Genetic variants in Nogo receptor signaling pathways may be associated with early life adversity in schizophrenia susceptibility

BACKGROUND: Schizophrenia is a severe neuropsychiatric disorder thought to result from abnormal brain development. Nogo, an oligodendrocyte bound molecule, signals by binding to the Nogo receptor (NgR) located on axonal membranes. The NgR co-receptors include p75 neurotrophin receptor or TNF receptor orphan Y (TROY). Nogo signaling is responsible for central nervous system myelin regulation and neurite outgrowth during neurodevelopment, and plasticity in the mature brain. METHODS: We examined single nucleotide polymorphisms (SNPs) in NgR, p75, and TROY receptor genes and downstream signaling partner With No Lysine (K) (WNK1) and Myelin transcription factor 1-like (Myt1l) genes in an Australian case–control schizophrenia cohort (n = 268/group). High-throughput SNP genotyping was performed using the MassARRAY® genotyping assay. RESULTS: Analysis revealed a significant association between the Myt1l SNP rs2304008 and female schizophrenia subjects. The WNK1 SNP rs1468326 and the Myt1l SNP rs3748988 showed significant associations with schizophrenia in subjects with a maternal mental history and in subjects who experienced childhood trauma respectively. Following Bonferroni correction, all significance was lost. CONCLUSIONS: Despite the lack of positive findings in our population after correction for multiple testing, previous gene expression and association studies in schizophrenia suggest the implication of NgR signaling pathway genes in the etiology of schizophrenia remains topical and timely. GENERAL SIGNIFICANCE: Further investigations will be necessary to fully assess the role of these genes in the pathophysiology of schizophrenia. However these genes may prove useful in further understanding the mechanism by which negative experiences early in life can affect myelin-related processes in the context of schizophrenia.