Gene Expression Profiles Associated with Brain Aging are Altered in Schizophrenia

Sarven Sabunciyan

doi:10.1038/s41598-019-42308-5

Abstract

Existence of aging associated transcriptional differences in the schizophrenia brain was investigated in RNA sequencing data from 610 postmortem Dorso-Lateral Pre-Frontal Cortex (DLPFC) samples in the CommondMind Consortium (CMC) and the psychENCODE cohorts. This analysis discovered that the trajectory of gene expression changes that occur during brain aging differed between schizophrenia cases and unaffected controls. Mainly, the identified gene expression differences between the diagnosis groups shrank in magnitude following 60 years of age. A differential expression analysis restricted to the 40 to 60 year age group identified 556 statistically significant loci that replicated and had highly consistent gene expression fold changes in the two cohorts. An interaction between age and diagnosis in the wider psychENCODE cohort was also detected. Gene set enrichment analysis discovered disruptions in mitochondria, RNA splicing and phosphoprotein gene pathways. The identified differentially expressed genes in the two cohorts were also significantly enriched in genomic regions associated with schizophrenia although no enrichment was observed for differentially expressed genes identified in the 40 to 60 year age group. This work implicates disruptions to the normal brain aging processes in the pathology of schizophrenia and demonstrates the need for age stratification in schizophrenia postmortem brain gene expression studies.

Highlights

Five hundred fifty six loci enriched in mitochondrial functions were identified that surpassed the threshold for multiple testing in both the CommondMind Consortium (CMC) and psychENCODE cohorts
The analysis of the entire CMC cohort yields much smaller gene expression difference compared to other cohorts - a mean of 1.09 and a range of 1.03–1.33 fold[1]
The similar differences observed between the CMC and psychENCODE when the analysis is restricted to the 40 to 60 year age group strongly suggests that age stratification in schizophrenia gene expression studies is beneficial

Summary

Introduction

As the largest expression differences between schizophrenia and control samples occurred consistently between 40 and 60 years of age in the CMC analysis, differential expression analysis for this age group in the CMC and psychENCODE cohorts was performed. The resulting analysis identified 2167 differentially expressed genes in the CMC and 4086 in psychENCODE that had an adjusted p-value of less than 0.1 and at least 20 reads per gene.

Results

Conclusion