Genetic Sources of Subcomponents of Event-Related Potential in the Dimension of Psychosis Analyzed From the B-SNIP Study

OBJECTIVE: Biological risk factors underlying psychosis are poorly understood. Biological underpinnings of the dimension of psychosis can be derived using genetic associations with intermediate phenotypes such as subcomponents of auditory event-related potentials (ERPs). Various ERP subcomponent abnormalities in schizophrenia and psychotic bipolar disorder are heritable and are expressed in unaffected relatives, although studies investigating genetic contributions to ERP abnormalities are limited. The authors used a novel parallel independent component analysis (para-ICA) to determine which empirically derived gene clusters are associated with data-driven ERP subcomponents, assuming a complex etiology underlying psychosis. METHOD: The authors examined the multivariate polygenic association of ERP subcomponents from 64-channel auditory oddball data in 144 individuals with schizophrenia, 210 psychotic bipolar disorder probands, and 95 healthy individuals from the multisite Bipolar-Schizophrenia Network on Intermediate Phenotypes study. Data were reduced by principal components analysis to two target and one standard ERP waveforms. Multivariate association of compressed ERP waveforms with a set of 20,329 single-nucleotide polymorphisms (SNPs) (reduced from a 1-million-SNP array) was examined using para-ICA. Genes associated with SNPs were further examined using pathway analysis tools. RESULTS: Para-ICA identified four ERP components that were significantly correlated with three genetic components. Enrichment analysis revealed complement immune response pathway and multiple processes that significantly mediate ERP abnormalities in psychosis, including synaptic cell adhesion, axon guidance, and neurogenesis. CONCLUSIONS: This study identified three genetic components comprising multiple genes mediating ERP subcomponent abnormalities in schizophrenia and psychotic bipolar disorder. The data suggest a possible polygenic structure comprising genes influencing key neurodevelopmental processes, neural circuitry, and brain function mediating biological pathways plausibly associated with psychosis.