Causality effect of 21 metals in plasma and serum, 731 immunocytes, and schizophrenia: an intermediary Mendelian randomization study in East Asian populations

Abstract

Background: Multiple clinical studies have observed a close relationship between metals in plasma and serum, immunocytes, and schizophrenia; however, it remains unclear whether there is a genetic causal effect between metals in plasma and serum,immunocytes, and schizophrenia.

Objective: This study aimed to investigate the causal effects of metals in the plasma and serum on schizophrenia and the mediating role of immunocytes using Mendelian randomization methods in an East Asian population.

Methods: Summary results for 21 metals in plasma and serum,731 immunocytes and schizophrenia were acquired from publicly available genome-wide association studies (GWASs). GWAS data for metals, immunocytes, and schizophrenia were accessed between 2024 and 11-26 and 2024-12-02,Authors had no access to identifiable individual participant data. This study utilized two-sample Mendelian randomization (MR) analysis to establish causal relationships, which was achieved by employing various statistical methods, including inverse variance-weighted, simple mode, MR-Egger, weighted median, and weighted mode. Multiple sensitivity analyses, including heterogeneity tests, horizontal pleiotropy tests, MR-PRESSO tests, and leave-one-out analyses, were performed to confirm the reliability of the MR data. Finally, mediation analysis was employed to ascertain the immunocyte pathway that leads to schizophrenia from the metals in the plasma and serum. The study used anonymized summary-level GWAS data from public databases (e.g., GWAS Catalog, iEU Open GWAS), which do not contain personally identifiable information.

Results: The data of the East Asian population were analyzed by Mendelian randomization and two serum metallic traits that may reduce the risk of schizophrenia were identified: Serum iron (odds ratio (OR):0.54, 95 % confidence interval (CI):0.30-0.96, p = 0.036) and serum molybdenum levels (odds ratio (OR):0.54, 95 % confidence interval (CI):0.34-0.87, p = 0.011) corresponds to a 46 % reduction in schizophrenia risk. A baseline lifetime risk of 1 % in the general population, this translates to an absolute risk reduction of 0.46 %, with a number needed to treat (NNT) of approximately 217 individuals to prevent one case. They exhibited a negative causal relationship with the risk of Schizophrenia. Through mediation analysis, we identified a specific immunocyte subtype, CD33dim HLA DR + CD11b- Absolute Count, that not only correlates with serum iron levels but also shows a strong association with schizophrenia risk, suggesting a potential pathway through which serum iron may influence schizophrenia development. Serum iron levels showed a negative causal relationship in schizophrenia through the mediation of immunocytes with CD33dim HLA DR + CD11b- Absolute Count (mediation proportion:21 %).

Conclusions: This study identified a causal relationship between plasma and serum metals, immunocytes, and schizophrenia in an East Asian population through Mendelian randomization analysis, providing a new theoretical basis for the early detection, diagnosis, and treatment of schizophrenia.

Keywords: Causal inference; Immunocytes; MR analysis; Metals; Schizophrenia.

Fig. 1

Flowchart of this research.

Fig. 2

Forest plots depicting the causal impacts of 21 metals in our plasma and serum on SCZ. OR, odds ratio; CI, confidence interval.

Fig. 3

Forest plots depicting the causal impacts of immunocytes on SCZ. OR, odds ratio; CI, confidence interval.

Fig. 4

Forest plots depicting the causal impacts of Serum iron levels on immunocytes. OR, odds ratio; CI, confidence interval.

Fig. 5

Forest plots depicting the causal impacts of Serum molybdenum levels on immunocytes. OR, odds ratio; CI, confidence interval.