Transcriptome analysis of cortical tissue reveals shared sets of downregulated genes in autism and schizophrenia.

S E Ellis,D E Arking,R Panitch,A B West

doi:10.1038/tp.2016.87

Abstract

Autism (AUT), schizophrenia (SCZ) and bipolar disorder (BPD) are three highly heritable neuropsychiatric conditions. Clinical similarities and genetic overlap between the three disorders have been reported; however, the causes and the downstream effects of this overlap remain elusive. By analyzing transcriptomic RNA-sequencing data generated from post-mortem cortical brain tissues from AUT, SCZ, BPD and control subjects, we have begun to characterize the extent of gene expression overlap between these disorders. We report that the AUT and SCZ transcriptomes are significantly correlated (P<0.001), whereas the other two cross-disorder comparisons (AUT–BPD and SCZ–BPD) are not. Among AUT and SCZ, we find that the genes differentially expressed across disorders are involved in neurotransmission and synapse regulation. Despite the lack of global transcriptomic overlap across all three disorders, we highlight two genes, IQSEC3 and COPS7A, which are significantly downregulated compared with controls across all three disorders, suggesting either shared etiology or compensatory changes across these neuropsychiatric conditions. Finally, we tested for enrichment of genes differentially expressed across disorders in genetic association signals in AUT, SCZ or BPD, reporting lack of signal in any of the previously published genome-wide association study (GWAS). Together, these studies highlight the importance of examining gene expression from the primary tissue involved in neuropsychiatric conditions—the cortical brain. We identify a shared role for altered neurotransmission and synapse regulation in AUT and SCZ, in addition to two genes that may more generally contribute to neurodevelopmental and neuropsychiatric conditions.

Highlights

The aggregation of psychiatric conditions and symptoms in families has long been recognized,[1,2,3,4,5] with more recent genetic analyses suggesting an overlap between a number of disorders.[1,6,7,8,9] Recent studies considering single-nucleotide polymorphism-based genetic correlation demonstrated a marked correlation between schizophrenia (SCZ) and bipolar disorder (BPD) and to a lesser extent between SCZ and autism spectrum disorder,[1] suggesting shared genetic etiologies
A summary of sample statistics is provided in note that these two genes, IQSEC3 and COPS7A, are syntenic
Despite the lack of global significant differential transcriptomic correlation between either BPD and SCZ or AUT and BPD, we highlight two genes, IQSEC3 and COPS7A, for their consistent downregulation across all three disorders, and support further investigation into these specific genes’ expression and function to better understand their role in neuropsychiatric disorders

Summary

Introduction

The aggregation of psychiatric conditions and symptoms in families has long been recognized,[1,2,3,4,5] with more recent genetic analyses suggesting an overlap between a number of disorders.[1,6,7,8,9] Recent studies considering single-nucleotide polymorphism-based genetic correlation demonstrated a marked correlation between schizophrenia (SCZ) and bipolar disorder (BPD) and to a lesser extent between SCZ and autism spectrum disorder,[1] suggesting shared genetic etiologies. We and others hypothesize that gene expression studies may begin to unravel how genetic correlations may functionally overlap in neuropsychiatric disorders. Zhao et al.[10] suggested that SCZ and BPD show concordant differential gene expression (R = 0.28) and that the genes contributing to this overlap are enriched for genetic association signal in both SCZ and BPD while highlighting several biological pathways.[10] Two separate recent studies of gene expression in autism (AUT) have resolved gene expression changes related to altered synaptic and neuronal signaling as well as immunological differences in AUT-affected brains.[11,12] In particular, a marked increase was observed in gene expression related to alternative activation of the innate immune system, or the M2 response in AUT-affected brains, relative to controls.[12]

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Results

Conclusion