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. 2012;7(9):e44736.
doi: 10.1371/journal.pone.0044736. Epub 2012 Sep 12.

Brain transcriptional and epigenetic associations with autism

Matthew R Ginsberg  1 , Robert A Rubin, Tatiana Falcone, Angela H Ting, Marvin R Natowicz
Affiliations

Brain transcriptional and epigenetic associations with autism

Matthew R Ginsberg et al. PLoS One. 2012.

Abstract

Background: Autism is a common neurodevelopmental syndrome. Numerous rare genetic etiologies are reported; most cases are idiopathic.

Methodology/principal findings: To uncover important gene dysregulation in autism we analyzed carefully selected idiopathic autistic and control cerebellar and BA19 (occipital) brain tissues using high resolution whole genome gene expression and whole genome DNA methylation microarrays. No changes in DNA methylation were identified in autistic brain but gene expression abnormalities in two areas of metabolism were apparent: down-regulation of genes of mitochondrial oxidative phosphorylation and of protein translation. We also found associations between specific behavioral domains of autism and specific brain gene expression modules related to myelin/myelination, inflammation/immune response and purinergic signaling.

Conclusions/significance: This work highlights two largely unrecognized molecular pathophysiological themes in autism and suggests differing molecular bases for autism behavioral endophenotypes.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Autistic brain shows transcriptional heterogeneity and differential expression of genes of mitochondrial oxidative phosphorylation and protein translation.
(A) Unsupervised correspondence analysis of whole-genome transcriptome expression data demonstrates that brain region is associated with the greatest source of variability in the data. The second principal component is associated with variability mostly among autistic samples. The first two principal components are listed on the x- and y-axis respectively, with percent of variance explained in parentheses. Bubbles represent individual samples, with area proportional to age, outline to brain region, and color to phenotype. (B) Heatmap of the top 50 differentially expressed probes between autistic and control brain, accounting for brain region, separates most autistic brains from controls (FDR ≤5%). Rows correspond to probes and columns to samples. The dendrogram represents sample similarity on the basis of the top 50 differentially expressed probes. Probes with log2-fold change >0.7 are listed in table S3. (C) The top 300 differentially expressed probes are enriched for gene ontology annotation clusters corresponding to mitochondrial oxidative phosphorylation and protein translation. ADI-R, Autism Diagnostic Interview-Revised; BA19, Brodmann area 19; CER, cerebellum; PMI, postmortem interval.
Figure 2
Figure 2. Specific domains of the Autism Diagnostic Interview-Revised (ADI-R) are associated with specific gene modules.
(A) Heatmap of module-variable associations for cerebellar hemisphere samples from weighted genome co-expression network analysis, including domain scores for the ADI-R. Cells are color-coded by correlation coefficient and * is placed in cells having associations with p-values ≤0.01. Autism, dichotomous variable autism vs control; PMI, postmortem interval; A, ADI-R Social interaction impairments domain; B, ADI-R Communication and language impairments domain; C, ADI-R Repetitive and stereotyped behaviors domain. (B) Gene ontology enrichment annotation clusters for the three significant gene modules associated with specific ADI-R domain scores. P, p-value; r, Pearson correlation coefficient.
Figure 3
Figure 3. No differential methylation of genomic DNA was identified between control and autism cerebellar cortex or BA19 cortex.
(A) Unsupervised correspondence analysis of genome-wide CpG methylation in control and autism cerebellar cortex and BA19 cerebral cortex demonstrates that brain region and age are associated with the largest two sources of variability, respectively, in the data. The first two principal components are listed on the x- and y-axis respectively, with percent of variance explained in parentheses. Bubbles correspond to individual samples with area proportional to age of subject, bubble outline to region, and color to phenotype. (B) Percent of genome-wide methylated probes in cerebellar cortex or BA19 cortex in control and autism samples. Error bars represent standard deviations. There was no significant difference in global methylation between autism vs control cerebellum or BA19 cortex. There was a significant difference between brain regions, as expected (alpha = 0.05; Wilcoxon rank-sum test). (C) Pyrosequencing of bisulfite-treated DNA. Percent methylation at individual CpG dinucleotides is reported in cerebellar cortex samples (n ≥7 per group) for a priori candidate genes suspected to exhibit differential methylation. X-axis represents locus relative to transcription start site. Error bars represent standard deviations.
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