Strong correlation of downregulated genes related to synaptic transmission and mitochondria in post-mortem autism cerebral cortex

Matthew Schwede,Neelroop N Parikshak,Eric M Morrow,Daniel H Geschwind,Karoly Mirnics,Shailender Nagpal,Michael J Gandal

doi:10.1186/s11689-018-9237-x

Abstract

BackgroundGenetic studies in autism have pinpointed a heterogeneous group of loci and genes. Further, environment may be an additional factor conferring susceptibility to autism. Transcriptome studies investigate quantitative differences in gene expression between patient-derived tissues and control. These studies may pinpoint genes relevant to pathophysiology yet circumvent the need to understand genetic architecture or gene-by-environment interactions leading to disease.MethodsWe conducted alternate gene set enrichment analyses using differentially expressed genes from a previously published RNA-seq study of post-mortem autism cerebral cortex. We used three previously published microarray datasets for validation and one of the microarray datasets for additional differential expression analysis. The RNA-seq study used 26 autism and 33 control brains in differential gene expression analysis, and the largest microarray dataset contained 15 autism and 16 control post-mortem brains.ResultsWhile performing a gene set enrichment analysis of genes differentially expressed in the RNA-seq study, we discovered that genes associated with mitochondrial function were downregulated in autism cerebral cortex, as compared to control. These genes were correlated with genes related to synaptic function. We validated these findings across the multiple microarray datasets. We also did separate differential expression and gene set enrichment analyses to confirm the importance of the mitochondrial pathway among downregulated genes in post-mortem autism cerebral cortex.ConclusionsWe found that genes related to mitochondrial function were differentially expressed in autism cerebral cortex and correlated with genes related to synaptic transmission. Our principal findings replicate across all datasets investigated. Further, these findings may potentially replicate in other diseases, such as in schizophrenia.

Highlights

Genetic studies in autism have pinpointed a heterogeneous group of loci and genes
We discovered that a gene pathway related to mitochondrial function was downregulated in autism cerebral cortex and correlated with a pathway related to synapse function
The gene set cluster with the highest score was largely related to synapse function and the gene set cluster with the second highest score was related to mitochondrial function

Summary

Introduction

Genetic studies in autism have pinpointed a heterogeneous group of loci and genes. Transcriptome studies investigate quantitative differences in gene expression between patient-derived tissues and control. These studies may pinpoint genes relevant to pathophysiology yet circumvent the need to understand genetic architecture or gene-by-environment interactions leading to disease. Over an affected individual’s lifetime, costs of care can reach about $3.2 million while the annual cost to society is an estimated $35 billion [2] Such burdensome costs combined with new high estimates in prevalence—including numbers as high as 1 in 68 children [3]—call for a need to understand pathophysiology fully and to develop new treatments. In addition to supporting a strong role for genetics, the results of Hallmayer et al implicate a shared twin environment, such as the in utero environment, as an additional factor that may play a role in susceptibility to autism

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Conclusion