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 1 . These heightened behavioral and physiological responses may have evolved to promote survival during resource scarcity but can become maladaptive in modern environments 2 . 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 ( Eed ) and a mitochondrial enzyme ( Me3 ) thereby influencing propensity to addiction-related behaviors and mitochondrial function. We further identify variation in a corresponding enhancer in humans regulating EED and ME3 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.