Multispecies, Integrative GWAS for Focal Segmental Glomerulosclerosis
Technical Report,15 Aug 2018,14 Aug 2019
COLUMBIA UNIVERSITY MEDICAL CENTER New York United States
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The goal of this project are to identify genetic determinants of focal segmental glomerulosclerosis FSGS using genomewide association studies in mouse strains. We have shown that the development nephropathy in the HIV-1 transgenic mice TgFVB is highly strain dependent. Linkage mapping in murine crosses have shown that there are at least 4 FSGS susceptibility loci among inbred strains. Furthermore, F1 hybrids between TgFVB and other inbred strains show highly variable penetrance of nephropathy, indicating the feasibility of mapping genes using F1 hybrids for association mapping. In the past funding periods, we have generated 459 F1 hybrids between TgFVB and 15 inbred strains and have determined variable susceptibility to kidney disease based on genetic background, with C57Bl6J, AJ, DBA1J, NZOHILtJ, C3HHeJ and CBAJ mice showing highest prevalence of injury as measured by proteinuria, and urinary NGAL levels. The increased prevalence of pathology, measured by glomerulosclerosis, was observed on the WSBEiJ, CBAJ, DBA1J, C3HHeJ, and AJ genetic backgrounds. By performing serial analysis of proteinuria, we have also determined the optimal timepoint for assessment of kidney disease in the f1 progeny. The initial QTL analysis shows the genes within a Chr 6 interval that maps to a previously identified QTL, and this contains the Ptpro gene. In addition, annotation of the genes located within the shared haplotype intervals using the Molecular Signature Database demonstrates a significant enrichment for transcriptional targets of NFAT and FOXO4. Once the final cohort has been generated, we will perform a GWAS to detect susceptibility loci for FSGS and compare results to the ongoing GWAS in humans.
- Medicine and Medical Research