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Transcriptomic analysis of autistic brain reveals convergent molecular pathology


Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity1,2,3. Thus, a fundamental question is whether autism represents an aetiologically heterogeneous disorder in which the myriad genetic or environmental risk factors perturb common underlying molecular pathways in the brain4. Here, we demonstrate consistent differences in transcriptome organization between autistic and normal brain by gene co-expression network analysis. Remarkably, regional patterns of gene expression that typically distinguish frontal and temporal cortex are significantly attenuated in the ASD brain, suggesting abnormalities in cortical patterning. We further identify discrete modules of co-expressed genes associated with autism: a neuronal module enriched for known autism susceptibility genes, including the neuronal specific splicing factor A2BP1 (also known as FOX1), and a module enriched for immune genes and glial markers. Using high-throughput RNA sequencing we demonstrate dysregulated splicing of A2BP1-dependent alternative exons in the ASD brain. Moreover, using a published autism genome-wide association study (GWAS) data set, we show that the neuronal module is enriched for genetically associated variants, providing independent support for the causal involvement of these genes in autism. In contrast, the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic aetiology for this process. Collectively, our results provide strong evidence for convergent molecular abnormalities in ASD, and implicate transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction in this disorder.

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Figure 1: Gene expression changes in autism cerebral cortex
Figure 2: Gene co-expression modules associated with autism
Figure 3: A2BP1-dependent differential splicing events
Figure 4: GWAS set enrichment analysis

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

All microarray and RNA-seq data are deposited in GEO under accession number GSE28521.


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We are grateful for the efforts of the Autism Tissue Program (ATP) of Autism Speaks and the families that have enrolled in the ATP, which made this work possible. We also thank S. Scherer and R. Wintle for sharing their SNP genotyping data on the AGP samples with us before its publication. We would also like to thank B. Abrahams for help in the initial stages of the project, B. Fogel, G. Konopka, N. Barbosa-Morais and J. Bomar for critically reading the manuscript, M. Lazaro for help with tissue dissection, and C. Vijayendran and K. Winden for useful discussions. This work was funded by an Autism Center of Excellence Network Grant from NIMH 5R01MH081754-03 and NIMH R37MH060233 to D.H.G. and by grants from the Canadian Institutes of Health Research and Genome Canada through the Ontario Genomics Institute to B.J.B. and others.

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Authors and Affiliations



I.V. and D.H.G. designed the study and wrote the manuscript. I.V. performed experiments, analysed the data and conducted the GWAS set enrichment analysis. X.W. and B.J.B. analysed the RNA sequencing data. J.K.L. contributed to the GWAS set enrichment analysis. Y.T. performed some of the microarray qRT-PCR validation experiments. R.M.C. supervised the GWAS set enrichment analysis. S.H. supervised the WGCNA analysis. P.J. and J.M. provided dissected tissue for the replication experiment. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Daniel H. Geschwind.

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The authors declare no competing financial interests.

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Voineagu, I., Wang, X., Johnston, P. et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011).

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