Identified pathways overlap with other conditions, involve signaling, metabolic and neural systems.
A group of Massachusetts General Hospital (MGH) investigators has identified key underlying biological processes that involve some of the hundreds of genes known to contribute to the risk of autism spectrum disorders (ASDs). Several separate analyses converged on a key molecular process – the overlap of two major signaling pathways – as well as on several groups of genes that participate in that process and contribute to other conditions.
“Our pathway network analysis is the first bioinformatics study in autism to connect the dots of brain and body – of autism and accompanying medical conditions, of autism and vulnerability to environmental stress – in one investigation,” says Ya Wen, PhD, a research fellow in the Department of Neurology at MGH and MassGeneral Hospital for Children (MGHfC) and lead author of the study published in the open-access journal PLOS One. “This coherence of results from different approaches reinforced our confidence that we were on to something fundamentally important.”
While it was originally expected that variations in only a few genes would explain the development of ASDs, major databases now list hundreds of genes that have been associated with the developmental disorders, with more added frequently. The MGH research team drew on the SFARI (Simons Foundation Autism Research Initiative) Gene database, which listed more than 650 genes as relevant to ASDs at the time the study was performed. To make sense of this diversity, they used additional databases to determine the pathways in which these genes participate and generate a network based on pathway interactions.
Not only did the pathways found to be most strongly associated with ASDs have many interactions with each other, they also had overlapping associations with conditions as diverse as cancer, metabolic and neurodegenerative disorders, and heart disease. Most prominent were the calcium and MAP kinase signaling pathways – which control key cellular activities – followed by metabolic and neural pathways. Particularly intriguing was that the calcium and MAP kinase pathways overlapped in a process known to play a central role in a large range of biological functions, the activities of which – when abnormal – are known to be associated with cancer, metabolic and neural disorders, and heart disease.
“As the science of autism has moved from looking for a few genes to finding hundreds, we have been challenged to explain how so many different genes could contribute to such a distinctive condition,” says Martha Herbert, MD, PhD, director of the TRANSCEND (Treatment Research and NeuroSCience Evaluation of Neurodevelopmental Disorders) research lab in the MGH/MGHfC Department of Neurology, senior author of the PLOS One report and an assistant professor of Neurology at Harvard Medical School. “Our pathway analyses show that the diversity of genes may be linked by a smaller number of impactful pathways, and we hope our findings contribute to increasing the coherence and power of autism research and treatment.”
The authors add that a better understanding of how pathways interact may lead to more successful strategies for treating and even preventing ASDs in the future. “Many present treatments attempt to control or reduce particular symptoms of autism, but this study suggests that targeting core biological processes may be a more efficient strategy,” says Wen. “Addressing a core process that generates a spectrum of symptoms may give you a shot at affecting all of those symptoms at ones. This is just a first step along what we hope will be a path to better care, but it is an important one.”
Mohamad Alshikho, MD, of MGH Neurology is also a co-author of the PLOS One report. The team’s work has been supported by the Higher Synthesis Foundation.
Source: McKenzie Ridings – Mass General
Image Source: The image is credited to Ya Wen, Mohamad J. Alshikho, and Martha R. Herbert/PLOS ONE.
Original Research: Full open access research for “Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling” by Ya Wen, Mohamad J. Alshikho, and Martha R. Herbert in PLOS ONE. Published online April 7 2016 doi:10.1371/journal.pone.0153329
Abstract
Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling
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.
“Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling” by Ya Wen, Mohamad J. Alshikho, and Martha R. Herbert in PLOS ONE. Published online April 7 2016 doi:10.1371/journal.pone.0153329
