Limits...
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.

Show MeSH

Related in: MedlinePlus

Enrichment of the ASD modules in cell-type-specific genes. Enrichment of ASD-enriched modules in neurons, oligodendrocytes, and astrocytes (represented in −log10(p), FDR-corrected)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4644211&req=5

Fig5: Enrichment of the ASD modules in cell-type-specific genes. Enrichment of ASD-enriched modules in neurons, oligodendrocytes, and astrocytes (represented in −log10(p), FDR-corrected)

Mentions: Each module was also tested for enrichment of specific neural cell populations (i.e., neurons, oligodendrocytes, and astrocytes), as described earlier. Three out of the four ASD-enriched modules were enriched for neurons (magenta, brown, and purple modules), as shown in Fig. 5. The orange module, which was related to mitochondrial functioning, was highly enriched in astrocytes but not neurons. This finding is of relevance, as multiple recent studies have implicated glia, and specifically astrocytes, in the brain pathology of autistic subjects (Lioy et al. 2011; Cao et al. 2012).Fig. 5


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)

Enrichment of the ASD modules in cell-type-specific genes. Enrichment of ASD-enriched modules in neurons, oligodendrocytes, and astrocytes (represented in −log10(p), FDR-corrected)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: Enrichment of the ASD modules in cell-type-specific genes. Enrichment of ASD-enriched modules in neurons, oligodendrocytes, and astrocytes (represented in −log10(p), FDR-corrected)
Mentions: Each module was also tested for enrichment of specific neural cell populations (i.e., neurons, oligodendrocytes, and astrocytes), as described earlier. Three out of the four ASD-enriched modules were enriched for neurons (magenta, brown, and purple modules), as shown in Fig. 5. The orange module, which was related to mitochondrial functioning, was highly enriched in astrocytes but not neurons. This finding is of relevance, as multiple recent studies have implicated glia, and specifically astrocytes, in the brain pathology of autistic subjects (Lioy et al. 2011; Cao et al. 2012).Fig. 5

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