Abstract
BACKGROUND: This study aims to investigate the causal relationship of human plasma metabolites and metabolic ratios with schizophrenia (SCZ). METHODS: We employed Mendelian Randomization (MR) approach to comprehensively analyze two large-scale metabolomics and schizophrenia Genome-Wide Association Study (GWAS) datasets, incorporating a total of 1091 metabolites and 309 metabolic ratios, with 52017 schizophrenia patients and 75889 healthy controls. The inverse variance-weighted (IVW) method was utilized to estimate the causal relationship between exposure and outcome. To provide a more comprehensive evaluation, additional Mendelian Randomization (MR) approaches were employed, including MR-Egger regression, weighted median, simple mode, and weighted mode methods. These analyses assessed the causal effects between blood metabolites, metabolic ratios, and schizophrenia. Tests for pleiotropy and heterogeneity were conducted. False Discovery Rate (FDR) correction was applied to account for multiple comparisons and heterogeneity, ensuring the robustness and reliability of our findings. Consistent with previous studies, an FDR threshold of < 0.2 was considered suggestive of a causal relationship, while an FDR of < 0.05 was considered to indicate a significant causal relationship. RESULTS: The final results revealed that a significant causal association was found between the levels of two metabolites and schizophrenia, Alliin (OR = 0.915, 95%CI = 0.879-0.953, P = 1.93 × 10(- 5), FDR = 0.013) was associated with a decreased risk of schizophrenia, N-actylcitrulline (OR = 1.058, 95%CI = 1.034-1.083, P = 1.4 × 10(- 6), FDR = 0.002) was associated with increased risk of schizophrenia. When adjusting FDR to 0.2, the results showed that 4 metabolite levels and 2 metabolite ratios were suggestively causally associated with a reduced risk of schizophrenia including 2-aminooctanoate (OR = 0.904, 95%CI = 0.847-0.964, P = 0.002, FDR = 0.160), N-lactoylvaline (OR = 0.853, 95%CI = 0.775-0.938, P = 0.001,FDR = 0.122), X - 21310 (OR = 0.917, 95%CI = 0.866-0.971, P = 0.003,FDR = 0.195), X - 26111 (OR = 0.932, 95%CI = 0.890-0.976, P = 0.003,FDR = 0.189), Arachidonate (20:4n6) to oleate to vaccenate (18:1) ratio (OR = 0.945, 95%CI = 0.914-0.977, P = 8.2 × 10(- 4), FDR = 0.104), and Citrulline to ornithine ratio (OR = 0.924, 95%CI = 0.881-0.969, P = 0.001, FDR = 0.122), while 4 metabolite levels and 2 metabolite ratios were suggestively causally associated with an increased risk of schizophrenia including N2, N5-diacetylornithine (OR = 1.090, 95%CI = 1.031-1.153, P = 0.003, FDR = 0.185), N - acetyl - 2-aminooctanoate (OR = 1.069, 95%CI=(1.027-1.114, P = 0.001, FDR = 0.127), N - acetyl - 2-aminoadipate (OR = 1.081, 95%CI = 1.030-1.133, P = 0.001, FDR = 0.128), X - 13844 (OR = 1.110, 95%CI = 1.036-1.190, P = 0.003, FDR = 0.196), X - 24556 (OR = 1.083, 95%CI = 1.036-1.132, P = 4.5 × 10(- 4), FDR = 0.098), X - 24736 (OR = 1.065, 95%CI = 1.028-1.104, P = 5.6 × 10(- 4), FDR = 0.098), N - acetylasparagine (OR = 1.048, 95%CI = 1.021-1.075, P = 4.5 × 10(- 4), FDR = 0.098), N - acetylarginine (OR = 1.060, 95%CI = 1.028-1.092, P = 1.8 × 10(- 4), FDR = 0.083), Cysteine to alanine ratio (OR = 1.086, 95%CI = 1.036-1.138, P = 6.5 × 10(- 4), FDR = 0.101), and Benzoate to linoleoyl - arachidonoyl - glycerol (18:2 to 20:4) ratio (OR = 1.070, 95%CI = 1.025-1.117, P = 0.002, FDR = 0.158). CONCLUSION: Our study results provide valuable insights for identifying diagnostic biomarkers related to schizophrenia and offer preliminary research findings for further exploration of the mechanisms linking schizophrenia and metabolism.