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Shared Pathways Among Autism Candidate Genes Determined by Co-expression Network Analysis of the Developing Human Brain Transcriptome.

Mahfouz A, Ziats MN, Rennert OM, Lelieveldt BP, Reinders MJ - J. Mol. Neurosci. (2015)

Bottom Line: Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology.Furthermore, we also constructed co-expression networks from the entire transcriptome and found that ASD candidate genes were enriched in modules related to mitochondrial function, protein translation, and ubiquitination.Overall, our multi-dimensional co-expression analysis of ASD candidate genes in the normal developing human brain suggests the heterogeneous set of ASD candidates share transcriptional networks related to synapse formation and elimination, protein turnover, and mitochondrial function.

View Article: PubMed Central - PubMed

Affiliation: Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands. a.mahfouz@tudelft.nl.

ABSTRACT
Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology. Hundreds of diverse genes have been implicated in ASD; yet understanding how many genes, each with disparate function, can all be linked to a single clinical phenotype remains unclear. We hypothesized that understanding functional relationships between autism candidate genes during normal human brain development may provide convergent mechanistic insight into the genetic heterogeneity of ASD. We analyzed the co-expression relationships of 455 genes previously implicated in autism using the BrainSpan human transcriptome database, across 16 anatomical brain regions spanning prenatal life through adulthood. We discovered modules of ASD candidate genes with biologically relevant temporal co-expression dynamics, which were enriched for functional ontologies related to synaptogenesis, apoptosis, and GABA-ergic neurons. Furthermore, we also constructed co-expression networks from the entire transcriptome and found that ASD candidate genes were enriched in modules related to mitochondrial function, protein translation, and ubiquitination. Hub genes central to these ASD-enriched modules were further identified, and their functions supported these ontological findings. Overall, our multi-dimensional co-expression analysis of ASD candidate genes in the normal developing human brain suggests the heterogeneous set of ASD candidates share transcriptional networks related to synapse formation and elimination, protein turnover, and mitochondrial function.

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ASD modules. aLeft, average expression pattern of the magenta module genes across different brain regions (different plot colors). Right, top GO terms enriched in the magenta module. bLeft, average expression pattern of the brown module genes. Right, top GO terms enriched in the brown module. cLeft, average expression pattern of the orange module genes. Right, top GO terms enriched in the orange module. dLeft, average expression pattern of the purple module genes. Right, top GO terms enriched in the purple module. All enrichment values are represtented by −log10(p), Benjamini-corrected
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Fig4: ASD modules. aLeft, average expression pattern of the magenta module genes across different brain regions (different plot colors). Right, top GO terms enriched in the magenta module. bLeft, average expression pattern of the brown module genes. Right, top GO terms enriched in the brown module. cLeft, average expression pattern of the orange module genes. Right, top GO terms enriched in the orange module. dLeft, average expression pattern of the purple module genes. Right, top GO terms enriched in the purple module. All enrichment values are represtented by −log10(p), Benjamini-corrected

Mentions: The resulting transcriptome-wide co-expression modules were then assessed for enrichment of genes belonging to the ASD list using the hypergeometric probability test. Four modules—magenta, brown, orange, and purple—were significantly enriched for ASD candidate genes (FDR-corrected p values <0.001), as shown in Fig. 3b. The magenta module (Fig. 4a) contained highly co-expressed genes during early childhood. The brown module (Fig. 4b) included genes with weak co-expression during childhood and differential spatial co-expression at late developmental stages. The orange module (Fig. 4c) contained genes with progressively increasing co-expression during development. Finally, the purple module (Fig. 4d) included genes with varied co-expression during development and high differential spatial co-expression in adolescence and adulthood.Fig. 4


Shared Pathways Among Autism Candidate Genes Determined by Co-expression Network Analysis of the Developing Human Brain Transcriptome.

Mahfouz A, Ziats MN, Rennert OM, Lelieveldt BP, Reinders MJ - J. Mol. Neurosci. (2015)

ASD modules. aLeft, average expression pattern of the magenta module genes across different brain regions (different plot colors). Right, top GO terms enriched in the magenta module. bLeft, average expression pattern of the brown module genes. Right, top GO terms enriched in the brown module. cLeft, average expression pattern of the orange module genes. Right, top GO terms enriched in the orange module. dLeft, average expression pattern of the purple module genes. Right, top GO terms enriched in the purple module. All enrichment values are represtented by −log10(p), Benjamini-corrected
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4644211&req=5

Fig4: ASD modules. aLeft, average expression pattern of the magenta module genes across different brain regions (different plot colors). Right, top GO terms enriched in the magenta module. bLeft, average expression pattern of the brown module genes. Right, top GO terms enriched in the brown module. cLeft, average expression pattern of the orange module genes. Right, top GO terms enriched in the orange module. dLeft, average expression pattern of the purple module genes. Right, top GO terms enriched in the purple module. All enrichment values are represtented by −log10(p), Benjamini-corrected
Mentions: The resulting transcriptome-wide co-expression modules were then assessed for enrichment of genes belonging to the ASD list using the hypergeometric probability test. Four modules—magenta, brown, orange, and purple—were significantly enriched for ASD candidate genes (FDR-corrected p values <0.001), as shown in Fig. 3b. The magenta module (Fig. 4a) contained highly co-expressed genes during early childhood. The brown module (Fig. 4b) included genes with weak co-expression during childhood and differential spatial co-expression at late developmental stages. The orange module (Fig. 4c) contained genes with progressively increasing co-expression during development. Finally, the purple module (Fig. 4d) included genes with varied co-expression during development and high differential spatial co-expression in adolescence and adulthood.Fig. 4

Bottom Line: Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology.Furthermore, we also constructed co-expression networks from the entire transcriptome and found that ASD candidate genes were enriched in modules related to mitochondrial function, protein translation, and ubiquitination.Overall, our multi-dimensional co-expression analysis of ASD candidate genes in the normal developing human brain suggests the heterogeneous set of ASD candidates share transcriptional networks related to synapse formation and elimination, protein turnover, and mitochondrial function.

View Article: PubMed Central - PubMed

Affiliation: Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands. a.mahfouz@tudelft.nl.

ABSTRACT
Autism spectrum disorder (ASD) is a neurodevelopmental syndrome known to have a significant but complex genetic etiology. Hundreds of diverse genes have been implicated in ASD; yet understanding how many genes, each with disparate function, can all be linked to a single clinical phenotype remains unclear. We hypothesized that understanding functional relationships between autism candidate genes during normal human brain development may provide convergent mechanistic insight into the genetic heterogeneity of ASD. We analyzed the co-expression relationships of 455 genes previously implicated in autism using the BrainSpan human transcriptome database, across 16 anatomical brain regions spanning prenatal life through adulthood. We discovered modules of ASD candidate genes with biologically relevant temporal co-expression dynamics, which were enriched for functional ontologies related to synaptogenesis, apoptosis, and GABA-ergic neurons. Furthermore, we also constructed co-expression networks from the entire transcriptome and found that ASD candidate genes were enriched in modules related to mitochondrial function, protein translation, and ubiquitination. Hub genes central to these ASD-enriched modules were further identified, and their functions supported these ontological findings. Overall, our multi-dimensional co-expression analysis of ASD candidate genes in the normal developing human brain suggests the heterogeneous set of ASD candidates share transcriptional networks related to synapse formation and elimination, protein turnover, and mitochondrial function.

Show MeSH
Related in: MedlinePlus