The OPRM1 A118G G Allele is Associated with Poorer Auditory-Verbal Learning and Memory, Executive Functions, and Working Memory in Veterans Undergoing Residential Treatment for Alcohol Use Disorder.

BACKGROUND:The neurocognitive dysfunction observed in Alcohol Use Disorder (AUD) is related to a complex interplay between genetic, neurobiological, and environmental factors. The μ-opioid receptor (MOR), encoded by the OPRM1 gene, modulates reward processing, stress responsivity, and excitatory-inhibitory activity within prefrontal-limbic and hippocampal circuits implicated in neurocognition. The common A118G (Asn40Asp, rs1799971) polymorphism alters MOR expression and signaling, but its contribution to domain-specific cognitive functioning in AUD, particularly among Veterans, has received limited investigation. METHODS:Veterans (n = 127) in residential treatment for AUD completed a neurocognitive battery assessing the following domains of functioning: auditory-verbal and visuospatial learning and memory, executive function, and working memory. Participants were genotyped for OPRM1 A118G, and A homozygotes and G-allele carriers (AG/GG) were compared on the above measures, using bootstrapped generalized linear models, adjusted for age, education, biological sex, race, pre-study alcohol consumption, and brain-derived neurotrophic factor (BDNF) (rs6265) and catechol-O-methyltransferase (COMT) (rs4680) genotypes, which have been previously shown to be associated with neurocognition. RESULTS:G-allele carriers demonstrated significantly worse performance than A homozygotes on measures of auditory-verbal learning and memory, cognitive flexibility/set shifting, auditory working memory, and on a composite average of all measures. BDNF or COMT genotypes were not associated with any measure, and there were no significant interactions among OPRM1, BDNF, and COMT genotypes. CONCLUSIONS:Findings suggest that altered MOR signaling in G-allele carriers may be associated with differences in prefrontal network efficiency, potentially justifying future studies investigating the relationship between OPRM1 and glutamatergic plasticity. The results highlight a potential genetically influenced contributor to the neurocognitive heterogeneity in AUD and underscore the possible value of integrating MOR-related biological markers into neurocognitive assessment of individuals with AUD.