肥胖是少有的几种可控的绝经后乳腺癌危险因素，身体质量指数是其最常用的衡量指标。观察性研究能够鉴定二者之间的流行病学关联，然而因其方法学上固有的缺陷，无法阐明该关联是否为直接的因果关联。因此这项极具价值的流行病学发现至今尚无法应用于绝经后乳腺癌的预防。基于对现有证据的综合分析以及申请人前期的研究基础，我们假设：肥胖与绝经后乳腺癌之间的关联是直接的因果关联。为了测试该假设，本项目拟使用多个身体质量指数易感位点所构建的遗传分数作为工具变量，开展孟德尔随机化分析，在汉族女性中调查遗传决定的肥胖与绝经后乳腺癌之间的关系。进一步，我们系统分析可能参与的生物学通路，以明确其对因果关联的贡献。由于肥胖对汉族女性乳腺癌发病风险的贡献高于白种人，本项目的研究结果不仅能促进深层次理解肥胖导致绝经后乳腺癌发生的病因学基础，而且有望为我国女性乳腺癌的预防与治疗提供全新的视点。

Excess body adiposity, commonly expressed as body mass index (BMI), is one of the few modifiable breast cancer risk factors. While observational studies could identify an epidemiological association between BMI and risk of breast cancer in postmenopausal women, it remains unclear whether the association is causal due to inherent defects in methodology. This important epidemiological finding, thus far, has not yet been delivered into prevention of breast cancer in postmenopausal women. Based on cumulative epidemiological evidence and our previous studies in this field, we hypothesized that adiposity is causally associated with breast cancer in postmenopausal women. To test this hypothesis, here we propose to conduct a Mendelian randomization analysis to investigate the relationship between genetically determined adiposity and risk of breast cancer in postmenopausal Han Chinese women using a genetic score comprising multiple BMI-associated variants as an instrumental variable. Furthermore, we will systematically analyze the potential biological pathways to uncover the contribution of these pathways to the causal association. Given that the relative risk of postmenopausal breast cancer associated with adiposity in Han Chinese women is stronger than that in White women, findings from this project will not only advance our understanding of the etiology that adiposity causes postmenopausal breast cancer, but also provide new insight into prevention and treatment of breast cancer in China.