A shared genetic regulator of metabolism and addiction-related behavior in mice and humans
Substance use disorders and other mental health conditions often co-occur with metabolic disorders, suggesting shared biological underpinnings <sup>1</sup> . These heightened behavioral and physiological responses may have evolved to promote survival during resource scarcity but can become maladaptive in modern environments <sup>2</sup> . The genetic mechanisms linking these traits have remained elusive. Here, we show that a variable gene enhancer in mice jointly regulates genes encoding an epigenetic factor ( <i>Eed</i> ) and a mitochondrial enzyme ( <i>Me3</i> ) thereby influencing propensity to addiction-related behaviors and mitochondrial function. We further identify variation in a corresponding enhancer in humans regulating <i>EED</i> and <i>ME3</i> associated with substance use, psychiatric and metabolic disorders. These findings reveal a convergent genetic regulatory network linking mitochondrial biology to behavioral and metabolic risk, offering insight into how genetic variation in beneficial regulatory pathways can predispose individuals to substance use disorders and related conditions.
Authors
- Udita Datta (ORCID: https://orcid.org/0000-0002-1404-7577)
- Troy Wilcox
- Heidi Fisher
- Lisa M. Tarantino (ORCID: https://orcid.org/0000-0001-9984-2600)
- Price E. Dickson (ORCID: https://orcid.org/0000-0003-3153-0170)
- Elissa J. Chesler (ORCID: https://orcid.org/0000-0002-5642-5062)
- Leona H. Gagnon
- Whitney Martin
- Robyn L. Ball (ORCID: https://orcid.org/0000-0002-7335-3339)
- Vivek M. Philip (ORCID: https://orcid.org/0000-0001-5126-707X)
- Michael C. Saul (ORCID: https://orcid.org/0000-0002-4916-8619)
- Jason A. Bubier (ORCID: https://orcid.org/0000-0001-5013-1234)
- Sarah A. Schoenrock (ORCID: https://orcid.org/0000-0001-7345-444X)
- Hao He (ORCID: https://orcid.org/0000-0002-2827-2820)
- Anee Czechanski
- A Phillip West
- Laura G Reinholdt
- James David Jentsch
- Christopher Lee Baker
Institutions
- University of North Carolina at Chapel Hill (US)
- Binghamton University (US)
- Centre for Addiction and Mental Health (CA)
- MaineHealth (US)
- Jackson Laboratory (US)
- Pediatrics and Genetics (US)
- Marshall University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-24
- DOI
- https://doi.org/10.64898/2025.12.23.696269
- Primary Topic
- Neurotransmitter Receptor Influence on Behavior
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health
- National Institute on Drug Abuse
- National Cancer Institute