392: GWAS of Cocaine Self-Administration in Heterogeneous Stock Rats

Lara MK et al et al., Nature Communications - Large GWAS in 836 outbred HS rats identifies six loci linked to cocaine self-administration traits, highlighting Ces1 carboxylesterase genes and other loci overlapping human substance-use genetics. Key terms: cocaine use disorder, GWAS, Heterogeneous Stock rats, Ces1, addiction-like behavior. Study Highlights:The study performed a genome-wide association analysis in 836 Heterogeneous Stock rats tested in extended-access cocaine self-administration paradigms and derived 27 behavioral traits. Six genome-wide significant loci were identified, including a chromosome 19 locus containing missense variants in Ces1c and Ces1d that are orthologous to human CES1 and associated with post-infusion interval. SNP-based heritability for traits was modest (h2 = 0.07–0.16) with the first LgA principal component showing the highest heritability (h2 = 0.16). Several loci contained coding variants and eQTL/sQTLs in brain regions, and one locus overlapped the rat homolog of human TRAK2. Conclusion:This largest-to-date rat GWAS of cocaine self-administration implicates drug-metabolizing carboxylesterases (Ces1c/Ces1d) and multiple neural genes in addiction-like behaviors, supports cross-species links to human SUD loci such as TRAK2, and highlights CES1-related pharmacological strategies as a potential avenue for follow-up. Music:Enjoy the music based on this article at the end of the episode. Article title:Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats First author:Lara MK et al Journal:Nature Communications DOI:10.1038/s41467-026-73694-w Reference:Lara MK et al., Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats. Nature Communications (2026). https://doi.org/10.1038/s41467-026-73694-w License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/gwas-cocaine-hs-rats-ces1 QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-06-12. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited portions of the transcript that cover: HS rat GWAS design and results; the chromosome 19 Ces1c/Ces1d locus and its link to post-infusion interval; metabolic role of Ces1 in cocaine breakdown; cross-species Trak2 findings; Rasd2/Gnas brain-region eQTLs; PC1 heritability; and broader discussion of implications an- transcript topics: Gwas in heterogeneous stock rats and six significant loci; Chromosome 19 Ces1c/Ces1d locus and post-infusion interval; Carboxylesterase Ces1 enzymes metabolizing cocaine; Trak2/TRAK2 cross-species overlap with human CUD; Rasd2 and Gnas expression in nucleus accumbens and cortex; LgA PC1 addiction-like behavior and heritability QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- Six genome-wide significant associations identified for cocaine self-administration traits in HS rats- Chromosome 19 locus containing...