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Genetic Mapping of Multiple Metabolic Traits Identifies Novel Genes for Adiposity, Lipids and Insulin Secretory Capacity in Outbred Rats

Le, Thu H; Crouse, Wesley L; Keele, Gregory R; Holl, Katie; Seshie, Osborne; Tschannen, Michael; Craddock, Ann; ... Solberg Woods, Leah C; + view all (2022) Genetic Mapping of Multiple Metabolic Traits Identifies Novel Genes for Adiposity, Lipids and Insulin Secretory Capacity in Outbred Rats. Diabetes , Article db220252. 10.2337/db22-0252. (In press). Green open access

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Abstract

Despite the successes of human genome-wide association studies, the causal genes underlying most metabolic traits remain unclear. We used outbred heterogeneous stock (HS) rats, coupled with expression data and mediation analysis, to identify quantitative trait loci (QTLs) and candidate gene mediators for adiposity, glucose tolerance, serum lipids, and other metabolic traits. Physiological traits were measured in 1519 male HS rats, with liver and adipose transcriptomes measured in over 410 rats. Genotypes were imputed from low coverage whole genome sequence. Linear mixed models were used to detect physiological and expression QTLs (pQTLs and eQTLs, respectively), employing both SNP- and haplotype-based models for pQTL mapping. Genes with cis-eQTLs that overlapped pQTLs were assessed as causal candidates through mediation analysis. We identified 14 SNP-based pQTLs and 19 haplotype-based pQTLs, of which 10 were in common. Using mediation, we identified the following genes as candidate mediators of pQTLs: Grk5 for a fat pad weight pQTL on Chr1, Krtcap3 for fat pad weight and serum lipids pQTLs on Chr6, Ilrun for a fat pad weight pQTL on Chr20 and Rfx6 for a whole pancreatic insulin content pQTL on Chr20. Furthermore, we verified Grk5 and Ktrcap3 using gene knock-down/out models, thereby shedding light on novel regulators of obesity.

Type: Article
Title: Genetic Mapping of Multiple Metabolic Traits Identifies Novel Genes for Adiposity, Lipids and Insulin Secretory Capacity in Outbred Rats
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.2337/db22-0252
Publisher version: https://doi.org/10.2337/db22-0252
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: GWAS, genetic architecture, heterogeneous stock rats, metabolic, obesity
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
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
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
URI: https://discovery.ucl.ac.uk/id/eprint/10159157
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