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Multiomic Profiling of the Liver Across Diets and Age in a Diverse Mouse Population

ABSTRACT: We profiled the liver transcriptome, proteome, and metabolome from 347 individuals from 58 isogenic strains of the BXD mouse population across age (7 to 24 months) and diet (low or high fat) to link molecular variations to metabolic traits. Several hundred genes are affected by diet and/or age at the transcript and protein levels. Orthologs of two aging-associated genes, St7 and Ctsd, were knocked down in C. elegans, reducing longevity in wildtype and mutant long-lived strains. The multiomics data were analyzed as segregating gene networks according to each independent variable, providing causal insight into segregating edges. Candidate hits were cross-examined in an independent Diversity Outbred mouse liver dataset segregating for similar diets, with ~80-90% of diet-related candidate genes found in common across datasets. Together, we have developed a large multiomics resource for multivariate analysis of complex traits and demonstrate a methodology for moving from observational associations to causal connections.

ORGANISM(S): Mus musculus

PROVIDER: GSE310411 | GEO | 2025/11/22

REPOSITORIES: GEO

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Project description:Ectopic calcification in synovial tissues is devastating to diarthrodial joints. While some forms of synovial ectopic calcification have genetically simple basis, most cases manifest as complex traits with environmental and multigenic components. The location of causal loci or the physiological processes affected by allelic variants is poorly understood. Here, we report on genetic susceptibility to ectopic calcification in the LG/J and SM/J advanced intercross mice. Using 347 mice in 98 full-sibships, destabilization of medial meniscus was performed to induce joint injury. We performed quantitative trait locus (QTL) analysis to map calcification phenotypes to discrete genomic locations. To validate the functional significance of the selected QTL candidate genes, we compared mRNA expression between parental LG/J and SM/J inbred strains. Our findings showed that joint destabilization instigated ectopic calcifications as detected and quantified by micro-CT. Overall, we detected 20 QTLs affecting synovial and meniscus calcification phenotypes with 11 QTLs linked to synovial calcification. Functional and bioinformatic analyses of single nucleotide polymorphism identified functional classifications relevant to angiogenesis (Myo1e, Kif26b, Nprl3, Stab2, Fam105b), bone metabolism/calcification (Tle3, Tgfb2, Lipc, Nfe2l1, Ank, Fam105b), arthritis (Stab2, Tbx21, Map4k4, Hoxb9, Larp6, Col1a2, Adam10, Timp3, Nfe2l1, Trpm3), and ankylosing-spondylitis (Ank, Pon1, Il1r2, Tbkbp1) indicating that ectopic calcification involves multiple mechanisms. Furthermore, the expression of 11 candidate genes was significantly different between LG/J and SM/J. Correlation analysis showed that Aff3, Fam81a, Syn3, and Ank were correlated with synovial calcification. Our findings of multiple genetic loci affecting the phenotype suggest the involvement of multiple genes contributing to its pathogenesis. We collected tissue lysates from the formalin-fixed paraffin-embedded sections from mouse knee joints and analyzed the expression of several genes by Affymetrix QuantiGene Plex assay.

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Multiomic Profiling of the Liver Across Diets and Age in a Diverse Mouse Population

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