Integration of background genome variation to dissect complex cardiovascular phenotypes (697.5)

Abstract

The genetic underpinnings of cardiovascular (CV) disease are far more complex than originally imagined. Human genome wide association studies (GWAS) have identified candidate genes, but to date have predicted only a small fraction of the genetic basis. Some of the “missing heritability” is likely due to the interaction of multiple genes and alleles contributing to the disease. Phenotypic and genotypic characterization of two complete comsomic rat panels provides the foundation to analyze the influence of genetic background on CV traits. Phenotyping of PhysGen consomic strains, developed by introgressing Brown Norway (BN) chromosomes onto the Salt‐Sensitive (SS) or Fawn Hooded Hypertensive (FHH) backgrounds, identified consomic strains in introgressed BN chromosomes alter phenotypes on only one genomic background or under only one environmental condition. Introgression of BN chromosome 1 differentially regulates left ventricle infarct size following ischemia on SS and FHH backgrounds. HIF pathway genes on chromosome 1 are nearly identical between SS and FHH, although 12 genes on background chromosomes contain non‐synonymous SNPs (2 in SS only, 6 in FHH only, and 4 in both compared to BN), potentially altering the HIF pathway and CV phenotypes in response to chronic hypoxia. Additional in silico analysis, using gene, QTL and phenotype annotations, in conjunction with strain‐specific sequence variation, enables virtual variant profiles for complex phenotypes or disease pathways to be created for each consomic strain.Grant Funding Source: Supported by R01HL094271 and R01HL064541