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Studies shed light on genetic variants in ASDs.

Three large genome-wide studies partly funded by the National Institutes of Health provide the strongest evidence yet of specific genetic factors that affect the risk of autism spectrum disorders.

The findings point to the importance of genes involved in forming and maintaining brain cell connectivity.

In a statement, acting NIH Director Raynard S. Kington said the findings "establish that genetic factors play a strong role in autism spectrum disorder. Detailed analyses of the genes and how they affect brain development is likely to yield better strategies for diagnosing and treating children with autism."

In the largest of the studies, published online April 28 in Nature, a team of researchers led by Dr. Hakon Hakonarson of the Center for Applied Genomics at Children's Hospital of Philadelphia carried out a genome-wide association study on a cohort of 780 families (3,101 subjects) with children affected by autism spectrum disorders (ASDs), and a second cohort of 1,204 affected subjects and 6,491 control subjects. All cases studied were of European ancestry (Nature 2009 April 28 [doi:10.1038/nature/07999]).

The researchers identified six single-nucleotide polymorphisms (SNPs) that had a strong association with cases of ASDs, especially rs4307059. The others were rs7704909, rs12518194, rs4327572, rs1896731, and rs10038113. The SNPs were located in chromosome 5 (5p14.1) between cadherin 10 (CDH10) and cadherin 9 (CDH9), two genes that encode neuronal cell-adhesion molecules. Replication studies in two independent cohorts confirmed the association.

That study is the most comprehensive of its kind to date.

In a second study, also published online April 28 in Nature, the same team of researchers (this time led by Dr. Hakonarson and Dr. Gerard D. Schellenberg, of the department of pathology and laboratory medicine at the University of Pennsylvania, Philadelphia) conducted a whole-genome copy number variations study on a cohort of 859 cases of ASD and 1,409 healthy children of European ancestry (Nature 2009 April 28 [doi:10.1038/nature/07953]).

Genes involved in neuronal cell adhesion (including NRXN1, CNTN4, NLGN1, ASTN2) were enriched with copy number variation in ASD cases, compared with controls, as were genes involved in ubiquitin degradation (including UBE3A, PARK2, RFWD2, and FBXO40).

Neuronal cell adhesion molecules "are critical in the development of the nervous system, contributing to axonal guidance, synaptic formation and plasticity, and neuronal-glial interactions," the researchers explained, while the ubiquitin-proteasome system "operates pre- and post-synaptic compartments, regulating synaptic attributes, including transmitter release, synaptic vesicle recycling in pre-synaptic terminals, and dynamic changes in dendritic spines and the post-synaptic density.

In a third study, Margaret A. Pericak-Vance, Ph.D., of The Miami Institute for Human Genomics at the University of Miami, in collaboration with Jonathan L. Haines, Ph.D., of the Center for Human Genetics Research at Vanderbilt University Medical Center, Nashville, Tenn., conducted an independent search for small genetic variations associated with ADS.

Reporting online April 28 in the Annals of Human Genetics, the duo confirmed that ASD is strongly associated with genetic variations near CDH9 and CDH10.

"We are starting to see genetic pathways in ASD that make sense," Dr. Pericak-Vance said in a statement.
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Author:Brunk, Doug
Publication:Clinical Psychiatry News
Date:May 1, 2009
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