Genetic linkage analysis of families with autism appears to strengthen the
case for a strong link to one gene and weaker links to several others.
And while a complete understanding of the genetic underpinnings of
autism—such as might provide the means for predictive testing—is
still at least several years away, the new findings will more immediately aid
in advancing an understanding of the pathophysiology of the disorder.
So say the authors of a report titled "Evidence for Multiple Loci
From a Genome Scan of Autism Kindreds," which appeared in the August 1
advance online edition of Molecular Psychiatry.
"We really need to understand autism at a cellular and molecular
level," lead author Gerard Schellenberg, Ph.D., told Psychiatric
News. "Today we are only grasping at straws. But if we find some of
the genes involved, then we know where we can start looking for the molecular
and cellular pathways. That's really the payoff from these
He is associate director for research at the Geriatric Research Education
and Clinical Center at the Veterans Affairs Puget Sound Health Care System,
Schellenberg said the analysis found strong evidence for genetic linkage to
autism on chromosome 7q, at a location that coincides with that found in
several other studies. The robustness of the finding and its confirmation by
other linkage analyses lends strong credibility to the hypothesis that 7q is
involved in the disorder.
But the study also identified several other genes with weaker but still
important links to the disease, and Schellenberg emphasized that the study
confirms once more that autism—like other neuropsychiatric and mental
disorders—is complex, involving multiple genes.
Moreover, the study findings suggest that autism may be several genetic
diseases with different genes that may be specific to autism as it appears
differentially in boys and girls, in late- and early-onset autism, and in the
different behavioral domains of autism.
For instance, Schellenberg and colleagues used measures of language
acquisition—the age at which a child with autism first spoke a word or a
phrase—and then identified a gene location on chromosome 9 that appears
to be at least weakly identified with this particular behavioral domain. (The
three domains of autism are failure to connect socially, delayed language
acquisition, and repetitive stereotypic interactions.)
"Within those three domains are subdomains that can be further
divided out," Schellenberg said. "One of our ideas is that there
are different genes that contribute to different domains. You put all those
domains together and the genes together, and you have autism."
Similarly, when the sample of families was stratified into those with only
males having autism, analysis suggested a link to chromosome 11. Families
having only females with autism were linked to chromosome 4.
These findings suggest the possibility that there is a gender-specific form
of autism that has a unique constellation of genes. "They probably
overlap in terms of what complement of genes is necessary," Schellenberg
said. "The same three or four may be necessary, plus one that is
specific to gender."
The same differential genetics were found when the researchers scanned
families with late-onset and early-onset autism. Modest links were found
between "regression" autism—in which a child may acquire
normal language by age 3 but regress thereafter—and chromosome 10; more
significant links were found between the early-onset form of the disorder and
"We think there may be some of the same genes involved in both
types," Schellenberg said. Nonetheless, "there may be some that
are specific to regression."
In the study genome-wide scans were performed on 222 families who
identified themselves as having two or more children with autism, pervasive
developmental disorder, or autistic spectrum disorder.
The families were recruited through five institutions (the University of
Washington, the University of Pittsburgh, the University of California at
Irvine, the University of Rochester, and the University of Utah), and
diagnosis was based on the National Institute of Child Health and Development
Collaborative Programs of Excellence in Autism diagnostic criteria.
Schellenberg expressed optimism about the advancing understanding of autism
and the role of genetics.
"I think genetics are so important for getting at the underlying
cause," he said. "And if there is going to be a pharmacologic
treatment, you need a molecular target. If you know the molecular pathway of
the disorder, you have a much better chance of designing a drug that will be
An abstract of "Evidence for Multiple Loci From a Genome Scan
of Autism Kindreds" is posted online at<www.nature.com/mp/journal/vaop/ncurrent/abs/4001874a.html>.▪