International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


PLENARY PRESENTATION

THURSDAY OCTOBER 21

1.30pm – 2.00pm

GENETICS OF ATHEROSCLEROSIS:  INTEGRATING GENETIC AND GENE EXPRESSION DATA

Schadt E1, Lamb J1, Lum P1, Leonardson A1, Wang S2, Doss S2, Yang X2, Ghazalpour A2, Davis R2, Zhang B2, Horvath S2, Drake T2, Lusis A2

1 Rosetta Inpharmatics, LLC, Seattle WA, United States, 2UCLA School of Medicine, Los Angeles, CA, United States

We are utilizing genetic variation between strains of mice to identify genes and pathways contributing to atherosclerosis and diabetes.  Using QTL mapping, numerous relevant loci have been identified and some positional candidates have been confirmed.  We are now developing approaches that integrate traditional gene mapping and expression array data to help identify genes and elucidate pathways involved in these complex diseases.  Thus far, we have applied expression-based mapping strategies to genetic crosses between strains DBA and C57BL/6 (liver) and strains C3H and C57BL/6 (liver, fat, muscle, brain).  Each cross has resulted in the identification of thousands of expression QTL (eQTL).  About a third of these appear to result from cis-acting variations (that is, the eQTL maps over the gene encoding the transcript in question).  These have been validated using a classical cis-trans test with F1 mice, in which the levels of transcript from each allele were determined using SNPs present in the mRNA.  Trans-acting eQTL are being validated using congenic strains.  For this, we are expression profiling a set of congenic strains between DBA and C57BL/6 containing introgressed segments (about 30-40 cM in size) covering all chromosomes.  A major goal of our studies is to use the combination of genetics and gene expression to construct causal expression networks involved in atherosclerosis and diabetes.

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