.07,P=0.784),但出生体重与管腔B样乳腺癌(OR=1.25,95%CI:1.02~1.53,P=0.029)和携带BRCA1基因的乳腺癌(OR=1.17,95%CI:1.00~1.36,P=0.044)的患病风险呈正相关。结论遗传多变性和母体宫内环境的长期影响,可能导致出生体重和乳腺癌某些亚型间有因果关系。

Objective To explore whether there is a causal and conclusive relationship between breast cancer(BRCA)and birth weight.Methods The summary statistics from large genome-wide association studies for birth weight,BRCA and related subtype research were used for investigation.The total effect of birth weight were divided into fetal and maternal components,the linkage disequilibrium score regression and Mendelian randomization(MR)analysis were used for analysis.Results The linkage disequilibrium score analysis found no genetic basis for birth weight and BRCA,but the fetal effect of birth weight was positively correlated with BRCA for carring BRCA1 gene(r_(g)=0.122,P=0.013).MR analysis did not confirm a causal association between birth weight and BRCA(OR=0.99,95%CI:0.92-1.07,P=0.784).However,a positive causal association was detected for the maternal effect of birth weight on the risk of luminal B-like BRCA(OR=1.25,95%CI 1.02-1.53,P=0.029)and BRCA carring BRCA1 gene(OR=1.17,95%CI:1.00-1.36,P=0.044).Conclusion The genetic pleiotropy and prolonged influence of maternal intrauterine environments may drive the relationship between birth weight and some of subtypes of BRCA.