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

Abstract

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.