RT Journal Article SR Electronic T1 Transcriptome-wide Analyses of Adipose Tissue in Outbred Rats Reveal Genetic Regulatory Mechanisms Relevant for Human Obesity JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.03.24.485632 DO 10.1101/2022.03.24.485632 A1 Wesley L. Crouse A1 Swapan K Das A1 Thu Le A1 Greg Keele A1 Katie Holl A1 Osborne Seshie A1 Ann L Craddock A1 Neeraj K. Sharma A1 Mary Comeau A1 Carl D Langefeld A1 Greg Hawkins A1 Richard Mott A1 William Valdar A1 Leah C Solberg Woods YR 2022 UL http://biorxiv.org/content/early/2022/03/24/2022.03.24.485632.abstract AB 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.Competing Interest StatementThe authors have declared no competing interest.