New Autism Risk Factors?

New Studies Reveal Autism Risk Factors, First Common Gene Variants

by Janis Kelly

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. Abstract

http://www.medscape.com/viewarticle/702213?sssdmh=dm1.465854&src=nldne