Complement C4 associations with altered microbial biomarkers exemplify gene-by-environment interactions in...

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Schizophrenia is a complex brain disorder influenced by genetic and environmental factors.
• Complement C4 genes are identified as schizophrenia susceptibility loci.
• C4 gene activation is associated with immune responses to infections and gut microbiome alterations.

Purpose of the Study:

• To investigate the hypothesis that C4 genetic susceptibility increases neuropathological risk from pathogen exposure or microbiome dysbiosis.
• To examine associations between C4 gene copy number, haplotype groups, schizophrenia diagnosis, and microbial plasma biomarkers.

Main Methods:

• Analysis of C4 gene copy number and haplotype groups in 214 individuals with schizophrenia and 123 non-psychiatric controls.
• Assessment of associations between C4 gene variations and microbial plasma biomarkers, including IgG antibodies to pathogens and lipopolysaccharide-binding protein (LBP).
• Evaluation of correlations between C4 haplogroups, cognitive functioning, and psychiatric symptom scores.

Main Results:

• Specific C4A and C4B gene variants (C4AL-C4AL, C4BS) showed significant associations with schizophrenia diagnosis.
• Multiple C4 haplogroup-microbe combinations, including Candida albicans, cytomegalovirus (CMV), and Toxoplasma gondii, were strongly linked to schizophrenia.
• Inverse correlations were observed between C4 gene copy numbers and LBP/CMV IgG levels in schizophrenia patients, and C4 haplogroups affected cognitive and psychiatric scores.

Conclusions:

• Findings link complement C4 genes to increased susceptibility to infections and gut microbiome dysbiosis in schizophrenia.
• Results support the role of immune system mechanisms and gene-environmental interactions in schizophrenia pathogenesis.
• This study provides a foundation for understanding the interplay of genetic predisposition and environmental factors in schizophrenia.