Plasma Homocysteine Levels On The Risk Of Schizophrenia And Mood Disorders:A Mendelian Randomization Study

Objective:Based on the available data of genome-wide association studies（GWAS）,a two-sample Mendelian Randomization（TSMR）was performed to investigate whether plasma homocysteine（Hcy）levels are causally related to the occurrence of schizophrenia and mood disorders.Methods:Using large-scale GWAS data related to homocysteine（a total of 44,147 subjects）,according to the basic hypothesis of Mendelian Randomization（MR）,14 single nucleotide polymorphisms（SNPs）were selected.All selected SNPs were significantly correlated with the plasma Hcy levels and met the genome-wide threshold(P<5×10^-8).Then,based on the GWAS data of public Psychiatric Genomics Consortium（PGC）,14 SNPs were extracted for association with SCZ,MDD,BD,and BD subtypes（BD-I and BD-II）.The instrumental variables（IV）and outcome data were sorted out and tabulated.TSMR analysis and mapping are carried out in R software.The inverse variance weighting method（IVW）,MR-Egger regression analysis.,and weighted median method（WM）were used to analyze the data.The main effect indicators were Odds Ratio（OR）and its 95%confidence interval（CI）.The results were presented in the form of a scatter map,forest map,funnel chart,and statistical table.The quality control included sensitivity analysis and heterogeneity test,and Cochran’s Q test,P<0.05 was used for heterogeneity test,and the difference was considered to be statistically significant.Results:1.The correlation between the increase of plasma Hcy levels and SCZ:according to MR IVs selection criteria,10 SNPs were included in the analysis,and the results of IVW analysis showed that:OR=1.110,SE=0.039,P_IVW=2.74×10^-3.The results showed that elevated plasma Hcy levels was significantly correlated with the increased risk of SCZ.2.The correlation between the increase of plasma Hcy levels and MDD:according to MR IVs selection criteria,13 SNPs were included in the analysis,and the results of IVW analysis showed that:OR=0.948,SE=0.032,P_IVW=0.115.The results suggest that elevated plasma Hcy levels had no effect on the increased risk of MDD.3.The correlation between the increase of plasma Hcy levels and BD:according to MR IVs selection criteria,11 SNPs were included in the analysis,and the results of IVW analysis showed that:OR=1.081,SE=0.041,P_IVW=0.05.The results suggest that elevated plasma Hcy levels had no effect on the increased risk of BD.4.The correlation between the increase of plasma Hcy levels and BD type I（BD-I）:according to MR IVs selection criteria,13 SNPs were included in the analysis,and the results of IVW analysis showed that:OR=1.133,SE=0.048,P_IVW=9.44×10^-3.The results showed that elevated plasma Hcy levels was significantly correlated with the increased risk of BD-I.5.The correlation between the increase of plasma Hcy levels and BD typeⅡ（BD-Ⅱ）:according to MR IVs selection criteria,13 SNPs were included in the analysis,and the results of IVW analysis showed that:OR=0.977,SE=0.082,P_IVW=0.773.The results suggest that elevated plasma Hcy levels had no effect on the increased risk of BD-Ⅱ.Conclusion:Our results suggest that elevated plasma Hcy levels may increase the risk of SCZ or BD-I.However,genetically determined Hcy levels were not causally associated with MDD,BD,or BD-II risks.The results of this study suggest that changes in plasma homocysteine levels are associated with the occurrence of SCZ and BD-I,and monitoring and intervention of plasma Hcy levels in high-risk populations can help reduce the incidence of SCZ and BD-I.