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New Studies Reveal Autism Risk Factors, First Common Gene Variants

May 1, 2009 — New research shows that autism rates are higher for
children who are firstborn or breech or whose mothers are 35 years old
or older when they give birth. Further, 2 new genetics studies identify
genetic abnormalities that affect 2 pathways involved in the formation
of brain-cell connections.

Deborah A. Bilder, MD, and colleagues from the University of Utah
School of Medicine, in Salt Lake City, found that having a child with
autism-spectrum disorder (ASD) is 1.7 times more likely for mothers who
give birth at 35 years or older compared with their women aged 20 to 34
years and 1.8 times more likely in the firstborn child. In addition,
ASD children were more than twice as likely to have been a breech
presentation.

"The findings of this study suggest that maternal age, parity, and
breech presentation are independently associated with ASD risk.
Additional investigations focused on both genetic and environmental
factors that link these factors individually or collectively are
necessary," the investigators write.

The study is published online April 27 in Pediatrics.

Results Warrant Careful Interpretation

Robert L. Hendren, DO, president of the American Academy of Child
and Adolescent Psychiatry and an advisor to the Autism Society of
America, told Medscape Psychiatry that clinicians should be
prepared to reassure patients who might overinterpret the results of
this study, despite the authors' careful presentation.

"Patients need to understand that association is not necessarily
cause and effect," Dr. Hendren said. "Taken in conjunction with an
earlier study that linked older fathers to increased ASD risk, this
study suggests that there is some vulnerability factor associated with
having older parents, but we have no idea what that might be. And older
potential mothers certainly do not need to avoid having children
because they are worried about this possible risk," said Dr. Hendren,
who is also executive director of the MIND Institute and chief of child
and adolescent psychiatry at the University of California, Davis.

Dr. Bilder and colleagues examined the birth records of Utah
children identified with ASD in a 2002 epidemiological study by the US
Centers for Disease Control and Prevention. The study included
8-year-old children in Utah's 3 most populous counties. The researchers
compared birth records for children identified with ASD with unaffected
counterparts.

The study suggests that more ASD children might be firstborns
because parents might be reluctant to have a second child if the first
is diagnosed with ASD. Maternal age might increase risk due to gene
changes that accumulate with time. Breech presentation and ASD might be
linked by ASD-related neuromuscular dysfunction.

Common Genetic Variants Found

Two genomewide association studies from research teams led by Hakon
Hakonarson, MD, PhD, director of the Center for Applied Genomics at the
Children's Hospital of Philadelphia, in Pennsylvania, have identified
new gene abnormalities that affect cell-to-cell adhesion and the
formation and maintenance of neuronal connectivity. Both studies were
reported online April 28 in Nature.

One study pinpoints a gene region that may account for up to 15% of
autism cases, while another identifies missing or duplicated stretches
of DNA along 2 crucial gene pathways. Both studies detected genes
implicated in the development of brain circuitry in early childhood.

"The genetic landscape in autism currently includes only a few
candidate genes/loci with rare variants (copy number changes). This
discovery shows for the first time that a common variant, present in
65% of children with autism, exists in autism. It unveils a biological
pathway involved with neuronal connectivity that we will be able to
target in the future for new therapy," Dr. Hakonarson told Medscape Psychiatry.

"The diagnostic value of this will become more meaningful as we find
more common variants, but if all variants that have been identified
today — common and rare — are put together, we can make meaningful
predictions for families who are at high risk," said Dr. Hakonarson.

"It is very interesting that the only genes that came up as
significant and replicated in independent cohorts belong to 2 gene
networks (neuronal cell-adhesion molecules and ubiquitin gene family)
that are involved with developing and shaping neuronal connections and
communications between brain cells," he added.

The researchers used genomewide analysis in over 10,000 individuals
to determine that children with ASD were more likely than healthy
controls to have gene variants on a particular region of chromosome 5
located between 2 genes, cadherin 9 (CDH9) and cadherin 10 (CDH10), which carry codes to produce neuronal cell-adhesion molecules.

Genetic Treatment a Long Way Off

In the second study, they identified copy number variations (CNVs)
that increase a child's risk of having ASD. These variants were
enriched in genes that belong to 2 biological pathways, 1 including the
same neuronal cell-adhesion molecule gene family that harbored the
common variant reported in Hakonarson's first study.

The other gene cluster affected by CNVs belongs to the ubiquitin
degradation pathway, a class of enzymes that eliminate connections
among nerve cells and are involved with processing and degrading
neuronal cell-adhesion molecules — thus linking the 2 gene pathways.

"The copy number variations we discovered are active on 2 gene
networks that play critical roles in the development of neuronal
connectivity within the central nervous system," Dr. Hakonarson said.
"Finding genes that are biologically relevant to these neuronal systems
increases our understanding of how autism originates."

Dr. Hendren told Medscape Psychiatry that the
Hakonarson data add weight to prior imaging studies that suggested that
ASD is the result of generalized connectivity dysfunctions, not just of
problems in 1 brain area.

"The hope is that we might be able to find ways to improve or
protect that connectivity," Dr. Hendren said. "We are not likely to be
doing gene engineering to treat autism, but we might be able to modify
factors that govern gene expression. Such treatments will require a lot
more work on the genetic factors, environmental factors, and epigenetic
factors that connect those 2 areas. New treatments are not right around
the corner."

Dr. Bilder discloses serving as a consultant to BioMarin's autism advisory board.

Pediatrics. Published online April 27, 2009.

Nature. Published online April 28, 2009.

LINK: http://www.medscape.com/viewarticle/702213