¹National Institute of Mental Health, National Center of Neurology and Psychiatry, Department of Neuropsychopharmacology, Tokyo, Japan, ²Tokyo Metropolitan Institute of Medical Science, Addictive Substance Project, Tokyo, Japan, ³National Center of Neurology and Psychiatry, Clinical Research and Education Promotion Division, Department of Clinical Data Science, Tokyo, Japan

Background: Alcohol-metabolizing genetic variants, ADH1B rs1229984 and ALDH2 rs671, are strongly associated with drinking behavior (Kranzler et al., 2019) and have also been linked to depressive symptoms (Hishimoto et al., 2010) and suicide-related behaviors (Yoshimasu et al., 2015). Whether these genetic variants modify the relationship between alcohol consumption and mental health outcomes remains unclear.

Aims & Objectives: To investigate the associations among alcohol-related polymorphisms, problematic alcohol use, and suicidal ideation, focusing on potential effect of modification by genotype.

Method: A cross-sectional survey was conducted among adult participants in Tokyo between June and August 2025. Buccal mucosa samples were collected for DNA extraction, and alcohol-related genetic polymorphisms (ADH1B rs1229984 and ALDH2 rs671) were genotyped using quantitative PCR. Participants were classified into five genotype groups (A–E) based on combinations of ADH1B rs1229984 (AA/AG = active type; GG = low-activity type) and ALDH2 rs671 (GG = active type; GA = low-activity type; AA = inactive type). Group A: ADH1B GG × ALDH2 GG, Group B: ADH1B AA/AG × ALDH2 GG, Group C: ADH1B GG × ALDH2 GA, Group D: ADH1B AA/AG × ALDH2 GA, Group E: Combinations including ALDH2 AA (ADH1B AA/AG or GG).
Drinking behavior was assessed using the Alcohol Use Disorders Identification Test (AUDIT), and a score of ≥8 was defined as problematic alcohol use. Suicidal ideation was examined as the mental health outcome. We evaluated:

1. The association between genotype and problematic alcohol use;
2. The association between problematic alcohol use and suicidal ideation was evaluated adjusting for sex, age, and relevant covariates, and stratified analyses by genotype group were also performed to assess whether the association differed across genotype groups.

Risk differences and 95% confidence intervals (CIs) were calculated.

Results: Problematic alcohol use prevalence was 26.8% (187/699). Genotypes were significantly associated with problematic alcohol use (Fisher’s exact test, p < 0.001). Overall, the association between problematic alcohol use and suicidal ideation was not statistically significant (risk difference 0.048, 95% CI −0.019 to 0.116, p = 0.16). Stratified analyses showed a significant association in group B (risk difference 0.091, 95% CI 0.013–0.169, p = 0.022), but not in group D.

Discussion & Conclusions: Alcohol-related genetic polymorphisms were strongly associated with problematic alcohol use. Although problematic alcohol use was not significantly associated with suicidal ideation in the overall analysis, a significant association was observed among individuals with the ALDH2 active genotype (group B). These findings suggest that differences in alcohol-metabolizing capacity may modify the association between problematic alcohol use and mental health outcomes.

References:
Kranzler, H. R., et al. (2019). Genome‑wide association study of alcohol consumption and use disorder in 274,424 individuals from multiple populations. Nat. Commun, 10:1499.
Hishimoto, A., et al. (2010). Alcohol and aldehyde dehydrogenase polymorphisms and risk for suicide: a preliminary observation in the Japanese male population. Genes, Brain and Behavior, 9(5):498‑502.
Yoshimasu, K., et al. (2015). Genetic alcohol sensitivity regulated by ALDH2 and ADH1B polymorphisms is strongly associated with depression and anxiety in Japanese employees. Drug and Alcohol Dependence, 147:130‑136.