Medical Population Genetics, The Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
PLoS Genet. 2012;8(8):e1002793. doi: 10.1371/journal.pgen.1002793. Epub 2012 Aug 2.
Genome-wide association studies have identified hundreds of loci for type 2 diabetes, coronary artery disease and myocardial infarction, as well as for related traits such as body mass index, glucose and insulin levels, lipid levels, and blood pressure. These studies also have pointed to thousands of loci with promising but not yet compelling association evidence. To establish association at additional loci and to characterize the genome-wide significant loci by fine-mapping, we designed the "Metabochip," a custom genotyping array that assays nearly 200,000 SNP markers. Here, we describe the Metabochip and its component SNP sets, evaluate its performance in capturing variation across the allele-frequency spectrum, describe solutions to methodological challenges commonly encountered in its analysis, and evaluate its performance as a platform for genotype imputation. The metabochip achieves dramatic cost efficiencies compared to designing single-trait follow-up reagents, and provides the opportunity to compare results across a range of related traits. The metabochip and similar custom genotyping arrays offer a powerful and cost-effective approach to follow-up large-scale genotyping and sequencing studies and advance our understanding of the genetic basis of complex human diseases and traits.
全基因组关联研究已经确定了数百个与 2 型糖尿病、冠状动脉疾病和心肌梗死以及与体重指数、葡萄糖和胰岛素水平、血脂水平和血压等相关特征相关的位点。这些研究还指出了数千个具有潜在关联但尚未具有令人信服关联证据的位点。为了在其他位点建立关联，并通过精细映射来描述全基因组显著位点，我们设计了“代谢芯片”，这是一种定制的基因分型阵列，检测近 20 万个 SNP 标记。在这里，我们描述了代谢芯片及其组成的 SNP 集，评估了它在捕获整个等位基因频率范围内的变异性方面的性能，描述了在分析中经常遇到的方法学挑战的解决方案，并评估了它作为基因型推断平台的性能。与设计单一特征的后续试剂相比，代谢芯片实现了显著的成本效率，并为比较一系列相关特征的结果提供了机会。代谢芯片和类似的定制基因分型阵列为后续大规模基因分型和测序研究提供了一种强大且具有成本效益的方法，并推进了我们对复杂人类疾病和特征遗传基础的理解。
