In three studies, including the most comprehensive study of autism genetics to date, investigators funded in part by the National Institutes of Health have identified common and rare genetic factors that affect the risk of autism spectrum disorders.
The results point to the importance of genes that are involved in forming and maintaining the connections between brain cells.
"These findings establish that genetic factors play a strong role in autism spectrum disorder," says Acting NIH Director Raynard Kington, M.D., Ph.D. "Detailed analysis of the genes and how they affect brain development is likely to yield better strategies for diagnosing and treating children with autism."
Autism spectrum disorders (ASD) comprise a group of disorders with core symptoms that include social interaction problems, poor verbal and nonverbal communication and repetitive behaviors. These disorders range from severe (autism) to mild (Asperger's syndrome), and in total affect some 1 in 150 American children, about three-quarters of whom are boys. Researchers theorize that the social parts of the brain are underdeveloped in ASD.
"Previous studies have suggested that autism is a developmental disorder resulting from abnormal connections in the brain. These three studies suggest some of the genetic factors which might lead to abnormal connectivity," says Thomas Insel, M.D., director of NIH's National Institute of Mental Health (NIMH).
The studies were funded in part by the NIMH, the National Institute of Neurological Disorders and Stroke (NINDS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Institute on Deafness and Other Communication Disorders (NIDCD) and the National Center for Research Resources (NCRR), all components of NIH.
All three studies were genome-wide association studies, which are undertaken to find clues about the causes of complex disorders. Typically, these studies involve scanning the genome – the entire set of DNA – for small differences between people who have a disorder and people who do not.
The largest study, reported in Nature , involved more than 10,000 subjects, including individuals with ASD, their family members and other volunteers from across the U.S. The study was led by Hakon Hakonarson, M.D., Ph.D., a professor at the University of Pennsylvania School of Medicine and director of the Center for Applied Genomics at The Children's Hospital of Philadelphia. Among other principal investigators on the study were Gerard D. Schellenberg, Ph.D., also a professor at the University of Pennsylvania School of Medicine; and Daniel Geschwind, M.D., Ph.D., a professor at the University of California, Los Angeles and director of UCLA's Center for Autism Research and Treatment; and Margaret Pericak-Vance, Ph.D., a professor at the University of Miami Miller School of Medicine and director of the Miami Institute for Human Genomics, who also led an independent study that generated similar results.
Major funding for Dr. Hakonarson's work came from The Children's Hospital of Philadelphia. Dr. Pericak-Vance's work was supported in part by the Hussman Foundation. The DNA samples came from a repository called the Autism Genetic Resource Exchange (AGRE), and from subjects recruited at clinics in Philadelphia, Miami, Los Angeles and other sites. AGRE is run by Autism Speaks, with partial support from NIMH.
Previous studies of twins with ASD, other children with ASD and their relatives provided evidence of a strong genetic contribution. Yet until now, only a few genetic risk factors had been identified, and most of those turned out to be rare, with unclear significance for ASD in the general population. Researchers came to realize that the genetics of ASD is complex.
"There are going to be many genes involved in causing autism," says Dr. Hakonarson. "In most cases, it's likely that each gene contributes a small amount of risk, and interacts with other genes and environmental factors to trigger the onset of disease."
In their large study, Dr. Hakonarson and his colleagues found several genetic variants that were commonly associated with ASD, all of them pointing to a spot between two genes on chromosome 5, called CDH9 and CDH10. Both genes encode cadherins – cell surface proteins that enable cells to adhere to each other. The researchers also found that a group of about 30 genes that encode cell adhesion proteins (including cadherins and neurexins) were more strongly associated with ASD than all other genes in their data set. In the developing brain, cell adhesion proteins enable neurons to migrate to the correct places and to connect with other neurons.
In a second study, Dr. Pericak-Vance completed an independent search for small genetic variants associated with ASD, in collaboration with Jonathan Haines, Ph.D., of Vanderbilt University Medical Center in Nashville. Published in the Annals of Human Genetics , the study provides a striking confirmation that ASD is associated with variation near CDH9 and CDH10.
"We are starting to see genetic pathways in ASD that make sense," says Dr. Pericak-Vance.
Finally, in a third study, reported in Nature , Drs. Hakonarson and Schellenberg led a search for genes that were duplicated or deleted in individuals with ASD. In the rare cases where those variations occurred, many tended to affect genes involved in cell adhesion. Others tended to affect genes involved in the ubiquitin-proteasome system, a cellular waste disposal system that probably affects the turnover of adhesion proteins at the cell surface.
Previous, smaller genetic studies reported a connection between male-only autism and CNTNAP2, a type of neurexin. Together, the three new studies suggest that genetic differences in cell-to-cell adhesion could influence susceptibility to ASD on a large scale. Dr. Hakonarson and his colleagues are planning an even more extensive genome-wide association study to gain a more complete picture of the genes and gene interactions involved in ASD.