Genetic analysis of blood pressure in 8 mouse intercross populations.

The genetic basis of hypertension is well established, yet very few genes that cause common forms of hypertension are known. Quantitative trait locus (QTL) analyses in rodent models can guide the search for human hypertension genes, but the excellent genetic resources for mice have been underused in this regard. To address this issue, we surveyed blood pressure variation in mice from 37 inbred strains and generated 2577 mice in 8 intercross populations to perform QTL analyses of blood pressure. We identified 14 blood pressure QTL in these populations, including \u3e or =7 regions of the mouse genome not linked previously to blood pressure. Many QTL were detected in multiple crosses, either within our study or in studies published previously, which facilitates the use of bioinformatics methods to narrow the QTL and focus the search for candidate genes. The regions of the human genome that correspond to all but 1 of the 14 blood pressure QTL in mice are linked to blood pressure in humans, suggesting that these regions contain causal genes with a conserved role in blood pressure control. These results greatly expand our knowledge of the genomic regions underlying blood pressure regulation in mice and support future studies to identify the causal genes within these QTL intervals

Genetic analysis of albuminuria in collaborative cross and multiple mouse intercross populations.

Albuminuria is an important marker of nephropathy that increases the risk of progressive renal and chronic cardiovascular diseases. The genetic basis of kidney disease is well-established in humans and rodent models, but the causal genes remain to be identified. We applied several genetic strategies to map and refine genetic loci affecting albuminuria in mice and translated the findings to human kidney disease. First, we measured albuminuria in mice from 33 inbred strains, used the data for haplotype association mapping (HAM), and detected 10 genomic regions associated with albuminuria. Second, we performed eight F(2) intercrosses between genetically diverse strains to identify six loci underlying albuminuria, each of which was concordant to kidney disease loci in humans. Third, we used the Oak Ridge National Laboratory incipient Collaborative Cross subpopulation to detect an additional novel quantitative trait loci (QTL) underlying albuminuria. We also performed a ninth intercross, between genetically similar strains, that substantially narrowed an albuminuria QTL on Chromosome 17 to a region containing four known genes. Finally, we measured renal gene expression in inbred mice to detect pathways highly correlated with albuminuria. Expression analysis also identified Glcci1, a gene known to affect podocyte structure and function in zebrafish, as a strong candidate gene for the albuminuria QTL on Chromosome 6. Overall, these findings greatly enhance our understanding of the genetic basis of albuminuria in mice and may guide future studies into the genetic basis of kidney disease in humans