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Transcriptome-wide analyses of adipose tissue in outbred rats reveal genetic regulatory mechanisms relevant for human obesity

Crouse, Wesley L; Das, Swapan Kumar; Le, Thu; Keele, Gregory; Holl, Katie; Seshie, Osborne; Craddock, Ann; ... Solberg Woods, Leah C; + view all (2022) Transcriptome-wide analyses of adipose tissue in outbred rats reveal genetic regulatory mechanisms relevant for human obesity. Physiological Genomics , 54 (6) pp. 206-219. 10.1152/physiolgenomics.00172.2021. Green open access

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Abstract

Transcriptomic analysis in metabolically active tissues allows a systems genetics approach to identify causal genes and networks involved in metabolic disease. Outbred heterogeneous stock (HS) rats are used for genetic mapping of complex traits, but to-date, a systems genetics analysis of metabolic tissues has not been done. We investigated whether adiposity-associated genes and gene co-expression networks in outbred heterogeneous stock (HS) rats overlap those found in humans. We analyzed RNAseq data from adipose tissue of 415 male HS rats, correlated these transcripts with body weight (BW) and compared transcriptome signatures to two human cohorts: the "African American Genetics of Metabolism and Expression" and "Metabolic Syndrome in Men". We used weighted gene co-expression network analysis to identify adiposity-associated gene networks and mediation analysis to identify genes under genetic control whose expression drives adiposity. We identified 554 orthologous "consensus genes" whose expression correlates with BW in the rat and with body mass index (BMI) in both human cohorts. Consensus genes fell within eight co-expressed networks and were enriched for genes involved in immune system function, cell growth, extracellular matrix organization and lipid metabolic processes. We identified 19 consensus genes for which genetic variation may influence BW via their expression, including those involved in lipolysis (e.g., Hcar1), inflammation (e.g., Rgs1), adipogenesis (e.g., Tmem120b) or no previously known role in obesity (e.g., St14, Msa4a6). Strong concordance between HS rat and human BW/BMI associated transcripts demonstrates translational utility of the rat model, while identification of novel genes expands our knowledge of the genetics underlying obesity.

Type: Article
Title: Transcriptome-wide analyses of adipose tissue in outbred rats reveal genetic regulatory mechanisms relevant for human obesity
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1152/physiolgenomics.00172.2021
Publisher version: https://doi.org/10.1152/physiolgenomics.00172.2021
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: RNA-seq, adipose tissue, mediation analysis, network analysis, weighted gene co-expression network analysis
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10147953
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