Correlation analysis between genome-wide expression profiles and cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders

Abstract

Cytoarchitectural abnormalities have been described in the prefrontal cortex of subjects with schizophrenia, bipolar disorder and depression. However, little is known about the gene expression profiles associated with these abnormalities. Genome-wide expression profiling technology provides an unbiased approach to identifying candidate genes and biological processes that may be associated with complex biological traits such as cytoarchitecture. In this study, we explored expression profiles associated with the abnormalities by using publicly available microarray metadata and cytoarchitectural data from post-mortem samples of the frontal cortex from 54 subjects (schizophrenia, n = 14; bipolar disorder, n = 13; depression, n = 12 and controls n = 15). Correlation analysis between genome-wide expression levels and cytoarchitectural traits revealed that 818 genes were significantly correlated with a decrease in the number of perineuronal oligodendrocytes across all subjects. A total of 600 genes were significantly correlated with a decrease in density of calbindin-positive interneurons across all subjects. Multiple biological processes including cellular metabolism, central nervous system development, cell motility and programmed cell death were significantly overrepresented in both correlated gene lists. These findings may provide novel insights into the molecular mechanisms that underlie the cytoarchitectural abnormalities of perineuronal oligodendrocytes and calbindin-containing GABAergic interneurons in the prefrontal cortex of the major psychiatric disorders.

Integrative genome-wide association analysis of cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders

“…26 Apoptosis was one of the main processes associated with the density of calbindin-containing GABAergic neurons in our previous correlation analysis. 3 Akt1 mRNA and protein levels and MAPK1 mRNA levels were positively correlated with the density of calbindin-containing GABAergic neurons in our previous study, suggesting that deficits in Aktmediated antiapoptotic activity may be associated with the cytoarchitectural abnormality in psychiatric disorders. 3 It remains to be determined whether differential expression of RAB2A affects synaptic vesicle transport or protein transport in GABAergic neurons.…”

“…3 Akt1 mRNA and protein levels and MAPK1 mRNA levels were positively correlated with the density of calbindin-containing GABAergic neurons in our previous study, suggesting that deficits in Aktmediated antiapoptotic activity may be associated with the cytoarchitectural abnormality in psychiatric disorders. 3 It remains to be determined whether differential expression of RAB2A affects synaptic vesicle transport or protein transport in GABAergic neurons. However, our previous and current findings, together with previous results concerning the role of RAB2, 27 suggest that differential expression of RAB2A may be involved in deficits of vesicle transport, neurotransmitter release or protein transport that eventually promote apoptosis of the calbindin-containing GABAergic cells by inhibiting anti-apoptotic pathways such as the Akt-mediated pathway.…”

“…4 Our previous study revealed that the expression level of genes in biological processes related to the central nervous system development and apoptosis was significantly associated with the density of calbindin-containing GABAergic neurons and with the number of perineuronal oligodendrocytes in the PFC of subjects with major mental disorders. 3 In this study, we explored the genetic causalities underlying those cytoarchitectural traits using an integrative SNP association analysis. Initially, we conducted genome-wide SNP association scans for the two cytoarchitectural traits.…”

“…In a previous study, we identified potential molecular mechanisms that may underlie these abnormalities using correlation analyses between genome-wide expression profiles and the cytoarchitectural traits. 3 Although we determined that neurodevelopmental deficits and apoptosis are likely to contribute to these cytoarchitectural abnormalities, [3][4][5] the genetic causalities remain to be determined.…”

“…10 Using public databases that contain genome-wide, high-throughput data sets and biological traits from the same subjects allows researchers to explore molecular mechanisms and genetic causalities underlying biological traits without time-consuming and labor-intensive benchwork. 3,11 The Stanley Medical Research Institute database (SMRIDB, http:// www.stanleyresearch.org/brain/) includes cytoarchitectural data sets from several brain regions of subjects in the Stanley Neuropathology Consortium (SNC). Moreover, microarray expression data from multiple independent studies 12 using both the SNC samples and an additional cohort, the Array Collection (AC), are available in the same database.…”