- Combined high polygenic risk, especially high on all three or high externalizing plus alcohol-specific PGS, predicts most severe AUD outcomes.
- Externalizing PGS exerts an outsized effect, particularly with alcohol-specific risk, linking to conduct disorder, antisocial traits, and arousal/relaxation alcohol expectancies.
- Major depressive disorder PGS associates with MDD and neuroticism, but MDD combinations generally do not increase AUD severity beyond single high PGS.
Alcohol Clin Exp Res (Hoboken). 2026 Oct;50(10):e70390. doi: 10.1111/acer.70390.
ABSTRACT
BACKGROUND: Research suggests that multiple genetically influenced pathways of risk impact alcohol use disorder (AUD), including externalizing (disinhibition, behavioral undercontrol), internalizing (negative affect, depression), and alcohol-specific (physiological response to alcohol) factors. This study examined the joint effects of genetic influences representing these risk domains on AUD and their influence on comorbid phenotypes among individuals with AUD.
METHODS: Participants of European-like ancestry from the Collaborative Study on the Genetics of Alcoholism (N = 6883) provided data on lifetime AUD, conduct disorder (CD), antisocial personality disorder (ASPD), major depressive disorder (MDD), alcohol expectancies, sensation seeking, and neuroticism. Polygenic scores (PGS) representing externalizing (EXT), major depressive disorder (MDD), and alcohol-specific (ALC-sp) risk were calculated. First, participants were grouped based on combinations of high versus low (top vs. bottom 30%) EXT, MDD, and ALC-sp PGS (n = 2006), and AUD outcomes were compared across groups. Second, among individuals with AUD, psychopathology, alcohol expectancies, sensation seeking, and neuroticism were compared across those with high versus low EXT (n = 1664), MDD (n = 1620), and ALC-sp (n = 1669) PGS.
RESULTS: Participants with three high PGS and those with high EXT + high ALC-sp PGS had the most severe AUD outcomes. High EXT + high MDD PGS and high MDD + high ALC-sp PGS groups generally did not differ from groups with only one high PGS. Comparisons between groups with only one high PGS were not significant. Among individuals with AUD, high EXT PGS was associated with CD/ASPD, arousal/aggression alcohol expectancies, and relaxation/tension reduction alcohol expectancies; high MDD PGS was associated with MDD and neuroticism.
CONCLUSIONS: Quantity and type of genetic risk are important for AUD outcomes. EXT plays an outsized role in AUD, particularly in the presence of other high PGS, and may potentiate alcohol expectancies that reinforce harmful patterns of use. Findings elucidate the role of multiple pathways of genetic risk for AUD and how they impact comorbid phenotypes.
PMID:42862091 | DOI:10.1111/acer.70390
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