An Integrated Systems Genetics and Omics Toolkit to Probe Gene Function

Li, Hao, Wang, Xu, Rukina, Daria, Huang, Qingyao, Lin, Tao, Sorrentino, Vincenzo, Zhang, Hongbo, Bou Sleiman, Maroun, Arends, Danny, McDaid, Aaron, Luan, Peiling, Ziari, Naveed, Velázquez-Villegas, Laura A., Gariani, Karim, Kutalik, Zoltan, Schoonjans, Kristina, Radcliffe, Richard A., Prins, Pjotr, Morgenthaler, Stephan, Williams, Robert W. and Auwerx, Johan (2018) An Integrated Systems Genetics and Omics Toolkit to Probe Gene Function. Cell Systems, 6 (1). 90-102.e4. ISSN 2405-4712

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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.

Item Type: Article
Additional Information: Funding information: H.L. is the recipient of a doctoral scholarship from the China Scholarship Council (CSC). This work was supported by grants from the École Polytechnique Fédérale de Lausanne, the Swiss National Science Foundation (31003A-140780), the Velux Stiftung, the Kristian Gerhard Jebsen Foundation; the AgingX program of the Swiss Initiative for Systems Biology (51RTP0-151019), and the NIH (R01AG043930, R01AA016957).
Uncontrolled Keywords: genetic reference population, BXD, mediation analysis, ePheWAS, TWAS, PheWAS, QTL, systems genetics
Subjects: C400 Genetics
C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Rachel Branson
Date Deposited: 16 Sep 2022 13:44
Last Modified: 16 Sep 2022 13:45

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