title: Shared Pathways Among Autism Candidate Genes Determined by Co-expression Network Analysis of the Developing Human Brain Transcriptome.
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.
authors.affiliation: Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands. a.mahfouz@tudelft.nl.|Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands. a.mahfouz@tudelft.nl.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mahfouz
authors.affiliation: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.|University of Cambridge, Cambridge, UK.|Baylor College of Medicine, Houston, TX, USA.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Ziats
authors.affiliation: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Rennert
authors.affiliation: Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Intelligent Systems, Delft University of Technology, Delft, The Netherlands.
authors.forename: Boudewijn P F
authors.initials: BP
authors.lastname: Lelieveldt
authors.affiliation: Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands.
authors.forename: Marcel J T
authors.initials: MJ
authors.lastname: Reinders
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D001921:Brain / Q000254:growth & development / Q000378:metabolism*; D053263:Gene Regulatory Networks; D006801:Humans; D059467:Transcriptome
keywords: Apoptosis; Autism spectrum disorder; Gene co-expression network; Mitochondrion; Synaptogenesis