Multimodal profiling of gray matter differences in alcohol use disorder: An integrated SDM-PSI meta-analysis with neuroimaging fusion study.

Abstract

Alcohol use disorder (AUD) represents a major global health and economic challenge. While neuroimaging consistently reports widespread gray matter (GM) differences in AUD, the underlying molecular mechanisms, neurotransmitter associations, and genetic architecture remain insufficiently characterized. A coordinate-based meta-analysis was performed using Seed-based d Mapping with Permutation of Subject Images (SDM-PSI) on 29 voxel-based morphometry studies (1112 individuals with AUD; 1136 controls). The resulting GM difference map was integrated with multimodal data to examine spatial associations with neurotransmitter systems (JuSpace), gene expression profiles (Allen Human Brain Atlas, noting its sample limitation of six donors), and behavioral and disease domains (BrainMap). Meta-regressions assessed associations with clinical variables. Compared to controls, individuals with AUD showed lower GM volume in the left anterior cingulate/paracingulate gyri, left postcentral gyrus, and right Rolandic operculum. Behavioral decoding linked these regions to executive function, attention, reward-related emotion, and somatosensory processing. The spatial pattern showed overlap with schizophrenia, major depressive disorder, and Alzheimer's disease. Meta-regression associated GM volume with AUD duration, age of onset, anxiety, and depression severity. GM differences were spatially associated with serotonergic, dopaminergic, noradrenergic, and opioidergic receptor and transporter distributions. Transcriptomic analysis revealed enrichment in genes related to synaptic signaling, glutamatergic function, and myelination. This multimodal meta-analysis identifies a consistent pattern of GM differences in AUD associated with behavioral domains, shared neuroanatomy across psychiatric conditions, and convergent neurotransmitter and genetic profiles, supporting a multi-system pathophysiological framework while highlighting the need for future causal investigations.