Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling
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We used established databases in standard ways to systematically characterize gene ontologies, pathways and functional linkages in the large set of genes now associated with autism spectrum disorders (ASDs). These conditions are particularly challenging--they lack clear pathognomonic biological markers, they involve great heterogeneity across multiple levels (genes, systemic biological and brain characteristics, and nuances of behavioral manifestations)-and yet everyone with this diagnosis meets the same defining behavioral criteria. Using the human gene list from Simons Foundation Autism Research Initiative (SFARI) we performed gene set enrichment analysis with the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database, and then derived a pathway network from pathway-pathway functional interactions again in reference to KEGG. Through identifying the GO (Gene Ontology) groups in which SFARI genes were enriched, mapping the coherence between pathways and GO groups, and ranking the relative strengths of representation of pathway network components, we 1) identified 10 disease-associated and 30 function-associated pathways 2) revealed calcium signaling pathway and neuroactive ligand-receptor interaction as the most enriched, statistically significant pathways from the enrichment analysis, 3) showed calcium signaling pathways and MAPK signaling pathway to be interactive hubs with other pathways and also to be involved with pervasively present biological processes, 4) found convergent indications that the process "calcium-PRC (protein kinase C)-Ras-Raf-MAPK/ERK" is likely a major contributor to ASD pathophysiology, and 5) noted that perturbations associated with KEGG's category of environmental information processing were common. These findings support the idea that ASD-associated genes may contribute not only to core features of ASD themselves but also to vulnerability to other chronic and systemic problems potentially including cancer, metabolic conditions and heart diseases. ASDs may thus arise, or emerge, from underlying vulnerabilities related to pleiotropic genes associated with pervasively important molecular mechanisms, vulnerability to environmental input and multiple systemic co-morbidities.
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Studies on hcASD genes and iPSC-derived ASD neurons highlight signaling pathways that are commonly disrupted, such as PI3K/AKT, RAS/ERK, WNT and β-catenin.
“Consistently, studies on hcASD genes and iPSC-derived ASD neurons highlight signaling pathways that are commonly disrupted, such as PI3K/AKT [79, 80], RAS/ERK [79, 80, 82, 83], WNT and β-catenin [57, 83, 84].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [82]
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- Authors
- Wen, Y., Alshikho, M. J., & Herbert, M. R.
- Affiliations
- Harvard University (US)
- Corresponding author
- Wen, Ya
- Herbert, Martha R.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-04-07
- Volume
- 11
- Issue
- 4
- Pages
- e0153329
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4824422
- OpenAlex
- W2330196942
- Cited by
- 150
- References
- 56
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 13 · 2023: 17 · 2022: 13 · 2021: 18 · 2020: 17 · 2019: 12 · 2018: 19 · 2017: 24 · 2016: 3
- FWCI
- 12.30
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, MAPK signaling, calcium signaling, protein kinase C, neuroactive ligand-receptor interaction, pleiotropic genes, environmental information processing, comorbidities, gene set enrichment analysis
- MeSH terms
- Autistic Disorder, Gene Expression Regulation, Humans, Biomarkers, Computational Biology, Calcium Signaling, Gene Expression Profiling, MAP Kinase Signaling System, Gene Regulatory Networks, Gene Ontology
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