Abstract 16: Genomewide Association Study of Isoproterenol-Induced Heart Failure in a Large Mouse Panel
Heart failure is highly heterogeneous and association studies in humans have yielded few insights into its genetic basis. We have developed a resource, the Hybrid Mouse Diversity Panel, to efficiently perform association studies on complex diseases in a mouse model. Each strain within the panel has been densely genotyped and the panel displays significant baseline inter-strain variation. We used the panel to explore isoproterenol (a β-adrenergic agonist) induced heart failure.
Eight week old females from 105 unique inbred strains (average N = 6.7) were divided into control (average N = 2.5) and treated (average N = 4.1) cohorts. Treated mice received 20 μg/g/day of drug through an abdominally implanted Alzet micropump. All mice underwent echocardiography to assess left ventricular function both before and at weekly timepoints after treatment. At three weeks, all mice were sacrificed. Hearts (sectioned by chamber) lungs, liver and adrenal glands were weighed before storage for further analysis. Phenotypes were analyzed using the Efficient Mixed-Model Association (EMMA) algorithm to correct for population substructure. Promising gene candidates were tested on zebrafish morpholino models to assess any phenotypic effects.
Here we report initial findings from the panel. Chronic β-adrenergic stimulation results in marked variations in both weight and echocardiographic measurements. EMMA analysis of the data revealed several dozen putative peaks, including several repeated peaks in correlated phenotypes as well as replication of previously reported loci in both human and mouse studies. Further analysis of these peaks will shed light on the genetics underlying heart failure.
- © 2012 by American Heart Association, Inc.