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Peer-reviewedCC BYNature Communications

Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats

  • Montana Kay Lara1
  • Lieselot L. G. Carrette1
  • Thiago Missfeldt Sanches1
  • Oksana Polesskaya1
  • Alicia Avelar2
  • Angela Beeson3
  • Hassiba Beldjoud1
  • Brent Boomhower1
  • Molly Brennan1
  • Denghui Chen1
  • Riyan Cheng1
  • Lindsey China1
31 more authors
  • Apurva S. Chitre1,4
  • Dana Conlisk4,1
  • McKenzie J. Fannon1
  • Benjamin B. Johnson1
  • Elaine Keung1,5
  • Adam Kimbrough5,4
  • Jenni Kononoff4,1
  • Angelica R. Martinez1
  • Lisa Maturin1
  • Khai‐Minh Nguyen1
  • Alex A. Morgan1
  • Joseph Mosquera1
  • Dyar N. Othman1
  • Sonja Lorean Plasil1
  • Jarryd Ramborger1,4
  • Paul Schweitzer1
  • Sharona Sedighim1,3
  • Osborne Seshie3,1
  • Kokila Shankar1
  • Benjamin C. Sichel1
  • Sierra Simpson1
  • Lauren C. Smith1
  • Elizabeth A. Sneddon1
  • Lani Tieu1
  • Nathan Velarde1,6
  • Sélène Bonnet-Zahedi1,7,3
  • Leah C. Solberg Woods3,1
  • Marsida Kallupi1
  • Giordano de Guglielmo1,8
  • Abraham A. Palmer9,10,1
  • Olivier George11
11 affiliations
  1. 1Department of Psychiatry, University of California San Diego, La Jolla, CA, USA
  2. 2Jamestown Community College, Olean, NY, USA
  3. 3Department of Internal Medicine, Section on Molecular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA
  4. 4The Scripps Research Institute, La Jolla, CA, USA
  5. 5Purdue University, West Lafayette, IN, USA
  6. 6Institut de Neurosciences de la Timone, Aix-Marseille Université, Marseille, 1300, France
  7. 7Institut de Neurosciences de la Timone, Aix-Marseille Université, Marseille, France
  8. 8Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA
  9. 9Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. [email protected]
  10. 10Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA. [email protected]
  11. 11Department of Psychiatry, University of California San Diego, La Jolla, CA, USA. [email protected]
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Abstract

Background Cocaine use disorder (CUD) is a major public health crisis with detrimental individual and societal effects. The specific genes mediating CUD remain largely unknown. Methods We conducted a genome-wide association study (GWAS) using outbred N/NIH Heterogeneous Stock (HS; n = 836, female = 415, male = 421) rats. We examined multiple CUD-related phenotypes that captured acquisition of self-administration, escalation of intake, and compulsive-like responding. Results Consistent with the existing literature, these traits were phenotypically and genetically correlated and exhibited modest heritability (h 2 = 0.07 – 0.16). We identified six genome-wide significant associations. One locus on chromosome 19 was associated with the 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 the genes Ces1c and Ces1d were in perfect linkage disequilibrium with this locus, suggesting that one or more of them might be the causal SNP. The other 5 loci also 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. Conclusions This is the largest genetic study of cocaine self-administration ever conducted in any species. Our results replicate previous loci associated with CUD in humans and provide several novel biological insights including the potential of pharmacological strategies targeting carboxylesterases for the treatment of CUD.

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Cite

BibTeXRIS
BibTeX
@article{lara2026genomewide,
  title = {{Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats}},
  author = {Montana Kay Lara and Lieselot L. G. Carrette and Thiago Missfeldt Sanches and Oksana Polesskaya and Alicia Avelar and Angela Beeson and Hassiba Beldjoud and Brent Boomhower and Molly Brennan and Denghui Chen and Riyan Cheng and Lindsey China and Apurva S. Chitre and Dana Conlisk and McKenzie J. Fannon and Benjamin B. Johnson and Elaine Keung and Adam Kimbrough and Jenni Kononoff and Angelica R. Martinez and Lisa Maturin and Khai‐Minh Nguyen and Alex A. Morgan and Joseph Mosquera and Dyar N. Othman and Sonja Lorean Plasil and Jarryd Ramborger and Paul Schweitzer and Sharona Sedighim and Osborne Seshie and Kokila Shankar and Benjamin C. Sichel and Sierra Simpson and Lauren C. Smith and Elizabeth A. Sneddon and Lani Tieu and Nathan Velarde and Sélène Bonnet-Zahedi and Leah C. Solberg Woods and Marsida Kallupi and Giordano de Guglielmo and Abraham A. Palmer and Olivier George},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-73694-w},
  url = {https://doi.org/10.1038/s41467-026-73694-w},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Genome-wide association study of cocaine self-administration behavior in Heterogeneous Stock rats
AU  - Montana Kay Lara
AU  - Lieselot L. G. Carrette
AU  - Thiago Missfeldt Sanches
AU  - Oksana Polesskaya
AU  - Alicia Avelar
AU  - Angela Beeson
AU  - Hassiba Beldjoud
AU  - Brent Boomhower
AU  - Molly Brennan
AU  - Denghui Chen
AU  - Riyan Cheng
AU  - Lindsey China
AU  - Apurva S. Chitre
AU  - Dana Conlisk
AU  - McKenzie J. Fannon
AU  - Benjamin B. Johnson
AU  - Elaine Keung
AU  - Adam Kimbrough
AU  - Jenni Kononoff
AU  - Angelica R. Martinez
AU  - Lisa Maturin
AU  - Khai‐Minh Nguyen
AU  - Alex A. Morgan
AU  - Joseph Mosquera
AU  - Dyar N. Othman
AU  - Sonja Lorean Plasil
AU  - Jarryd Ramborger
AU  - Paul Schweitzer
AU  - Sharona Sedighim
AU  - Osborne Seshie
AU  - Kokila Shankar
AU  - Benjamin C. Sichel
AU  - Sierra Simpson
AU  - Lauren C. Smith
AU  - Elizabeth A. Sneddon
AU  - Lani Tieu
AU  - Nathan Velarde
AU  - Sélène Bonnet-Zahedi
AU  - Leah C. Solberg Woods
AU  - Marsida Kallupi
AU  - Giordano de Guglielmo
AU  - Abraham A. Palmer
AU  - Olivier George
PY  - 2026
DA  - 2026/06/11
JO  - Nature Communications
DO  - 10.1038/s41467-026-73694-w
UR  - https://doi.org/10.1038/s41467-026-73694-w
AB  - Background Cocaine use disorder (CUD) is a major public health crisis with detrimental individual and societal effects. The specific genes mediating CUD remain largely unknown. Methods We conducted a genome-wide association study (GWAS) using outbred N/NIH Heterogeneous Stock (HS; n = 836, female = 415, male = 421) rats. We examined multiple CUD-related phenotypes that captured acquisition of self-administration, escalation of intake, and compulsive-like responding. Results Consistent with the existing literature, these traits were phenotypically and genetically correlated and exhibited modest heritability (h 2 = 0.07 – 0.16). We identified six genome-wide significant associations. One locus on chromosome 19 was associated with the 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 the genes Ces1c and Ces1d were in perfect linkage disequilibrium with this locus, suggesting that one or more of them might be the causal SNP. The other 5 loci also 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. Conclusions This is the largest genetic study of cocaine self-administration ever conducted in any species. Our results replicate previous loci associated with CUD in humans and provide several novel biological insights including the potential of pharmacological strategies targeting carboxylesterases for the treatment of CUD.
SN  - 2041-1723
ER  -