Tiffin Nicki, Okpechi Ikechi, Perez-Iratxeta Carolina, Andrade-Navarro Miguel A, Ramesar Rajkumar
Division of Human Genetics, MRC Human Genetics Research Unit, Institute for Infectious Diseases and Molecular Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
Physiol Genomics. 2008 Sep 17;35(1):55-64. doi: 10.1152/physiolgenomics.90247.2008. Epub 2008 Jul 8.
There is a rapid increase in the world-wide burden of disease attributed to metabolic syndrome, as defined by co-occurrence of an array of phenotypes including abdominal obesity, dysglycemia, hypertriglyceridemia, low levels of high density lipoprotein cholesterol, and hypertension. Familial studies clearly indicate a genetic component to the disease and many linkage studies have identified a large number of linked loci. No disease-causing genes, however, have been conclusively identified, most likely because this is a multigenic disease for which effects of many causative genes may be small and combined with environmental effects. To assist empirical identification of metabolic syndrome associated genes, we present here a novel computational approach to prioritize candidate genes. We have used linkage studies and the clinical and population-specific presentation of the disease to select a final candidate gene list of 19 most likely disease-causing genes. These are predominantly involved in chylomicron processing, transmembrane receptor activity, and signal transduction pathways. We propose here that information about the clinical presentation of a complex trait can be used to effectively inform computational prioritization of disease-causing genes for that trait.
由代谢综合征导致的全球疾病负担正在迅速增加，代谢综合征的定义是一系列表型同时出现，包括腹部肥胖、血糖异常、高甘油三酯血症、高密度脂蛋白胆固醇水平低以及高血压。家族研究清楚地表明该疾病存在遗传因素，许多连锁研究已经确定了大量的连锁基因座。然而，尚未最终确定致病基因，这很可能是因为这是一种多基因疾病，许多致病基因的影响可能较小，并且与环境影响相结合。为了帮助通过实验确定与代谢综合征相关的基因，我们在此提出一种新的计算方法来对候选基因进行优先级排序。我们利用连锁研究以及该疾病的临床和人群特异性表现，选择了一份包含19个最有可能致病基因的最终候选基因列表。这些基因主要参与乳糜微粒处理、跨膜受体活性和信号转导途径。我们在此提出，关于复杂性状临床表现的信息可用于有效地为该性状致病基因的计算优先级排序提供依据。
