Metabolism and Inflammation, MRC Harwell Mammalian Genetics Unit, Harwell Science and Innovation Campus, Oxfordshire, UK.
Dis Model Mech. 2011 Mar;4(2):155-64. doi: 10.1242/dmm.000414. Epub 2011 Feb 14.
Within the last 3 years, genome-wide association studies (GWAS) have had unprecedented success in identifying loci that are involved in common diseases. For example, more than 35 susceptibility loci have been identified for type 2 diabetes and 32 for obesity thus far. However, the causal gene and variant at a specific linkage disequilibrium block is often unclear. Using a combination of different mouse alleles, we can greatly facilitate the understanding of which candidate gene at a particular disease locus is associated with the disease in humans, and also provide functional analysis of variants through an allelic series, including analysis of hypomorph and hypermorph point mutations, and knockout and overexpression alleles. The phenotyping of these alleles for specific traits of interest, in combination with the functional analysis of the genetic variants, may reveal the molecular and cellular mechanism of action of these disease variants, and ultimately lead to the identification of novel therapeutic strategies for common human diseases. In this Commentary, we discuss the progress of GWAS in identifying common disease loci for metabolic disease, and the use of the mouse as a model to confirm candidate genes and provide mechanistic insights.
在过去的 3 年中，全基因组关联研究（GWAS）在鉴定与常见疾病相关的基因座方面取得了前所未有的成功。例如，迄今为止，已经确定了超过 35 个 2 型糖尿病易感基因座和 32 个肥胖易感基因座。然而，特定连锁不平衡块中的因果基因和变体通常并不清楚。通过结合使用不同的小鼠等位基因，我们可以极大地促进对特定疾病基因座中与人类疾病相关的候选基因的理解，并通过等位基因系列提供对变体的功能分析，包括对低功能和高功能点突变、敲除和过表达等位基因的分析。对这些等位基因进行特定感兴趣特征的表型分析，结合对遗传变异的功能分析，可能揭示这些疾病变异的分子和细胞作用机制，并最终导致为常见人类疾病确定新的治疗策略。在这篇评论中，我们讨论了 GWAS 在鉴定代谢疾病常见疾病基因座方面的进展，以及将小鼠作为模型来确认候选基因并提供机制见解的用途。
