Developing cross-population Mendelian randomization for generalizing evidence ondrug targets: the MRC Cross-Population Mendelian Randomization Network

MRC跨种群孟德尔随机化网络的总体目标是整合四个MRC单位的研究专业知识和资源，并结合跨种群遗传流行病学的专业知识，探索使用孟德尔随机化（MR）来评估现有药物和靶向药物对特定亚种群的普遍性。该网络将实施试点研究，重点关注特定的既定药物靶点（例如CETP、HMGCR），以调查人群之间遗传结构的差异如何影响疗效的估计。同时，我们将探讨人群之间环境相互作用的差异（包括叶酸补充剂等公共卫生政策）如何改变这种补充剂的疗效的MR估计（使用MTHFR作为工具）。该网络将专注于磁共振的跨祖先和特定祖先遗传工具的开发，并研究基因共定位与分子靶标（代谢组学、蛋白质组学和转录组学）在不同人群中的差异。

The overarching aim of the MRC Cross-Population Mendelian Randomization Network is to integrate research expertise and resources across four MRC Units with expertise in cross-population genetic epidemiology to explore the use of Medelian randomization (MR) to evaluate generalisability of existing drugs and target drugs to specific sub-populations. The network will implement pilot studies focused on specific established drug targets (e.g. CETP, HMGCR) to investigate how differences in genetic architecture between populations affect estimates of efficacy. In parallel we will explore how differences in environmental interactions between populations (including public health policy such as folate supplementation) alter MR estimates of efficacy of such supplementation (using MTHFR as the instrument). The network will focus on the development of both cross-ancestry and ancestry-specific genetic instruments for MR and investigate how genetic colocalization with molecular targets (metabolomic, proteomic and transcriptomic) vary across populations.