An Integrated Systems Genetics and Omics Toolkit to Probe Gene Function

Cell Syst. 2018 Jan 24;6(1):90-102.e4. doi: 10.1016/j.cels.2017.10.016. Epub 2017 Nov 30.


Identifying genetic and environmental factors that impact complex traits and common diseases is a high biomedical priority. Here, we developed, validated, and implemented a series of multi-layered systems approaches, including (expression-based) phenome-wide association, transcriptome-/proteome-wide association, and (reverse-) mediation analysis, in an open-access web server ( to expedite the systems dissection of gene function. We applied these approaches to multi-omics datasets from the BXD mouse genetic reference population, and identified and validated associations between genes and clinical and molecular phenotypes, including previously unreported links between Rpl26 and body weight, and Cpt1a and lipid metabolism. Furthermore, through mediation and reverse-mediation analysis we established regulatory relations between genes, such as the co-regulation of BCKDHA and BCKDHB protein levels, and identified targets of transcription factors E2F6, ZFP277, and ZKSCAN1. Our multifaceted toolkit enabled the identification of gene-gene and gene-phenotype links that are robust and that translate well across populations and species, and can be universally applied to any populations with multi-omics datasets.

Keywords: BXD; PheWAS; QTL; TWAS; ePheWAS; genetic reference population; mediation analysis; systems genetics.

MeSH terms

  • Animals
  • Carnitine O-Palmitoyltransferase / genetics
  • Carnitine O-Palmitoyltransferase / physiology
  • Databases, Genetic
  • Gene Expression Profiling / methods*
  • Genome-Wide Association Study
  • Genomics / methods*
  • Genotype
  • Mice
  • Mice, Inbred Strains / genetics
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics
  • Proteomics / methods*
  • Quantitative Trait Loci
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / physiology
  • Systems Biology / methods
  • Transcriptome


  • Ribosomal Proteins
  • Rpl26 protein, mouse
  • CPT1B protein, mouse
  • Carnitine O-Palmitoyltransferase