A. Mortimer

Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function

Schizophrenia is a severe psychiatric disorder with a world-wide prevalence of 1%. The pathophysiology of the illness is not understood, but is thought to have a strong genetic component with some environmental influences on aetiology. To gain further insight into disease mechanism, we used microarray technology to determine the expression of over 30u2009000 mRNA transcripts in post-mortem tissue from a brain region associated with the pathophysiology of the disease (Brodmann area 10: anterior prefrontal cortex) in 28 schizophrenic and 23 control patients. We then compared our study (Charing Cross Hospital prospective collection) with that of an independent prefrontal cortex dataset from the Harvard Brain Bank. We report the first direct comparison between two independent studies. A total of 51 gene expression changes have been identified that are common between the schizophrenia cohorts, and 49 show the same direction of disease-associated regulation. In particular, changes were observed in gene sets associated with synaptic vesicle recycling, transmitter release and cytoskeletal dynamics. This strongly suggests multiple, small but synergistic changes in gene expression that affect nerve terminal function.

Transcription and pathway analysis of the superior temporal cortex and anterior prefrontal cortex in schizophrenia

The molecular basis of schizophrenia is poorly understood; however, different brain regions are believed to play distinct roles in disease symptomology. We have studied gene expression in the superior temporal cortex (Brodmann area 22; BA22), which may play a role in positive pathophysiology, and compared our results with data from the anterior prefrontal cortex (BA10), which shows evidence for a role in negative symptoms. Genome‐wide mRNA expression was determined in the BA22 region in 23 schizophrenics and 19 controls and compared with a BA10 data set from the same subjects. After adjustments for confounding sources of variation, we carried out GeneGO pathway enrichment analysis in each region. Significant differences were seen in age‐related transcriptional changes between the BA22 and the BA10 regions, 21.8% and 41.4% of disease‐associated transcripts showing age association, respectively. After removing age associated changes from our data, we saw the highest enrichment in processes mediating cell adhesion, synaptic contact, cytoskeletal remodelling, and apoptosis in the BA22 region. For the BA10 region, we observed the strongest changes in reproductive signalling, tissue remodelling, and cell differentiation. Further exploratory analysis also identified potentially disease‐relevant processes that were undetected in our more stringent primary analysis, including autophagy in the BA22 region and the amyloid process in the BA10 region. Collectively, our analysis suggests disruption of many common pathways and processes underpinning synaptic plasticity in both regions in schizophrenia, whereas individual regions emphasize changes in certain pathways that may help to highlight pathway‐specific therapeutic opportunities to treat negative or positive symptoms of the disease.

Intellectual differences between schizophrenic patients and normal controls across the adult lifespan

A debate persists about whether IQ declines during the duration of schizophrenia or whether an early deficit remains static across the lifespan. To examine this, we measured estimated current IQ (Quick Test Revised: QTR) and estimated premorbid IQ (National Adult Reading Test: NART) in schizophrenic patients (n = 110) and matched healthy controls (n = 71) across a wide age range (20–88). Age correlated negatively with NARTand QTR IQ for schizophrenic patients, but not for controls. A subset of 23 schizophrenic patients was also retested on the NART after 4 years to determine NART stability and they showed no significant change. We propose that the lower NART IQ in older patients reflects a lower ‘starting point’ and that this may be related to lower educational opportunities in older patients.