UW News

June 9, 2010

People with autism have more duplicated and deleted DNA sequences in their genomes than do those without the disorder

UW Health Sciences/UW Medicine

A multi-institutional study of 1,000 people with autism found that their genomes had more duplicates and deletions of DNA sequences when compared with the genomes of 1,300 controls without the disorder. The repeated and missing segments are called copy number variations, many of which were concentrated in genes already implicated in autism and intellectual disabilities.

The study also identified several new possible autism susceptibility genes. A few of these influence connections between brain cells, while others play a role in cell motility and proliferation, or in cell signaling. The newly identified genes include SHANK2, SYNGAP1, DLGAP2, and the DDX53-PTCHD2 location on the X chromosome.

Most of the copy number variations were transmitted from parents to child, but about 5 percent arose spontaneously in the affected offspring.

Autism is a neurological disorder than inhibits the ability to communicate and form social relationships, and is often accompanied by self-absorbed, repetitive behaviors and restricted interests.The findings support a growing belief among experts in the genetics of autism that the cause lies partially in many rare genetic changes found in less than 1 percent of the population. Each genetic variant may account for only a fraction of cases, but collectively the variants underlie a significant percentage of autism spectrum disorders.

The study, published June 9 in Nature, involved an international consortium of 120 scientists as well as numerous participating families. Researchers at the University of Washington (UW) in Seattle contributed to the study design, the local recruitment of families, and the genetic data analysis. The lead scientist for the UW portion of this project was Dr. Ellen Wijsman, professor of medicine in the Division of Medical Genetics in the School of Medicine, and professor of biostatistics in the School of Public Health. Other UW researchers on the project were Dr. Annette Estes of the Department of Speech and Hearing Sciences and Dr. Jeff Munson from the Department of Psychiatry and Behavioral Sciences. All are members of the UW Autism Research Center.

What set this study apart was its large sample size from across Europe and North America, Wijsman said. “We would never have been able to discover rare variants and determine the association between many rare genetic variants and autism disorders without comparing a significant number of individuals and families.” The project pooled genetic data already being gathered using the same platform at more than 60 institutions. The selection of families and individuals followed stringent criteria.

Unraveling the genetics of autism is likely to continue to be very complex, as is determining how the implicated genetic variations function or malfunction in the development of autism.  

“Some of the copy number variations identified in this study may later prove to be significant in autism, and others may just be noise,” Wijsman said. Scientists will have to figure out which structural changes in the genome are actually involved in the disease.

“In reducing the list of potentially disruptive copy number variations,” Wijsman said, “we need to figure out which mean business and which are just along for the ride.”

Wijsman pointed out an intriguing aspect of trying to separate out the culprit copy number variations from the benign. Some of the parents and siblings in the study have the same structural variations in their genomes as the affected child, but don’t have autism.

It may be possible, she said, that, in looking more closely at the unaffected family members with the genetic variation, that some of them may have subtle attributes that make them differ from the controls. Or perhaps the lack of distinctions between them and the controls may suggest that a particular copy number variation is not a key player in autism.

The Autism Genome Project  is co-funded by Autism Speaks, the Medical Research Council, Canadian Institutes of Health Research, Health Research Board of Ireland, Genome Canada and the Hilbrand Foundation, as well as ongoing grants from other public and private foundations to individual autism centers, including the National Institutes of Health, which supports the UW autism sample collection.