Causality between alcohol consumption and schizophrenia: A bidirectional Mendelian randomization study

Abstract Background: Observational studies have revealed an association between alcohol consumption and schizophrenia (SZ), and have identified high alcohol consumption as an independent risk factor for SZ. However, due to the limitations of observational studies, the causal relationship between SZ and alcohol consumption is unknown. This study used two-way Mendelian randomization (MR) to determine the causal relationship between alcohol consumption phenotype (drinks consumed per week, DPW) and SZ risk. Methods: We conducted bidirectional MR analysis using the aggregate statistical data of a European individual genome-wide association study (GWAS). Causality was evaluated using the inverse variance weighting (IVW), MR-Egger, and weighted median methods. We also used the MR-Egger intercept to detect horizontal multiplicity, and conducted sensitivity analysis to evaluate the robustness of the results. Results: High DPW did not increase the risk of SZ according to IVW, MR-Egger, and weighted median methods using 78 single nucleotide polymorphisms (SNPs) from the GWAS database. Similarly, MR-Egger analysis with 123 SNPs revealed no causal effect of SZ on DPW (OR = 1.00, 95% Cl: 0.95–1.04, p = 0.92). However, both IVW and weighted median methods (n=123 SNPs) indicated that SZ increased DPW (OR = 1.01, 95% Cl: 1.00–1.02; p = 0.01 and p = 8.78 × 10-3, respectively). Further, MR-Egger regression showed that directional multiplicity did not bias the MR results (intercept = 9.70 × 10-4, p = 0.52), while leave-one-out sensitivity analysis indicated that no single SNP significantly influenced the association. Conclusions: This MR study suggests that the genetic factors associated with SZ also increase the risk of excessive alcohol consumption. Interventions for reducing or eliminating alcohol consumption may improve the clinical management of SZ.