2026-06-11 カリフォルニア大学サンディエゴ校（UCSD）
This image shows the Ces1 protein, which plays a role in metabolizing cocaine.
＜関連情報＞
- https://today.ucsd.edu/story/genetic-mapping-identifies-potential-new-targets-for-cocaine-addiction
- https://www.nature.com/articles/s41467-026-73694-w
異系交配ラットにおけるコカイン自己投与行動のゲノムワイド関連解析 Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats
Montana Kay Lara,Lieselot L. G. Carrette,Thiago Missfeldt Sanches,Oksana Polesskaya,Alicia Avelar,Angela Beeson,Hassiba Beldjoud,Brent Boomhower,Molly Brennan,Denghui Chen,Riyan Cheng,Lindsey China,Apurva S. Chitre,Dana Elizabeth Conlisk,McKenzie Fannon,Benjamin B. Johnson,Elaine Keung,Adam Kimbrough,Jenni Kononoff,Angelica Renee Martinez,Lisa Maturin,Khai-Minh Nguyen,Alex Morgan,Joseph Mosquera,… Olivier George
Nature Communications Published:11 June 2026
DOI:https://doi.org/10.1038/s41467-026-73694-w
Abstract
Cocaine use disorder (CUD) is a major public health crisis. The specific genes mediating CUD remain largely unknown. We conducted a genome-wide association study (GWAS) using outbred N/NIH Heterogeneous Stock (HS; n = 836, female = 415, male = 421) rats. We examined CUD-related phenotypes including acquisition of self-administration, escalation of intake, and compulsive-like responding. These traits were phenotypically correlated and exhibited modest SNP heritability (h2 = 0.07 – 0.16). We identified six genome-wide significant associations (>-log10(p)=5.58; α = 0.05 by permutation). One locus on chromosome 19 was associated with variable time between cocaine infusions (post infusion interval) and contains several carboxylesterase genes that are orthologous to the human CES1 gene. Notably, carboxylesterases metabolize cocaine. Three non-synonymous coding variants in Ces1c and Ces1d were in perfect linkage disequilibrium with this locus. The other five loci contained promising coding and expression variants, including Trak2, a gene previously associated with CUD in human GWAS and Slc10a7, Plcl1, and Satb2 which have been associated with alcohol and tobacco use disorder. This is the largest genetic study of cocaine self-administration ever conducted in rats. Our results replicate previous loci associated with CUD in humans and provide several novel biological insights including the potential of pharmacological strategies targeting carboxylesterases.
