Autism Pathways Linked To Multisystem Involvement and To Other Disease States Interview with:
Ya Wen PhD
TRANSCEND Research, Neurology Department
Massachusetts General Hospital, Charlestown, Massachusetts,
Harvard Medical School, Harvard University, Boston, Massachusetts
Higher Synthesis Foundation, Cambridge, Massachusetts What is the background for this study?

Dr. Ya Wen: At the time of this study (December 2014), the SFARI (Simons Foundation Autism Research Initiative) Gene-Human Gene Module recorded 667 human genes implicated as relevant to Autism spectrum disorders (ASDs). Now the number is close to 800. We sought to address the challenge of making sense of this large list of genes by identifying coherent underlying biological mechanisms that link groups of these genes together. To do this, we used information from several existing and well established databases and created a “demographics” of autism genes and pathways. What are the main findings?

Dr. Ya Wen: From these hundreds of autism genes, we first found the relatively most important pathways, and then we generated a pathway network by mapping the pathway-pathway interactions into an Autism Pathway Network. Our systems analyses of this network converged upon an important role in autism pathophysiology for two pathways: MAPK signaling and calcium signaling, and specifically the process where they overlap, “calcium-protein kinase C-Ras-Raf-MAPK/ERK”. Our study also illuminated genetic relationships between autism and several other kinds of illness, including cancer, metabolic and heart diseases. Many of the significant genes and pathways were associated with vulnerability in the processing of challenging environmental influences. What should clinicians and patients take away from your report?

Dr. Ya Wen: Our findings remind us that genes do not function alone, but in groups (pathways). Also, we need to remember that it is not just individual genes on their own but also the function or teamwork of the gene pathways that shapes our vulnerabilities and strengths. So we need to be mindful of the whole picture, the whole map.

Pathways are like streets in a city (with each cell being like a little city in itself). Molecules and other gene products move around the “city” in the “streets”. A traffic jam in key processes can easily extend to many places – not just to one or two genes or “intersections”, but to many activities (or locations) quite a distance away. On the other hand, if we can overcome this “traffic jam”, we might fix many problems all at the same time.

The “hubs” or core processes we identified can be thought of as major intersections or traffic circles that connect many different processes—and these other processes can get jammed up when the hubs are not working right. It can also work the other way around: traffic jams near the hubs may also slow down the hubs, with big effects.

This is why we say that when you address a core process that generates a spectrum of symptoms you have a shot at affecting all of these symptoms at once. For patients this means making as many healthy choices as you can, because so many of your core processes are interconnected. What recommendations do you have for future research as a result of this study?

Dr. Ya Wen: The KEGG database that we used for pathway information includes information not only about genes but also about other types of influences on pathways, including metabolism and environmental information. This means that even though we all know that gene mutations can cause problems, it can also be the other way around: systemic metabolic glitches or environmental factors outside of the cells can have impacts on the receptor activities on the cell membrane, leading to a series of reactions inside the cells, including possible effects on gene transcriptions.

So we think that there should be more research on influences going down to genes and gene expression as well as up from genes to everything else. Given the overlaps we have found between autism and other illnesses, we also think that our systems analysis methods of genes could help clarify relationships among genes and pathways for other conditions.

Mainly, though, we hope our findings will inspire further investigations that could help create more successful strategies for autism treatment and possibly even prevention in the future. Thank you for your contribution to the community.


Pathway Network Analyses for Autism Reveal Multisystem Involvement, Major Overlaps with Other Diseases and Convergence upon MAPK and Calcium Signaling

Ya Wen , Mohamad J. Alshikho, Martha R. Herbert

PLOS One Published: April 7, 2016

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Ya Wen PhD (2016). Autism Pathways Linked To Multisystem Involvment and Links To Other Disease

Last Updated on April 9, 2016 by Marie Benz MD FAAD