November 24, 2014

Gene Disruptions Associated with Autism Risk

At a Glance

  • Researchers identified mutations in 107 genes that may contribute to the risk for autism spectrum disorder.
  • The findings provide a better understanding of pathways thought to be involved in the disorder, and may help lead to potential therapies.
Illustration of puzzle pieces in a human head. Many genes that are important for normal development may have a modest impact on the risk for autism spectrum disorder.

Autism is a complex brain disorder characterized by difficulties with social interactions and communication. The symptoms and levels of disability can range from mild to severe. The wide range of disorders is collectively referred to as autism spectrum disorder (ASD). ASD affects about 1 in 68 American children.

Researchers previously linked less than a dozen genes to ASD. To further uncover genes that might be associated with the disorder, a large international team led by Dr. Joseph D. Buxbaum at the Icahn School of Medicine at Mount Sinai, Dr. Mark J. Daly at Broad Institute of Harvard and MIT, and the Autism Sequencing Consortium analyzed more than 14,000 DNA samples. More than 3,800 were from children with autism. The others were from parents and control samples of unrelated people. The study was funded in part by NIH’s National Human Genome Research Institute (NHGRI) and National Institute of Mental Health (NIMH). Results were published on November 13, in Nature.

The scientists looked for genetic lesions that were either inherited or de novo—spontaneous variations found in a child’s DNA but not in either parent’s. The team sequenced the exome regions of DNA, which comprise the 1% of the human genome that codes for proteins. This is in contrast to whole-genome sequencing, which analyzes the entire 3 billion DNA base pairs of the human genome.

The researchers identified changes in 107 genes that are likely to contribute to the risk for ASD. More than 5% of the people with ASD had de novo loss-of-function mutations, which prevent production of a normal protein. The researchers predicted that more than 1,000 genes may be involved in the risk for ASD, many of which will only have a modest impact on risk.

Among the genes found to be associated with a risk for ASD, many coded for proteins involved in 3 pathways important for normal development. One involves the structure of synapses, the connections between nerve cells across which brain signals travel. A second involves the remodeling of chromatin—the way DNA is packaged in cells, which can affect whether genes are turned on or off. A third pathway involves transcription, the process by which instructions in genes are read to build proteins.

Together, the findings provide a better understanding of some of the genetic and cellular changes in the pathways and processes thought to be involved in ASD. Eventually, this knowledge may help lead to potential therapies.

“The steps we added to our analysis over past studies provide the most complete theoretical picture to date of how many genetic changes pile up to affect the brains of children with autism,” Buxbaum says. “While we have very strong findings in these genetic analyses, newfound genetic discoveries must next be moved into molecular, cell, and animal studies to realize future benefits for families.”

—by Carol Torgan, Ph.D.

Related Links

Reference: Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Ercument Cicek A, Kou Y, Liu L, Fromer M, Walker S, Singh T, Klei L, Kosmicki J, Fu SC, Aleksic B, Biscaldi M, Bolton PF, Brownfeld JM, Cai J, Campbell NG, Carracedo A, Chahrour MH, Chiocchetti AG, Coon H, Crawford EL, Crooks L, Curran SR, Dawson G, Duketis E, Fernandez BA, Gallagher L, Geller E, Guter SJ, Sean Hill R, Ionita-Laza I, Jimenez Gonzalez P, Kilpinen H, Klauck SM, Kolevzon A, Lee I, Lei J, Lehtimäki T, Lin CF, Ma'ayan A, Marshall CR, McInnes AL, Neale B, 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 LS, Weiss LA, Jeremy Willsey A, Yu TW, Yuen RK; 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, Buxbaum JD. Nature. 2014 Nov 13;515(7526):209-15. doi: 10.1038/nature13772. Epub 2014 Oct 29. PMID: 25363760.

Funding: NIH’s National Human Genome Research Institute (NHGRI) and National Institute of Mental Health (NIMH); the Howard Hughes Medical Institute; National Children’s Research Foundation, Beatrice and Samuel A. Seaver Foundation; Charles and Ann Schlaifer Memorial Fund; UK National Institute for Health Research; Maria Jose Jove Foundation; Strategic Action from Health Carlos III Institute (FEDER).