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Synaptic, Transcriptional, and Chromatin Genes Disrupted in Autism
De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE,  Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Fu S-C, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NJ, Carracedo A, Chahrour AH, Chiocchetti AG, Coon H, Crawford EL, Crooks L, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Hill RS, Ionita-Laza I, Jimenez Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei J, Lehtimäki T, Lin C-F, Ma'ayan A, Marshall CR, McInnes AL, Neale B, Michael J. Owen MJ, Ozaki N, Parellada M, Parr JR, Purcell S, Puura K, Rajagopalan D, Rehnström K, Reichenberg A, Sabo A, Sachse M, Sanders SJ, Schafer C, Schulte-Rüther M, Skuse D, Stevens C, Szatmari P, Tammimies K, Valladares O, Voran A, Wang L-S, Weiss LA, Willsey AJ, Yu TW, Yuen RKC, the DDD Study§, Homozygosity Mapping Collaborative for Autism, UK10K Consortium, the Autism Sequencing Consortium§, Cook EH, Freitag CM, Gill M, Hultman CM,  Lehner T, Palotie A, Schellenberg GD, Sklar P, State MW, Sutcliffe JS, Walsh CA, Scherer SW, Zwick ME, Barrett JC, Cutler DJ, Roeder K, Devlin B, Daly MJ, and Buxbaum JD
Nature, 2014, 515(7526):209-215

Recent genetic studies have suggested that as many as a thousand genes contribute to risk for autism. This observation has been confirmed by a study published in the journal Nature by the Autism Sequencing Consortium (ASC). The ASC team involves 37 institutions and is led by four principal investigators:  Dr. Bernie Devlin (Department of Psychiatry, University of Pittsburgh School of Medicine); Dr. Joseph Buxbaum (Ichan School of Medicine at Mt. Sinai); Dr. Mark Daly (The Broad Institute of MIT and Harvard University) and; Dr. Matthew State (Department of Psychiatry, University of California at San Francisco).  

The new study generated DNA sequence data from the largest autism sample to date, more than 14,000 DNA samples from parents, affected children, and unrelated individuals. Scrutinizing these sequences the team identified rare changes that increased the number of definitive autism genes almost threefold to 33, compared to the nine genes previously tied to risk by similar studies. They also identified 70 more genes with strong but not yet conclusive evidence for involvement.  The genes implicated concentrate around two essential processes: regulation of suites of genes, which for autism must be affecting very early brain development; and synapses, which are structures critical for how brain cells communicate with each other. The team speculates that the two processes are linked. This makes sense because typical development of brain cells requires intricate coordination amongst thousands of genes and appropriate communication between cells to ensure development of the most complicated organ in the human body. Moreover, it comports with theories of autism such as abnormal development of brain connectivity, a theory championed by Nancy Minshew, PhD, Professor of Psychiatry and Neurology at the University of Pittsburgh School of Medicine jointly with Marcel Just, Professor of Psychology at Carnegie Mellon University. 

"The next priorities for the ASC are to expand the list of definitive autism genes even more and drill down into exactly what is different about the brain of someone with autism versus more typical development," said Dr. Devlin.  "I'm confident that the list of autism genes will expand rapidly because there are already many more samples sequenced. What goes awry is a harder question, but the ever increasing list of genes involved will surely provide pieces that could solve the puzzle that is autism."

Drs. Devlin and Daly lead the ASC analytical group in collaboration with Dr. Kathryn Roeder, Professor of Statistics at Carnegie Mellon University. Drs. Buxbaum and State are responsible for the administrative leadership , and all contribute to the direction of the ASC research.

The findings of this study appear in the journal Nature. Click here to view the abstract.