Glaucoma, a leading cause of blindness, has multifactorial causes, including environmental and genetic factors. We evaluated genetic risk factors of glaucoma with gene-gene interaction and explored modifications of genetic risk with gene-lifestyles interaction in adults >40 years. The present study included 377 subjects with glaucoma and 47,820 subjects without glaucoma in a large-scale hospital-based cohort study from 2004 to 2013. The presence of glaucoma was evaluated by a diagnostic questionnaire evaluated by a doctor. The genome-wide association study was performed to identify genetic variants associated with glaucoma risk. Food intake was assessed using a semiquantitative food frequency questionnaire. We performed generalized multifactor dimensionality reduction analysis to construct polygenetic-risk score (PRS) and explored gene × nutrient interaction. PRS of the best model included LIM-domain binding protein-2 (LDB2) rs3763969, cyclin-dependent kinase inhibitor 2B (CDKN2B) rs523096, ABO rs2073823, phosphodiesterase-3A (PDE3A) rs12314390, and cadherin 13 (CDH13) rs12449180. Glaucoma risk in the high-PRS group was 3.02 times that in the low-PRS group after adjusting for confounding variables. For those with low serum glucose levels (<126 mg/dL), but not for those with high serum glucose levels, glaucoma risk in the high-PRS group was 3.16 times that in the low-PRS group. In those with high carbohydrate intakes (≥70%), but not in those with low carbohydrate intakes, glaucoma risk was 3.74 times higher in the high-PRS group than in the low-PRS group. The glaucoma risk was 3.87 times higher in the high-PRS group than in the low-PRS group only in a low balanced diet intake. In conclusion, glaucoma risk increased by three-fold in adults with a high PRS, and it can be reduced by good control of serum glucose concentrations and blood pressure (BP) with a balanced diet intake. These results can be applied to precision nutrition to reduce glaucoma risk.