The Effects of Plasma Homocysteine Level on the Risk of Three Major Psychiatric Disorders: A Mendelian Randomization Study

Abstract

BackgroundHigher homocysteine (Hcy) level has been suggested to be associated with major psychiatric disorders (MPDs), such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). We investigated the causal relationships between plasma Hcy level and MPDs risks using the Mendelian randomization (MR) method.MethodsWe selected 18 loci associated with plasma Hcy level from a large-scale genome-wide association study (GWAS) as genetic instruments. Genetic associations with SCZ, MDD, BD and BD subtypes (BD-I and BD-II) were extracted from several GWAS datasets from the Psychiatric Genomics Consortium. We used the Generalized Summary-data-based Mendelian Randomization (GSMR) method to estimate the associations of genetically predicted plasma Hcy levels with MPDs risks. We also performed inverse variance-weighted (IVW) analysis to verify the GSMR results and used MR-Egger regression and leave-one-out analysis to test the assumptions for a valid MR analysis.ResultsGenetically predicted plasma Hcy levels were associated with risks of SCZ (odds ratio [OR] = 1.12, PGSMR = 1.73 × 10−3) and BD-I (OR = 1.14, PIVW = 5.23 × 10−3) after Bonferroni correction. These associations were statistically significant when using IVW analysis (SCZ: OR = 1.11, PIVW = 2.74 × 10−3; BD-I: OR = 1.13, PIVW = 9.44 × 10−3). Furthermore, no significant horizontal pleiotropy was found by sensitivity analysis, and leave-one-out analyses showed no specific SNP affected the overall estimate. However, genetically determined plasma Hcy levels were not causally associated with MDD, BD, or BD-II risks.ConclusionOur results suggest that elevated plasma Hcy levels may increase the risk of SCZ or BD-I. Further randomized clinical trials are warranted to validate the MR findings in our study.

Increased serum homocysteine in first episode and drug-naïve individuals with schizophrenia: sex differences and correlations with clinical symptoms

“…These studies partially explain the mechanisms involved in Hcy abnormalities leading to schizophrenia. A Mendelian randomization study reported that increased plasma Hcy levels increased the risk of schizophrenia and bipolar disorders [ 12 ]. A systematic review and meta-analysis reported that levels of Hcy were higher in first-episode psychosis compared to controls, suggesting that an imbalance of antioxidant status may be relevant to first-episode psychosis [ 13 ].…”

Individuals with Bipolar Disorder Have a Higher Level of Homocysteine Than Major Depressive Disorder: A Retrospective Chart Review and Observational Study

“…However, no causal relationship was found between plasma Hcy levels and the risk of MDD and BD-II. 31 Nevertheless, there are several limitations of the MR study that need to be considered carefully. For example, the number of genetic instruments used in the MR analysis was limited, and the risk of BD may be affected by exposure to higher Hcy levels at a particular time, whereas their MR analysis investigated lifelong elevated Hcy levels in BD.…”

Abnormalities in one-carbon metabolism in young patients with psychosis

“…An increase of 5 μmol/L in homocysteinemia appears to correspond to a 70% (OR 1.7) inflation of the risk of schizophrenia ( 14 ). A Mendelian randomisation study also showed that elevated plasma homocysteine levels could increase the risk of schizophrenia ( 15 ). Folate deficiency and hyperhomocysteinemia appears to be more specifically associated with negative symptoms and cognitive alterations in this population ( 16 ).…”