Genetic factors contributing to autism

Genetics is a complicated field. Applying that to a complicated developmental disorder such as ASD, can be overwhelming for most people. In this post, I will try to explain some of the theories about how genetics is contributing to ASD. This is based on the recent publication by Berg and Geschwind in Genome Biology (here). Importantly, however, this approach does not consider the contribution of environmental effects, for which there is sufficient evidence in ASD and other diseases.

To begin with, our DNA is individual, but not so different that it can't be traced to our parents and grandparents. DNA changes that occur during conception of an individual are called variants. When you look across the DNA of hundreds and thousands of people there are common variants (shared by at least 5% of people) and rare variants. These variants may cause disease, or have no effect. Studies investigating the DNA of thousands of people, including hundreds of individuals with ASD have been undertaken. Given that ASD is relatively common (~1%) it could be expected that common variants are responsible for ASD. However, the results reveal that, apart from a handfull of common variants, ASD is not associated with common variants. Given that ASD remains unexplained by common variants, researchers thought that maybe rare variants might explain the remainder of ASD cases. But, like common variants, rare variants were insufficient to explain most cases of ASD. Rare variants including whole deletions of DNA or duplications of DNA do increase the risk of ASD, but not guarantee it.

But what if there was a combination of common and rare variants, that when coming together in the same person, caused ASD. And it is more or less this point of understanding that ASD researchers have reached. To add another layer of complexity to this, rare DNA variants can have a large, medium or small effect on an individual. The size of this effect depends on the function of the DNA where the variant is occurring. 

To summarise the genetic possibilities that can account for ASD, I have listed them below (paraphrased from the Genome Biology article).

1. A few common variants may mean you develop ASD-like traits. Many common variants means you develop ASD.

2. A few common variants plus one medium-large rare variant may mean you develop ASD-like traits. But, many common variants plus one medium-large rare variant means you develop ASD.

3. A few common variants plus one medium-large rare variant may mean you develop ASD-like traits. But, many common variants plus one medium-large rare variant and/or many small rare variants means you develop ASD.

4. One small rare variant may mean you develop ASD-like traits. But many small rare variants means you develop ASD.

5. One large rare variant means you develop ASD.

From the evidence, it appears that theories 2-4 are likely, but not 1 or 5.

Theories 2-4 help explain why one child might have ASD, but the brother or sister does not. They also help explain why a child with a variant has ASD, but the parent with the same variant does not have ASD (they will have additional variants that effect the individual differently).

This synopsis of genetics portrays variants as disease causing, or predisposing to disease. But some variants may inadvertantly act in a healthy way by counter-acting disease causing variants. This of course means that the possbilities above are slightly simplistic.

Based on the information above, it is also important to understand that current DNA testing available to the public is unlikely to explain why an individual has ASD. It will only reveal if there is a large rare variant. And from the information above, we know that a large rare variant alone may only be a part of the cause.

Randal