International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

G7. Combined Linkage Analysis and Microarray-based Expression Profiling for Identification of Complex Trait Genes

Timothy J. Aitman, Caroline A. Wallace, Anne M. Glazier, Penny J. Norsworthy, Jennefer K. Gray, *Lawrence W. Stanton and James Scott
Molecular Medicine Group, MRC Clinical Sciences Centre and Imperial College Genetics and Genomics Research Institute, Hammersmith Hospital, London, UK.
*Scios Inc., Sunnyvale, California, USA.

Insulin resistance, or defective insulin action, is a common human disorder associated with type 2 diabetes, hypertension, dyslipidaemia and risk of coronary heart disease. We have analysed the genetics of insulin action in the spontaneously hypertensive rat (SHR) a rodent model of these common "insulin resistance syndromes". Using conventional microsatellite genome screens in experimental crosses, we mapped four quantitative trait loci (QTLs) for SHR defects in insulin action, carbohydrate metabolism and fatty acid metabolism. One of these QTLs, on chromosome 4, shared peak linkage with previously mapped SHR QTLs for dyslipidaemia and hypertension. We generated expression profiles with DNA microarrays and identified 329 genes that are differentially expressed between SHR and the Brown Norway strain, an insulin-sensitive, normotensive control. One of these genes, Cd36 or fatty acid translocase, is defective in this strain of SHR, and underlies the chromosome 4-linked defects in insulin action and fatty acid metabolism in this rat strain (Aitman et al 1999, Nature Genet 21:76-83). These results suggested that combined linkage analysis and expression profiling may be a useful strategy for identification of genes underlying other SHR QTLs for blood pressure, cardiac mass and insulin resistance. As a first step towards characterising further this data set of differentially expressed genes we used radiation hybrid (RH) mapping to localise 80 unique genes and expressed sequences in the rat genome. The genes were localised relative to the whole-genome RH framework maps of the Whitehead Institute and the Otsuka GEN Research Institute. Twenty-three of the genes map to SHR QTLs for blood pressure, dyslipidaemia, blood glucose or insulin resistance. These genes are now being tested as candidates by tissue distribution studies with custom microarrays and by DNA sequence analysis. These studies represent a systematic analysis of microarray-based expression data. The approach may be useful in other linkage studies of genetically complex traits.

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