Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease

Abstract

Integration of genome-wide expression profiling with linkage analysis is a new approach to identifying genes underlying complex traits. We applied this approach to the regulation of gene expression in the BXH/HXB panel of rat recombinant inbred strains, one of the largest available rodent recombinant inbred panels and a leading resource for genetic analysis of the highly prevalent metabolic syndrome. In two tissues important to the pathogenesis of the metabolic syndrome, we mapped cis- and trans-regulatory control elements for expression of thousands of genes across the genome. Many of the most highly linked expression quantitative trait loci are regulated in cis, are inherited essentially as monogenic traits and are good candidate genes for previously mapped physiological quantitative trait loci in the rat. By comparative mapping we generated a data set of 73 candidate genes for hypertension that merit testing in human populations. Mining of this publicly available data set is expected to lead to new insights into the genes and regulatory pathways underlying the extensive range of metabolic and cardiovascular disease phenotypes that segregate in these recombinant inbred strains.

Fine mapping of regulatory loci for mammalian gene expression using radiation hybrids

“…To date, expression quantitative trait loci, or eQTLs, have been mapped in populations segregating polymorphisms [2][3][4][5][6][7][8][9][10][11][12] , but power in such studies is limited by the frequency of ~1 crossover per chromosome per meiosis.…”

Bench to Bedside: The Quest for Quality in Experimental Stroke Research

“…Although traditionally experimental stroke research has focused on early mechanisms of damage, only recently a surprising capacity of the central nervous system (CNS) for regeneration and plasticity has been identified, raising the hopes of developing therapeutic approaches based on these findings (Chen et al, 2002;Lindvall and Kokaia, 2004;Savitz et al, 2004Savitz et al, , 2002Roitberg, 2004;Chopp and Li, 2002). Further progress in the field has come from a recent tremendous expansion of the methodological portfolio of experimental stroke research, ranging from genome-wide transcriptional and protein expression screens (Carmichael, 2003;Hubner et al, 2005), to the targeted deletion or overexpression of candidate genes (Liang et al, 2004), to sophisticated highresolution in vivo imaging (Dijkhuizen and Nicolay, 2003).…”

Multiple sclerosis genetics: leaving no stone unturned

“…Using this approach, a gene expression pattern strongly associated with murine obesity was identified leading to the identification of four new QTL linked to this complex phenotype. 110 More recently, genetical genomics yielded the identification of regulatory networks affecting stem cell function, 111 blood pressure, 112 and some neural phenotypes. 113 In humans, analysis of genomically controlled variation in gene expression has also been reported 114 opening a promising venue for unraveling biological pathways in complex diseases.…”