Purpose: To explore whether there is a causal relationship between coffee consumption and primary open-angle glaucoma (POAG).

Design: Two-sample Mendelian randomization (MR). Participants: The single-nucleotide polymorphisms (SNPs) associated with coffee consumption (including phenotypes 1 and 2) were selected from a genome-wide association study (GWAS) involving 121 824 individuals of European descent. Coffee intake from the MRC-IEU UK Biobank was also used to identify instruments for coffee intake. Summary-level data for POAG were obtained from the largest publicly available meta-analyses involving 16 677 POAG cases and 199 580 controls of European descent.

Methods: The inverse variance-weighted (IVW) method was the main MR analysis, whereas weighted-median, weighted mode-based estimate (MBE), MR Pleiotropy RESidual Sum and Outlier (PRESSO) test, and MR-Egger regression were used for sensitivity analysis. Main outcome measures: Diagnosis of POAG.

Results: Three sets of instrumental variables were used to evaluate the causal association between coffee consumption and POAG risk. Results showed that genetically predicted higher coffee consumption phenotype 1 (cups/day) was significantly associated with higher risk of POAG (odds ratio [OR], 1.241; 95% confidence interval [CI], 1.041-1.480; P = 0.016). Genetically predicted higher coffee consumption phenotype 2 (high vs. no/low) was also significantly associated with higher risk of POAG (OR, 1.155; 95% CI, 1.038-1.284; P = 0.008, using the IVW method). Moreover, genetically predicted higher coffee intake from the MRC-IEU UK Biobank OpenGWAS was significantly associated with a higher risk of POAG (OR, 1.727; 95% CI, 1.230-2.425; P = 0.002, using the IVW method). Sensitivity analyses confirmed that the findings were robust to possible pleiotropy.

Conclusions: These findings provide the genetic evidence that higher coffee consumption is associated with a higher risk of POAG. Given that coffee is widely consumed, our findings provide new insights into potential strategies to prevent and manage POAG.