D1.126 - Deciphering Genetic Causal Relationships and Molecular Mechanisms Linking Multiple Allergic Diseases and Schizophrenia

Allergic diseases and schizophrenia are complex disorders involving abnormalities in both of the allergic immune system and the nervous system. Common allergic conditions include asthma, atopic dermatitis, and allergic rhinitis. Recent observational studies suggest a potential correlation between allergic diseases and schizophrenia, yet the causal relationship remains unclear. This study aims to elucidate the genetic causal relationships between multiple allergic diseases and schizophrenia using Mendelian randomization (MR) methods and to further elucidate the underlying mechanisms of their associations.

We utilized publicly available datasets containing genome-wide association study (GWAS) summary statistics on allergic diseases, schizophrenia, and immune-related components. A bidirectional two-sample MR analysis was conducted to investigate genetic causal relationships and the mediating effects of immune-related components. Additionally, we employed multi-layered data, including tissue-specific gene expression, expression quantitative trait loci (eQTL), and single-cell RNA sequencing (scRNA-seq), to analyze the shared genetic architecture from enriched tissues, functional genes, and specific cell types. We also integrated mRNA transcriptome sequencing data from brain tissues to examine expression changes of shared functional genes at different developmental stages.

Our MR analyses revealed significant genetic causal effects of schizophrenia on asthma, atopic dermatitis, and generalized allergic diseases in the European population, while only asthma showed a significant causal effect on schizophrenia in reverse MR analysis. Various immune components exhibited notable causal effects on both disorders, with lymphocytes and platelets mediating the bidirectional relationship between asthma and schizophrenia. Tissue enrichment analysis indicated significant overlap in the frontal cortex for both conditions, with shared functional genes and risk cell types identified. Additionally, developmental trajectory analysis of shared functional gene expression across different brain developmental stages revealed significantly differential expression between prenatal and postnatal periods.

The present study identified significant genetic causal effects of schizophrenia on several allergic diseases, while asthma is the only allergic condition with a significant effect on schizophrenia. The associations may stem from immune-related abnormalities involving key immune cells and cytokines. These findings enhance our understanding of the shared genetic mechanisms, aiding in the identification of high-risk populations for early intervention, and may inform the development of targeted immunomodulatory therapies.