Back-translating GWAS findings to animal models reveals a role for Hgfac and Slc39a8 in alcohol and nicotine consumption

F. K.El Banna, Jacqueline M Otto, S. M. Mulloy, W. Tsai, S. M. McElroy, A. L. Wong, G. Cutts, S. I. Vrieze, Anna M Lee

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Alcohol and tobacco are the most commonly used addictive substances, with high comorbidity rates between alcohol use disorder and tobacco use disorder. Risk for alcohol and nicotine addiction is highly heritable, and they share common genetic factors. A GWAS in over 1 million individuals has revealed 566 genetic variants in 406 loci associated with multiple stages of alcohol and tobacco use. Three novel genes—SLC39A8, GRK4 and HGFAC—within loci associated with altered alcoholic drinks per week (ADW) or cigarettes per day (CPD) were selected to further study their role in alcohol and tobacco use disorder. The role of these genes was assessed using the two-bottle choice addiction paradigm in transgenic mice for each of the genes. We found significant decreases in chronic alcohol consumption and preference in female Hgfac knockout (KO) mice, and decreased nicotine preference in male Hgfac KO compared with wild-type (WT) mice. Additionally, male Slc39a8 hypomorph mice showed greater overall nicotine preference compared with WT mice, while no differences were detected for Grk4 KO mice in alcohol or nicotine consumption and preference in either sex. Thus, this study implicates Hgfac and Slc39a8 in alcohol and tobacco use in a sex-specific manner.

Original languageEnglish (US)
Article number9336
JournalScientific reports
Issue number1
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This work was supported by R01 AA026598 (AML), R01 DA044283 (SIV).

Publisher Copyright:
© 2022, The Author(s).


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