Genes that are common in the population may account for most genetic risk for autism rather than rare variants or spontaneous glitches, according to a recent study.
Researchers found that nearly 52 percent of the risk for autism was traced to common and rare inherited variation, with spontaneous mutations contributing a modest 2.6 percent of the total risk.
"Genetic variation likely accounts for roughly 60 percent of the liability for autism, with common variants comprising the bulk of its genetic architecture," researcher Joseph Buxbaum of the Icahn School of Medicine at Mount Sinai (ISMMS) said in a statement. "Although each exerts just a tiny effect individually, these common variations in the genetic code add up to substantial impact, taken together."
Although autism is thought to be caused by an interplay of genetic and other factors, including environmental, consensus on their relative contributions and the outlines of its genetic architecture has remained elusive. Recently, evidence has been mounting that genomes of people with autism are prone to harboring rare mutations, often spontaneous, that exert strong effects and can largely account for particular cases of disease.
More challenging is to gauge the collective impact on autism risk of numerous variations in the genetic code shared by most people, which are individually much subtler in effect. Limitations of sample size and composition made it difficult to detect these effects and to estimate the relative influence of such common, rare inherited, and rare spontaneous variation.
For the study, researchers compared a very large sample of about 3,000 people with autism with matched controls. Researchers also brought to bear new statistical methods that allowed them to more reliably sort out the heritability of the disorder. In addition, they were able to compare their results with a parallel study in 1.6 million Swedish families, which took into account data from twins and cousins, and factors like age of the father at birth and parents' psychiatric history. A best-fit statistical model took form, based mostly on combined effects of multiple genes and non-shared environmental factors.
"This is a different kind of analysis than employed in previous studies," Thomas Lehner, chief of NIMH's Genomics Research Branch, said in a statement. "Data from genome-wide association studies was used to identify a genetic model instead of focusing just on pinpointing genetic risk factors. The researchers were able to pick from all of the cases of illness within a population-based registry."
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 of genetic material and spontaneous mutations. Even though such rare 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, the mutations could be a critical determinant that leads to the manifestation of ASD in a particular family member," Buxbaum said. "The family may have common variation that puts it at risk, but if there is also a de novo [spontaneous} mutation on top of that, it could push an individual over the edge. So for many families, the interplay between common and spontaneous genetic factors could be the underlying genetic architecture of the disorder."
The findings were recently published in the journal Nature Genetics.
