© 2025 . Created for free using WordPress and Kubio

CASTxB6-HDL

Add Local Links Admin.

A Systems Genetic Analysis of High Density Lipoprotein Metabolism and Network Preservation across Mouse Models

Peter Langfelder1, Lawrence W. Castellani2, Zhiqiang Zhou2, Eric Paul2, Richard Davis2, Eric E. Schadt4, Aldons J. Lusis1,2,3, Steve Horvath1,5, Margarete Mehrabian2,

1Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles
2Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles
3Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles
4Pacific Biosciences, Menlo Park, CA 94025
5Department of Biostatistics, University of California, Los Angeles

Contact: Peter (dot) Langfelder (at) gmail (dot) com, mehrabi (dot) m (at) gmail (dot) com

Abstract

We report a systems genetics analysis of high density lipoproteins (HDL) levels in an F2 intercross between inbred strains CAST/EiJ and C57BL/6J. We previously showed that there are dramatic differences in HDL metabolism in a cross between these strains, and we now report co-expression network analysis of HDL that integrates global expression data from liver and adipose with relevant metabolic traits. Using data from a total of 293 F2 intercross mice, we constructed weighted gene co-expression networks and identified modules (subnetworks) associated with HDL and clinical traits. These were examined for genes implicated in HDL levels based on large human genome-wide associations studies (GWAS) and examined with respect to conservation between tissue and sexes in a total of 9 data sets.

Data

Expression, clinical phenotype, and genotype data are all included in this zip bundle:

Supplementary methods: R code for statistical analysis

Here we provide R code we used for the statistical analysis of the data. All code is provided in annotated pdf documents. Code can be copy-pasted into an R session to reproduce our results.

  1. Expression data pre-processing and cleaning
  2. eQTL analysis
  3. QTL analysis for HDL and other traits
  4. Standard (a.k.a. marginal) analysis: associations of individual genes with HDL and other traits
  5. Gene co-expression network analysis
  6. Causal testing
  7. Analysis of module preservation in adipose
  8. Analysis of module preservation in other crosses
  9. Analysis of preservation of module significance in other crosses

Supplementary figures

Supplementary figures, including captions are provided in this document.

Supplementary tables

Our supplementary tables provide more detailed information and resources for additional research and analysis.

  • Supplementary table 1: QTL analysis for clinical traits, sex as a covariate. Each row corresponds to a SNP marker, each column to a trait (first 3 columns identify the SNPs). Where present, prefix “b_” identifies traits measured for chow diet, prefix “e_” identifies traits measured for Western diet. Entries in the table are LOD scores.
  • Supplementary table 2: QTL analysis for clinical traits, sex as interactive trait. Each row corresponds to a SNP marker, each column to a trait (first 3 columns identify the SNPs). Where present, prefix “b_” identifies traits measured for chow diet, prefix “e_” identifies traits measured for Western diet. Entries in the table are LOD scores.
  • Supplementary table 3: Suggestive and significant QTL peaks for HDL on chow diet with sex as interactive trait. Suggestive and significant loci identified for sex x genotype interactions on chow diet. HDL levels by sex (F, M)/genotype (BB, BC, CC) combinations at peak markers with half-range of 95% confidence interval indicated in brackets, the corresponding R/qtl LOD score, and the genome-wide significance (permutation test p-value).
  • Supplementary table 4: Suggestive and significant QTL peaks for HDL on Western diet with sex as interactive trait. Suggestive and significant loci identified for sex x genotype interactions on Western diet. HDL levels by sex (F, M)/genotype (BB, BC, CC) combinations at peak markers with half-range of 95% confidence interval indicated in brackets, the corresponding R/qtl LOD score, and the genome-wide significance (permutation test p-value).
  • Supplementary table 5: Association of liver gene expression profiles and clinical traits on Western diet. Columns 1-3 identify the probe and the associated gene and Locus Link (Entrez) Id. Subsequent columns give the robust correlations, p-values, and q-values (local FDR) for each trait.
  • Supplementary table 6: Association of adipose gene expression profiles and clinical traits on Western diet. Columns 1-3 identify the probe and the associated gene and Locus Link (Entrez) Id. Subsequent columns give the robust correlations, p-values, and q-values (local FDR) for each trait.
  • Supplementary table 7: Enrichment analysis of HDL-associated genes in liver. Columns list the direction (sign) of the association (Both, Positive, Negative), number of genes, rank, Bonferroni-correct enrichment p-value (Bonferroni correction for the number of tested GO terms), fraction of the associated genes in the term, and basic information about the GO term.
  • Supplementary table 8: Enrichment analysis of HDL-associated genes in adipose. Columns list the direction (sign) of the association (Both, Positive, Negative), number of genes, rank, Bonferroni-correct enrichment p-value (Bonferroni correction for the number of tested GO terms), fraction of the associated genes in the term, and basic information about the GO term.
  • Supplementary table 9: Module-trait associations, measured as robust correlation of the module eigengene with the trait, in liver. Each row corresponds to one module, and pairs of columns give the correlations and p-values with each trait.
  • Supplementary table 10: Module-trait associations, measured as robust correlation of the module eigengene with the trait, in adipose. Each row corresponds to one module, and pairs of columns give the correlations and p-values with each trait.
  • Supplementary table 11: Enrichment analysis of liver network modules. Columns list the module label, number of genes in module and in GO, enrichment rank, Bonferroni-correct enrichment p-value (Bonferroni correction for the number of tested GO terms), fraction of module genes in the term, and basic information about the GO term.
  • Supplementary table 12: Enrichment analysis of adipose network modules. Columns list the module label, number of genes in module and in GO, enrichment rank, Bonferroni-correct enrichment p-value (Bonferroni correction for the number of tested GO terms), fraction of module genes in the term, and basic information about the GO term.
  • Supplementary table 13: Fuzzy module membership in liver. Each row corresponds to one microarray. Columns 1-6 identify the probe and the corresponding gene. Columns moduleLabel, moduleColor give the module label and color to which the probe was assigned. Columns KME.labelModule, pKME.labelModulecolumns give the fuzzy module membership in the label module. Subsequent columns give gene significances (GS) and the corresponding p-values (p.GS) for the clinical traits. Finally, columns starting with kME and p.KME list the signed module membership and the corresponding p-values in each of the modules.
  • Supplementary table 14: Fuzzy module membership in adipose. Each row corresponds to one microarray. Columns 1-6 identify the probe and the corresponding gene. Columns moduleLabel, moduleColor give the module label and color to which the probe was assigned. Columns KME.labelModule, pKME.labelModulecolumns give the fuzzy module membership in the label module. Subsequent columns give gene significances (GS) and the corresponding p-values (p.GS) for the clinical traits. Finally, columns starting with kME and p.KME list the signed module membership and the corresponding p-values in each of the modules.
  • Supplementary table 15: Association of genes with HDL across tests sets in liver. Columns 1 and 2 list gene symbol and Entrez (Locus Link) ID code. Columns ModuleLabel and ModuleColor specify the module label and color in CASTxB6 liver. Columns pValueExtremeScale and qValueExtremeScale give the p- and q-value (local FDR) of the consistent (positive or negative) association of the gene with HDL. Columns NEO.anchor,NEO.leo.nb.AtoB,NEO.leo.nb.BtoA summarize the results of causal analysis and list the anchor SNP and LEO scores for the models gene -> HDL and HDL -> gene. For the subsequent columns, repres.probe lists the representative probe, GS.HDL lists the gene significance for (robust correlation with) HDL (Western diet), and p.GS and q.GS list the corresponding p- and q-values in each of the studied data sets.
  • Supplementary table 16: Association of genes with HDL across tests sets in adipose. Columns 1 and 2 list gene symbol and Entrez (Locus Link) ID code. Columns ModuleLabel and ModuleColor specify the module label and color in CASTxB6 liver. Columns pValueExtremeScale and qValueExtremeScale give the p- and q-value (local FDR) of the consistent (positive or negative) association of the gene with HDL. Columns NEO.anchor, NEO.leo.nb.AtoB, NEO.leo.nb.BtoA summarize the results of causal analysis and list the anchor SNP and LEO scores for the models gene -> HDL and HDL -> gene. For the subsequent columns, repres.probe lists the representative probe, GS.HDL lists the gene significance for (robust correlation with) HDL (Western diet), and p.GS and q.GS list the corresponding p- and q-values in each of the studied data sets.

© 2025 . Created for free using WordPress and Kubio