Multivariate Genetic Correlates of the Auditory Paired Stimuli-Based P2 Event-Related Potential in the Psychosis Dimension From the BSNIP Study

Abstract

Objective: The complex molecular etiology of psychosis in schizophrenia (SZ) and psychotic bipolar disorder (PBP) is not well defined, presumably due to their multifactorial genetic architecture. Neurobiological correlates of psychosis can be identified through genetic associations of intermediate phenotypes such as event-related potential (ERP) from auditory paired stimulus processing (APSP). Various ERP components of APSP are heritable and aberrant in SZ, PBP and their relatives, but their multivariate genetic factors are less explored.

Methods: We investigated the multivariate polygenic association of ERP from 64-sensor auditory paired stimulus data in 149 SZ, 209 PBP probands, and 99 healthy individuals from the multisite Bipolar-Schizophrenia Network on Intermediate Phenotypes study. Multivariate association of 64-channel APSP waveforms with a subset of 16 999 single nucleotide polymorphisms (SNPs) (reduced from 1 million SNP array) was examined using parallel independent component analysis (Para-ICA). Biological pathways associated with the genes were assessed using enrichment-based analysis tools.

Results: Para-ICA identified 2 ERP components, of which one was significantly correlated with a genetic network comprising multiple linearly coupled gene variants that explained ~4% of the ERP phenotype variance. Enrichment analysis revealed epidermal growth factor, endocannabinoid signaling, glutamatergic synapse and maltohexaose transport associated with P2 component of the N1-P2 ERP waveform. This ERP component also showed deficits in SZ and PBP.

Conclusions: Aberrant P2 component in psychosis was associated with gene networks regulating several fundamental biologic functions, either general or specific to nervous system development. The pathways and processes underlying the gene clusters play a crucial role in brain function, plausibly implicated in psychosis.

Keywords: bipolar disorder; event-related potential; gene; pathway; psychosis; schizophrenia; single nucleotide polymorphism.

Fig. 1.

Mean loading coefficients (LC) for significantly associated component pair (A) ERP (B) gene network. (C) Scatter plot of LC for all subjects (including schizophrenia, bipolar disorder, and healthy comparison) combined as a single group. The ERP and SNP LC denote each subject’s contribution to the component waveform and the minor allele frequency from the SNP variants, respectively. The LC was adjusted for effects of demographics variables including sex, site, and age. Error bars represent standard errors. Post hoc comparisons included pairwise t tests between groups. The overall association between the LCs across 3 groups is displayed as the linear fit. *Groups significantly differed at P < .001. +trend at P < .1. ERP = event-related potential; SNP = single nucleotide polymorphism.

Fig. 2.

Gene networks and pathways associated with event-related potential (ERP) components from auditory paired stimulus processing obtained using multivariate data fusion analysis. Of the 2 ERP components, only 1 ERP-gene pair was significantly correlated. E1 represents a fronto-centrally distributed component (at peak location Fcz) capturing the N1-P2 complex with a dominant P2 in response to stimulus S1. The horizontal dotted line denotes the threshold of 2.5 for selecting dominant ERP feature. SNPs within each gene network were selected using a threshold of 2.5 and mapped to genes, which were in turn entered into enrichment analysis to obtain biological functions associated with gene clusters.

Fig. 3.

Venn diagram showing the overlap in gene ontology process, process networks, and pathway maps across 3 different electrophysiological phenotypes. The overlap between the processes and pathway maps is shaded. The intersection of gene clusters obtained from 3 independent multivariate genetic associations of different electroencephalogram (EEG) phenotypes derived from resting EEG, auditory oddball, and auditory paired stimulus processing event-related potentials (ERPs) were entered into GeneGo’s enrichment analysis. The P values denote the significance or the probability of over-representation of the common genes in the data relative to GeneGo’s database by chance.