Autism, researchers agree, is caused by a mix of genetic and environmental factors. At this point, however, consensus dissolves. Views differ, sometimes dramatically, over the degrees of risk that should be associated with specific factors—and how multiple factors should be added together to better account for how autism occurs.

A key challenge has been harmonizing the different kinds of studies that have been conducted, particular the different kinds of genetic studies, some of which have focused on rare variants, some of which have focused on common variants. Differences in methods and statistical models have resulted in sometimes wildly discrepant estimates of autism’s heritability—ranging from 17 to 50%.

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 make it difficult to detect these effects and to estimate the relative influence of such common, rare inherited, and rare spontaneous variation. These limitations, however, have been overcome in large measure by a recent study, the Population-Based Autism Genetics and Environmental Study (PAGES).

PAGES was made possible by Sweden’s universal health registry, which allowed investigators to compare 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.

After sifting through the data, the PAGES researchers arrived at the following conclusions about autism's genetic architecture: “Its narrow-sense heritability is about 52.4%, with most due to common variation, and rare de novo mutations contribute substantially to individual liability, yet their contribution to variance in liability, 2.6%, is modest compared to that for heritable variation.”

These findings appeared July 20 in Nature Genetics, in a paper entitled, “Most genetic risk for autism resides with common variation.” Essentially, the PAGES team found that heritability outweighs other risk factors. Moreover, they determined that most of the genetic risk for autism comes from versions of genes that are common in the population rather than from rare variants or spontaneous glitches.

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,” explained Joseph Buxbaum, Ph.D., of the Icahn School of Medicine at Mount Sinai and one of the PAGES study’s authors. “The family may have common variation that puts it at risk, but if there is also a de novo 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.”

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