Computational protocol: A Mouse Diversity Panel Approach Reveals the Potential for Clinical Kidney Injury Due to DB289 Not Predicted by Classical Rodent Models

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Protocol publication

[…] Genome-wide association (GWA) mapping was performed as described elsewhere using efficient mixed-model association (EMMA; ). In this approach, a mixed model was used to incorporate pairwise genetic relatedness between every pair of mouse strains in the statistical model directly. Thus, the number of false positives due to the inherent genetic relatedness of strains is reduced, while simultaneously increasing the power to detect causative QTL. Briefly, GWA was performed in R (http://cran.r-project.org) using a 260,733 single-nucleotide polymorphism (SNP) dataset and the fold change (DB289/vehicle) for urinary KIM-1 or for serum ALT for each strain. Eight strains (NOD/ShiLtJ, NZW/LacJ, SWR/J, C57BR/cdJ, C58/J, P/J, SEA/GnJ, and I/LnJ) had KIM-1 values below the limit of quantitation or mortality that prevented sample collection, and were therefore excluded from association analysis. −Log P values were plotted across the mouse genome using the RGenetics package in Galaxy (http://main.g2.bx.psu.edu/). Genomic intervals with association scores greater than the Bonferroni correction threshold were considered significant (−log10 P ≥ 6.84). Genes within significant intervals were identified with Ensembl and the UCSC Genome Browser using NCBI mouse genome build 37 (http://www.ensembl.org; http://genome.ucsc.edu). Network analysis was performed using the pathway explorer function in Ingenuity Pathway Analysis (Ingenuity Systems, Redwood City, CA). The genetic network was recreated using Microsoft PowerPoint for visual clarity. […]

Pipeline specifications

Software tools EMMA, IPA
Databases UCSC Genome Browser
Applications GWAS, Genome data visualization
Organisms Mus musculus
Diseases Ectromelia, Infectious, Kidney Diseases, Trypanosomiasis, African, Chemical and Drug Induced Liver Injury, Drug-Related Side Effects and Adverse Reactions
Chemicals Cholesterol, Creatinine