Autism research has hit a breakthrough point equivalent to the one that revolutionised the understanding and treatment of cancer 30 years ago, it has been claimed.
Three major studies have for the first time pinpointed genetic mechanisms underlying autistic disorders, including ones which are relatively common.
Scientists believe the findings could mark as big a transformation in tackling autism as occurred when researchers began to unravel the genetic causes of cancer.
Autism covers a group of conditions known as autism spectrum disorders (ASDs) which affect about one in 150 mostly male children.
They are marked by an impaired ability to communicate and interact socially, narrowly focused attention, and repetitive behaviour.
A complex genetic jigsaw is believed to underpin autism, but identifying the pieces has proved difficult.
Although a number of genetic variants have previously been implicated in ASDs, the connections have not been clear.
The new research, which involved screening the DNA of many thousands of volunteers, may at last have lifted the lid on the causes of autism, scientists believe.
It suggests that proteins called cell adhesion molecules, which play a vital role in shaping brain “wiring” and the way nerve cells communicate, play a key role in autism disorders.
New treatments could now be developed that target these proteins or the genes that provide the instructions for making them.
Two of the new studies were American-led and reported yesterday in an early online edition of the journal 'Nature'. The third was conducted by British scientists at Oxford University and appears in the journal 'Molecular Psychiatry'.
The largest investigation, conducted in the US, involved analysing the DNA of almost 13,000 people including many from families affected by autism.
Comparing the entire genetic code of these different individuals enabled scientists to focus on a “hotspot” on chromosome five – one of the coiled up “packets” of DNA within the nuclei of cells that contain the genes.
Children with autism were significantly more likely than their healthy counterparts to have variations in the genetic code in this chromosomal region.
The hotspot is located between two genes, CDH9 and CDH10, that code for neuronal cell adhesion molecules.
Study leader Dr Hakon Hakonarson, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia, said: “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.
“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% of ASD cases in a population typically referred to as the population-attributed risk of the variant.”
Part of the new research involved looking at the activity of CDH10 in the foetal brain. Scientists from the University of California at Los Angeles found that it was most active in key regions of the brain that support language, speech and interpreting social behaviour.
The second US study, also led by Dr Hakonarson, identified deletions or duplications or DNA known as “copy number variations” that increase a child’s risk of autism.
These abnormalities mostly affected two biological pathways that again implicated cell adhesion molecules. One directly involved genes for the molecules, and the other a class of enzymes called “ubiquitins” that erase connections between nerve cells. Ubiquitins play a role in processing and degrading neuronal cell adhesion molecules.
The discoveries resonated with brain scan and anatomy studies showing that the frontal lobes of the brains of autistic children were abnormally developed, Dr Hakonarson said.
Dr Philip Johnson, chief scientific officer at The Children’s Hospital of Philadelphia, said: “This comprehensive research opens the door to more focused investigations into the causes of autism disorders.
“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.”
Dr Margaret Pericak-Vance, director of the Miami Institute for Human Genomics, who also took part in the US research, said: “Until now, no common genetic variant has been identified with such overwhelming evidence to support its role in autism spectrum disorders. The identification of a common variant for autism is a monumental achievement. Researchers have been looking for clues about the genetic architecture of autism for decades. Many thought that this day would never come, but we persisted.”
The British scientists, who analysed the DNA of more than 500 people, looked for single-letter changes in the genetic code in two particular chromosomes as well as copy number variations.
They pinpointed a gene on chromosome 7 called DOCK4 that appeared to be significantly associated with autism. The gene is thought to be involved in the growth of dendrites, brain cell extensions that form nerve connections.
Study leader Professor Tony Monaco, from the Wellcome Trust Centre for Human Genetics at Oxford, said: “Most of the genes that have been identified in these studies are involved in the connections between neurons called synapses. This does seem to fit with what we know from brain scans – that people with autism may show different or reduced connectivity between different parts of the brain.
“This new knowledge allows us to focus our studies on developing new treatments and intervention therapies for the future.”