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Transcriptomic regulation in the NAcc, PL, and pVTA brain regions in heterogeneous stock rats [nucleus accumbens core]

ABSTRACT: To aid in the investigation of behavioral trait genetic associations, we collected RNA-seq from three brain regions of 200 genotyped outbred heterogeneous stock (HS) rats. We mapped molecular QTLs and conducted transcriptome-wide association study (TWAS) involving a collection of 281 complex traits.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE325482 | GEO | 2026/03/26

REPOSITORIES: GEO

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Project description:Obesity is in large part a brain disease that is caused by genetics, the environment (e.g., diet) and their interactions. Identifying genes in the brain that interact with diet to influence obesity is not possible in humans. The goal of this study was to use outbred heterogeneous stock (HS) rats to identify genetic loci for diet-induced obesity followed by RNAseq in the ventromedial hypothalamus (VMH) to identify candidate causal genes. We measured multiple metabolic traits (including fat and lean mass, fasting glucose, insulin, and lipids, glucose tolerance, food intake and activity levels) after long-term consumption of a low-fat (LFD) or high-fat diet (HFD) in 2000 HS rats, split equally be sex and diet. Rats were genotyped using low-coverage whole genome sequencing. RNAseq was run in the VMH of a sub-set of 400 HS rats split equally by sex and diet. We used linear mixed models to detect physiological and expression quantitative trait loci (pQTLs and eQTLs, respectively) in the full dataset and separately by diet and sex. Genes with cis-eQTLs that overlapped pQTLs were assessed as candidate causal genes through mediation analysis. We also identified VMH genes differentially expressed by diet in both sexes, followed by pathway analysis. We identified 47 pQTLs where seven mapped multiple traits, 11 were diet-specific and 13 were sex-specific. We identified nine candidate causal genes, including Pcare, Rbks, Mpv17 and Gpn1 within a pleiotropic pQTL for multiple adiposity traits on rat chr. 6 and Tnsfs9 within a pQTL for fat pad weight on rat chr. 9. We also identified Ccdc77 as a candidate gene within a LFD-specific pQTL for activity levels and Rtel1 and Polr3k within a male-specific pQTL for fatty liver. Genes involved in extracellular matrix and inflammation were dysregulated by diet, particularly in females, while males on HFD showed upregulation of several addiction pathways. This work demonstrates the importance of accounting for diet and sex in genetic studies for obesity and identifies novel candidate genes as neural regulators of diet-induced obesity and related traits.

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Transcriptomic regulation in the NAcc, PL, and pVTA brain regions in heterogeneous stock rats [nucleus accumbens core]

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