The role of immune genes in schizophrenia
Project Overview
Schizophrenia (SCZ) is ranked among the top ten illnesses contributing to the global burden of disease, yet its etiology is still poorly understood. The neuroinflammatory hypothesis of SCZ is rooted in evidence that prenatal infection triggers an immune-mediated inflammatory response in the fetal brain, disrupting neurodevelopment and increasing SCZ risk. Genetic variation in immunoregulatory genes may contribute to the impact of prenatal infection on neurodevelopment. In a meta-analysis of genome-wide association studies in SCZ, 94.8% of single-nucleotide polymorphisms (SNPs) reaching significance (n=136) mapped to the immunoregulatory MHC genes. The translocator protein (TSPO) has emerged as a neuroinflammatory biomarker, and TSPO binding affinities appear to be significantly increased in SCZ. TSPO expression is upregulated by protein kinase C ε (PRKCE), which is activated in response to the immune system’s toll-like receptors (TLRs) in a MyD88-dependent manner (the neuroinflammatory ‘TSPO pathway’). TSPO also plays an important role in regulating mitochondrial function. Mitochondria regulate basal metabolic rate, and are therefore suspected to play a role in antipsychotic-induced weight gain (AIWG). AIWG of 7% initial body mass occurs in 2-23% of SCZ patients in the first 6 weeks of second-generation antipsychotic (SGA) treatment. There is large inter-individual variability in AIWG, suggesting genetic contribution. TSPO may play a key role in AIWG, as treatment with SGA clozapine enhances TSPO binding affinity and function. We hypothesize that 1) variation in the TSPO pathway genes (TLR4, MyD88, PRKCE, and TSPO) will be associated with SCZ and 2) variation in the TSPO pathway genes will be associated with AIWG. Research Aims: 1) Investigate association between variants in TSPO pathway genes and SCZ 2) Investigate association between variants in TSPO pathway genes and AIWG 3) Determine influence of associated gene variants found in Aims 1 and 2 on biological function.
Principal Investigator
Jennie Pouget , Centre for Addiction and Mental Health
Partners and Donors
Bell Canada