Autism Genes Discovered; Help Shape Connections Among Brain Cells

-Findings Suggest Biological Reasons for Altered Early Neural Development-

PHILADELPHIA, April 28 /PRNewswire-USNewswire/ -- A research team has
connected more of the intricate pieces of the autism puzzle, with two studies
that identify genes with important contributions to the disorder. One study
pinpoints a gene region that may account for as many as 15 percent of autism
cases, while another study identifies missing or duplicated stretches of DNA
along two crucial gene pathways. Significantly, both studies detected genes
implicated in the development of brain circuitry in early childhood.

"Because other autism researchers have made intriguing suggestions that autism
arises from abnormal connections among brain cells during early development,
it is very compelling to find evidence that mutations in genes involved in
brain interconnections increase a child's risk of autism," said study leader
Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at
The Children's Hospital of Philadelphia. He is on the faculty of the
University of Pennsylvania School of Medicine, as is his main collaborator,
neuroscientist Gerard D. Schellenberg, Ph.D.

"This comprehensive research opens the door to more focused investigations
into the causes of autism disorders," said Philip R. Johnson, M.D., chief
scientific officer at The Children's Hospital of Philadelphia. "It moves the
field of autism research significantly ahead, similar to the way oncology
research progressed a few decades ago with the discovery of specific genes
that give rise to cancers. Our extensive pediatric genomics program has
pinpointed particular genes and biological pathways, and this discovery
provides a starting point for translating biological knowledge into future
autism treatments." The hospital's Center for Applied Genomics, launched in
2006, is the world's largest facility dedicated to the genetic analysis of
childhood diseases.

Collaborating with researchers from more than a dozen institutions, including
members of the Autism Genome Project (AGP), Hakonarson led both studies, which
appear today in the online publication Nature.

Autism is the best known of the autism spectrum disorders (ASDs), a group of
childhood neurodevelopmental disorders that cause impairments in verbal
communication, social interaction and behavior. Currently estimated to affect
as many as one in 150 U.S. children, ASDs are known from family studies to be
strongly influenced by genetics. Previous studies have implicated several
chromosome regions harboring rare variants in raising the risk of ASDs, but
until now, research has not been consistent in identifying and replicating
common genetic variants.

One of the two studies by Hakonarson's team is the first to identify common
genetic variants associated with autism. By using highly automated genotyping
tools that scan the entire genome of thousands of individuals, the researchers
found that children with ASDs were more likely than healthy controls to have
gene variants on a particular region of chromosome 5. That region is located
between two genes, cadherin 9 (CDH9) and cadherin 10 (CDH10), which carry
codes to produce neuronal cell-adhesion molecules.

Neuronal cell-adhesion molecules are important because they affect how nerve
cells communicate with each other, thought to be an underlying problem in
ASDs. "These molecules are expressed on the cell surfaces of neurons, and they
are involved with shaping both the physical structure of the developing brain
and the functional connections among different brain regions," Hakonarson
said. "Although a particular gene variant may contribute a small risk for an
ASD in a particular individual, we estimate that the variants we discovered
may contribute to as many as 15 percent of ASD cases in a population --
typically referred to as the population -- attributed risk of the variant."

Hakonarson's team first performed genome-wide association studies on DNA from
over 3,100 subjects from 780 families of children affected with ASDs, then
performed further studies in a cohort of 1,200 affected subjects and 6,500
unaffected controls. They then replicated their results in two additional
independent cohorts. In total, they analyzed DNA from 12,834 subjects.

"Autism Speaks is pleased to have facilitated this critical research, having
provided both funding and access to thousands of DNA samples through Autism
Speaks' Autism Genome Research Exchange (AGRE)," said Geraldine Dawson, Ph.D.,
Chief Science Officer for Autism Speaks. "Access to biomaterials and clinical
data from thousands of families through the AGRE substantially expedites the
research our community seeks and needs. Our goal is to accelerate genetic
research that can ultimately lead to improved detection and medical
treatments." Dawson also is a co-author of both studies in her role as a
faculty member of the University of Washington.

Hakonarson's second study in Nature, also using genome-wide association tools,
identified copy number variations -- deletions or duplications of DNA -- that
increase a child's risk of having an ASD. Interestingly, these variants were
enriched in genes that belong to two biological pathways, one including the
same neuronal cell-adhesion molecule gene family that harbored the common
variant reported in Hakonarson's first study. The other gene cluster impacted
by copy number variations belongs to the ubiquitin degradation pathway.
Ubiquitins are a class of enzymes that eliminate connections among nerve
cells, and are involved with processing and degrading neuronal cell-adhesion
molecules --
thus linking the two gene pathways together.

"The copy number variations we discovered are active on two gene networks that
play critical roles in the development of neuronal connectivity within the
central nervous system," said Hakonarson. "Finding genes that are biologically
relevant to these neuronal systems increases our understanding of how autism
originates."

The gene discoveries, added Hakonarson, converge with evidence from functional
magnetic resonance imaging that children with ASDs may have reduced
connectivity among neural cells, and with anatomy studies that have found
abnormal development of the brain's frontal lobes in patients with autism.

"Many of the genes we identified concentrate their effects in brain regions
that develop abnormally in autistic children," said Hakonarson. "Our current
findings, when coupled with anatomical and imaging studies, may suggest that
ASDs are a problem of neuronal disconnection."

His group's ongoing research, continued Hakonarson, focuses on investigating
the exact mechanisms by which these genetic variations cause autistic
disorders. "For instance, we expect to manipulate similar cell-adhesion genes
in mice to see if the animals show altered social behaviors that may
correspond to human behaviors." In addition, other genes remain to be
discovered.

"Although we cannot immediately apply this research to clinical treatments,
these findings increase our understanding of how autism spectrum disorders
arise, and may in time foster the development of strategies for prevention and
early treatment," said developmental pediatrician Susan E. Levy, M.D., a
co-author of both studies who is the medical director of the Regional Autism
Center and a member of the Center for Autism Research (CAR), both at
Children's Hospital.

Support for both studies was provided by The Children's Hospital of
Philadelphia, the National Institutes of Health, Autism Speaks, and many other
sources, including the Margaret Q. Landenberger Foundation, the Cotswold
Foundation, the Beatrice and Stanley A. Seaver Foundation, the Department of
Veterans Affairs, and the Utah Autism Foundation. Scientists from 14 other
centers in addition to Children's Hospital and the University of Pennsylvania
contributed to the discovery or replication of the findings.

Wang et al, "Common genetic variants on 5p14.1 associate with autism spectrum
disorders," Nature, published online April 28, 2009.
(http://dx.doi.org/10.1038/nature07999)

Glessner et al, "Autism genome-wide copy number variation reveals ubiquitin
and neuronal genes," Nature, published online April 28, 2009.
(http://dx.doi.org/10.1038/nature07953)

About The Children's Hospital of Philadelphia

The Children's Hospital of Philadelphia was founded in 1855 as the nation's
first pediatric hospital. Through its long-standing commitment to providing
exceptional patient care, training new generations of pediatric healthcare
professionals and pioneering major research initiatives, Children's Hospital
has fostered many discoveries that have benefited children worldwide. Its
pediatric research program is among the largest in the country, ranking second
in National Institutes of Health funding. In addition, its unique
family-centered care and public service programs have brought the 430-bed
hospital recognition as a leading advocate for children and adolescents. For
more information, visit http://www.chop.edu.

About Autism Speaks

Autism Speaks is the nation's largest autism science and advocacy
organization, dedicated to funding research into the causes, prevention,
treatments and a cure for autism; increasing awareness of autism spectrum
disorders; and advocating for the needs of individuals with autism and their
families. Autism Speaks funds more than $30 million each year in new autism
research, in addition to supporting the Autism Treatment Network, Autism
Genetic Resource Exchange, Autism Clinical Trials Network, Autism Tissue
Program and a range of other scientific and medical programs. To learn more
about Autism Speaks, please visit www.AutismSpeaks.org.

SOURCE The Children's Hospital of Philadelphia

Rachel Salis-Silverman of The Children's Hospital of Philadelphia,
+1-267-426-6063, Salis@email.chop.edu