Langfelder Peter, Castellani Lawrence W, Zhou Zhiqiang, Paul Eric, Davis Richard, Schadt Eric E, Lusis Aldons J, Horvath Steve, Mehrabian Margarete
Department of Human Genetics, David Geffen School of Medicine at UCLA, Gonda (Goldschmied) Neuroscience and Genetics Research Center, 695 Charles E. Young Drive South, Box 708822, Los Angeles, CA 90095-7088, USA.
Biochim Biophys Acta. 2012 Mar;1821(3):435-47. doi: 10.1016/j.bbalip.2011.07.014. Epub 2011 Jul 23.
We report a systems genetic analysis of high density lipoprotein (HDL) levels in an F2 intercross between inbred strains CAST/EiJ and C57BL/6J. We previously showed that there are dramatic differences in HDL metabolism in a cross between these strains, and we now report co-expression network analysis of HDL that integrates global expression data from liver and adipose with relevant metabolic traits. Using data from a total of 293 F2 intercross mice, we constructed weighted gene co-expression networks and identified modules (subnetworks) associated with HDL and clinical traits. These were examined for genes implicated in HDL levels based on large human genome-wide associations studies (GWAS) and examined with respect to conservation between tissue and sexes in a total of 9 data sets. We identify genes that are consistently ranked high by association with HDL across the 9 data sets. We focus in particular on two genes, Wfdc2 and Hdac3, that are located in close proximity to HDL QTL peaks where causal testing indicates that they may affect HDL. Our results provide a rich resource for studies of complex metabolic interactions involving HDL. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
我们报告了近交系CAST/EiJ和C57BL/6J之间F2杂交后代中高密度脂蛋白（HDL）水平的系统遗传学分析。我们之前表明，这两个品系杂交后代的HDL代谢存在显著差异，现在我们报告HDL的共表达网络分析，该分析整合了来自肝脏和脂肪组织的整体表达数据以及相关代谢性状。利用总共293只F2杂交小鼠的数据，我们构建了加权基因共表达网络，并鉴定了与HDL和临床性状相关的模块（子网络）。基于大型人类全基因组关联研究（GWAS），对这些模块中与HDL水平相关的基因进行了检查，并在总共9个数据集中对组织和性别之间的保守性进行了检查。我们鉴定出在9个数据集中与HDL关联始终排名靠前的基因。我们特别关注两个基因，Wfdc2和Hdac3，它们位于HDL数量性状基因座（QTL）峰值附近，因果检验表明它们可能影响HDL水平。我们的结果为研究涉及HDL的复杂代谢相互作用提供了丰富的资源。本文是名为《高密度脂蛋白形成与代谢进展：纪念约翰·F·奥拉姆（1945 - 2010）》特刊的一部分。
