Better balance found for DNA's role in autism
Nearly 60 per cent of the risk of developing autism is genetic and most of that risk is caused by common, inherited variant genes that are in individuals without the disorder, according to a new study.
Researchers from the US say in a study published by Nature Genetics that the common variants account for more of the risk than many had assumed.
"We show very clearly that inherited common variants comprise the bulk of the risk that sets up susceptibility to autism... but while families can be genetically loaded for autism risk, it may take additional rare genetic factors to actually produce the disorder in a particular family member,” says Dr Joseph Buxbaum, the study's lead investigator.
Dr. Buxbaum and colleagues conducted a rigorous analysis of DNA sequence variations from an ongoing study of autism in Sweden.
Although autism is thought to be caused by the interplay of genetic and other factors, there has been no consensus on how much each factor contributes, and the nature of its genetic architecture.
Recently, evidence has been mounting that genomes of people with autism are prone to harbouring de novo mutations - rare, spontaneous mutations that exert strong effects and can largely account for particular cases of the disorder.
Specifically, the current study found that about 52.4 percent of autism was traced to common and rare inherited variations, with spontaneous mutations contributing a modest 2.6 percent of the total risk.
“Many people have been focusing on de novo mutations, such as the ones that can occur in the sperm of an older father,” explains Dr. Buxbaum.
“While we find these mutations are also key contributors, it is important to know that there is underlying risk in the family genetic architecture itself.”
The study was made possible by Sweden's universal health registry, which allowed investigators to compare very large samples (about 3000 in the current study) of people with autism with matched controls.
Researchers employed new statistical methods to more reliably sort out the heritability of the disorder. In addition, they were able to compare their results with a parallel family-based study in the Swedish population, which took into account data from twins, cousins and factors such as age of the father at birth and parents' psychiatric history.
Now that the genetic architecture is better understood, the researchers are identifying specific genetic risk factors detected in the sample, such as deletions and duplications in genetic material and spontaneous mutations.
Even though spontaneous mutations accounted for only a small fraction of autism risk, the potentially large effects of these glitches makes them important clues to understanding the molecular underpinnings of the disorder, say the researchers.
“Within a given family, a de novo mutation could be a critical determinant that leads to the manifestation of autism spectrum disorder in a particular family member,” says Dr. Buxbaum.
“If the family has a common variation that puts it at risk, an added de novo mutation could push an individual over the edge and result in that person developing the disorder.”