Autism and genes, more compelling evidence of links

Autism and genes, more compelling evidence of links

Three new genome-wide association studies bring together the most compelling evidence to date that genes and autism are linked. The studies scanned and compared the entire set of human DNA of people who have an autism spectrum disorder (ASD) with that of people who do not and found small genetic differences that affect the way brain cells link up to make the circuitry of a child's brain. The largest study looked at the DNA of over 10,000 people.

Two of the studies are published online in Nature on 3 May and the other is published in Annals of Human Genetics, also online on 3 May.

In the first and largest study, published in Nature, Dr Hakon Hakonarson, 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, and colleagues found several genetic variants located between genes CDH9 and CDH10 on chromosome 5, and a group of another 30 genes that do a similar job, were linked to ASD. What all these genes have in common is that they control the production of cell adhesion proteins that help brain cells connect to each other properly.

In the second study, published in Annals of Human Genetics, Dr Margaret Pericak-Vance, a professor at the University of Miami Miller School of Medicine and director of the Miami Institute for Human Genomics, and Dr Jonathan Haines, of Vanderbilt University Medical Center in Nashville, did a separate DNA search and found a striking confirmation that ASD is significantly linked to small variations near CDH9 and CDH10. Pericak-Vance was also involved in the Hakonarson study.

And in the third study, published in Nature, Hakonarson and a colleague who was a principal investigator in the larger study, Dr Gerard D Schellenberg, also a professor at the University of Pennsylvania School of Medicine, led another DNA search for genes that were duplicated or deleted in individuals with ASD. Again they found that in the very rare cases where this occurred, many of the finds involved genes that code for cell adhesion proteins, while others affected mostly genes that influence the turnover of adhesion proteins at the cell surface via a system called ubiquitin-proteasome which affects how cellular waste is disposed of.

Hakonarson said there are probably many genes involved in the development of autism.

"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 disease," he added.

Studies of children with ASD, including twins, and their relatives, show there is a strong genetic component to the development of this complex group of disorders. And apart from a very few small studies, few genetic risk factors have actually been identified, and those that have tend to be rare, and give little information about risks for ASD in the general population, which is thought to affect about 1 in every 150 children in the US.

But these three new genome-wide studies, by scanning the whole of the DNA of very large numbers of people with and without ASD now help to put some of the complex pieces of the puzzle together. And one of those pieces now shows that genetic differences in how cells in the brain link together could influence susceptibility to ASD on a large scale.

As Pericak-Vance said:

"We are starting to see genetic pathways in ASD that make sense."

Hakonarson and colleagues now plan to do a more extensive genome-wide association study to find more pieces of the complex ASD genetics puzzle.

The studies were part funded by the US National Institutes of Health (NIH).

"Common Genetic Variants on 5p14.1 Associate with Autism Spectrum Disorder."

Wang K et al.

Nature, published online May 3, 2009.

"Autism Genome-Wide Copy Number Variation Reveals Ubiquitin and Neuronal Genes."

Glessner JT et al.

Nature, published online May 3, 2009.

"A Genome-Wide Association Study of Autism Reveals a Common Novel Risk Locus at 5p14.1."

Ma D et al.

Annals of Human Genetics, published online May 3, 2009.

-- Nature

-- Annals of Human Genetics

Additional sources: NIH/National Institute of Neurological Disorders and Stroke.

In autism, genes drive eye gaze abnormalities (Video Medical And Professional 2020).

Section Issues On Medicine: Psychiatry