Three Separate Studies Now Connect Autism with Genes


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

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.

The mission of NIMH ( is to reduce the burden of mental and
behavioral disorders through research on mind, brain and behavior.
NICHD ( sponsors research on development, before and
after birth; maternal, child, and family health; reproductive biology and population
issues; and medical rehabilitation.
NIDCD ( supports and conducts
research and research training on the normal and disordered processes of hearing,
balance, smell, taste, voice, speech and language and provides health information,
based upon scientific discovery, to the public. NCRR ( provides
laboratory scientists and clinical researchers with the resources and training
they need to understand, detect, treat and prevent a wide range of diseases.
NCRR supports all aspects of translational and clinical research, connecting
researchers, patients and communities across the nation.
NINDS ( is the nation’s primary supporter of biomedical
research on the brain and nervous system.

For more information about autism, visit or

Can autism be cured or managed? See the Opposing Views debate.


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