**Background:** Alcohol consumption is a leading cause of death and disability worldwide, implicated in over 200 health conditions. Glaucoma is a major cause of irreversible blindness, and while IOP is the main modifiable risk factor, identifying other modifiable lifestyle factors is of clinical interest. Previous studies of alcohol and glaucoma have yielded inconsistent results, limited by heterogeneity and high risk of bias. This study leveraged the UK Biobank to examine associations of alcohol consumption with glaucoma and related traits, assess modification by genetic predisposition, and perform Mendelian randomization (MR) to probe causal effects.
**Methods:** This cross-sectional study used UK Biobank data from participants with IOP measurements (n=109,097), OCT-derived macular inner retinal thickness measures (n=46,236), and glaucoma status (n=173,407). Participants were categorized as never, infrequent, regular, or former drinkers. Quantitative alcohol intake (g/week) was calculated from beverage-specific questions and food composition tables. Multivariable linear, logistic, and restricted cubic spline regression were adjusted for age, sex, ethnicity, Townsend deprivation index, body mass index, height, systolic blood pressure, spherical equivalent, diabetes, smoking status/intensity, physical activity, and assessment season. A multitrait glaucoma polygenic risk score (PRS) was used for gene–environment interaction analyses. Two-sample MR used summary statistics from large consortia (GWAS & Sequencing Consortium of Alcohol and Nicotine use, n=941,280 for exposure; IOP GWAS n=139,555; primary open-angle glaucoma GWAS n=216,257; OCT GWAS n=31,434; vCDR GWAS n=23,899).
**Key Results:** Among regular drinkers (80% of participants, median intake ~91 g/week), each SD increase in alcohol intake (111–112 g/week) was associated with higher IOP (β=0.08 mmHg; 95% CI, 0.05–0.11; P<0.001), thinner mRNFL (β=−0.17 μm; 95% CI, −0.22 to −0.12; P<0.001), thinner mGCIPL (β=−0.34 μm; 95% CI, −0.40 to −0.27; P<0.001), and higher glaucoma prevalence (OR=1.11; 95% CI, 1.05–1.18; P<0.001). Compared with the lowest quintile (median 18–19 g/week), the highest quintile (median 278–280 g/week) had higher IOP (β=0.27 mmHg; 95% CI, 0.19–0.36), thinner mRNFL (β=−0.41 μm; 95% CI, −0.56 to −0.27), thinner mGCIPL (β=−0.83 μm; 95% CI, −1.02 to −0.63), and higher glaucoma prevalence (OR=1.36; 95% CI, 1.12–1.66) (all P-trend ≤0.001). Restricted cubic spline analyses suggested threshold effects at approximately 50 g/week for mRNFL and mGCIPL thickness. Former drinkers had higher glaucoma prevalence (OR=1.53; 95% CI, 1.16–2.02; P=0.002). The glaucoma PRS significantly modified the alcohol–IOP association (P-interaction <0.001), with stronger associations in higher genetic risk quintiles. MR analyses using the full instrument provided evidence for a causal effect on mGCIPL thickness (−1.52 μm per SD; 95% CI, −2.55 to −0.50; P=0.004), with stronger results using the restricted instrument excluding rs1229984 (−2.07 μm per SD; 95% CI, −3.22 to −0.93; P<0.001).
**Clinical Implications:** This study provides strong, consistent evidence that alcohol consumption is adversely associated with glaucoma and related traits in a dose-dependent manner, with effects observed at intake levels below current UK and US drinking guidelines. The findings suggest alcohol may be a modifiable risk factor for glaucoma, with potential clinical and public health implications for people with or at risk of glaucoma. The gene–environment interaction raises the possibility of targeted lifestyle recommendations based on genetic risk. However, the cross-sectional design limits causal inference, and results require replication in independent and diverse populations.