An integrated systems genetics and omics toolkit to probe gene function

Article Article scientifique Article An integrated systems genetics and omics toolkit to probe gene function eng 2018 author Li Hao 699230 author Wang Xu author Rukina Daria author Huang Qingyao author Lin Tao author Sorrentino Vincenzo author Zhang Hongbo author Bou Sleiman Maroun author Arends Danny author McDaid Aaron author Luan Peiling author Ziari Naveed author Velázquez-Villegas Laura A author Gariani Karim 542849 author Kutalik Zoltan author Schoonjans Kristina author Radcliffe Richard A author Prins Pjotr author Morgenthaler Stephan author Williams Robert W author Auwerx Johan 90-102.e4 10.1016/j.cels.2017.10.016 29199021 2405-4720 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 (systems-genetics.org) 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. Animals Carnitine O-Palmitoyltransferase/genetics/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/physiology Systems Biology/methods Transcriptome Dewey 616 Swiss National Science Foundation Transcriptional cofactor networks and metabolism 140780 CH Project funding 56 Département de médecine 221 false 1263 MASLD/MASH et résistance à l'insuline 997 Cell Systems 6 1 11cb3a86-86ce-4dc0-836e-66a11088fd85 Article (Published version) Public anintegratedsystems(1).pdf 8832955 application/pdf CC BY-NC-ND openAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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An integrated systems genetics and omics toolkit to probe gene function	Cell Systems			2018	314	379

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Li, Hao