autismSmall differences in as many as a 1,000 genes contribute to the risk of an autism spectrum disorder (ASD), according to a US study. 

The study, led by Mount Sinai researchers and the Autism Sequencing Consortium (ASC), and published in the journal Nature, examined data on several types of rare, genetic differences in more than 14,000 DNA samples from parents, children with autism, and unrelated individuals to dramatically expand the list of genes identified with ASD.

Most of the genes that contribute to autism remain unknown, but the study increases the number of definitive autism genes almost fourfold to 33, compared to the 9 genes most closely tied to risk in recent years by similar studies. It also identified more than 70 additional, likely ASD genes. Each of these genes is mutated in more than 5% of individuals with autism, signifying a large, relative contribution to risk for a complex genetic disease.

By casting a wider net, a research team from 37 institutions found that previously unsuspected sets of genes may be involved in ASD risk, including some that control how nerve networks form in the brain. 

For the first time, the study authors were able to assess the effects of both inherited genetic differences and those that happen spontaneously in the sperm and eggs that go on to form human embryos. While small, rare genetic differences in the top 107 genes were found to confer a relatively large jump in a person’s risk, many more changes in other genes add smaller amounts of risk. According to the authors, the interplay between gene variations, both common and rare, holds the key to understanding autism. Along these lines, the team, by looking at how many times variations occurred in each of the 107 genes, was able to predict that small differences in about 1,000 genes will eventually be found to increase autism risk.

“The steps we added to our analysis over past studies provide the most complete theoretical picture to date of how many genetic changes pile up to affect the brains of children with autism,” said Joseph D. Buxbaum, professor of psychiatry, neuroscience and genetics and genomic cciences at the Icahn School of Medicine at Mount Sinai and director of the Seaver Autism Center, and senior author of the study. “Beyond autism, we think this work will yield insights into what makes us social beings.

“While we have very strong findings in these genetic analyses, newfound genetic discoveries must next be moved into molecular, cell and animal studies to realize future benefits for families. A study like this creates an industry for years to come, with labs worldwide checking the brain changes linked to each new genetic finding, and searching for drugs to counter them.”

New gene links

One group of genes newly linked to autism, for instance, codes for an enzyme that regulates histones by attaching or removing methyl groups to one of their building blocks, lysine amino acids. By doing so, the enzyme influences when specific genes are turned on or off, and the study results support the theory that such mechanisms may be altered in autism, such that developing brain cells may not mature, divide, or migrate the same way.  

Other variations linked to autism by the study were in genes that govern synapses, the spaces between nerve cells in pathways that ‘decide’ whether signals travel onward. Nerve cells must be able to execute well-timed manoeuvres, such as allowing charged particles to build up or rush out of them, to pass on nerve signals normally. A third set of genes linked to risk by the study regulate basic steps that turn genes into proteins. For a protein to be built based on genetic code, the code must be translated into related molecules (transcription) and cut up and rebuilt (spliced) into the core instructions for protein building.

The study results also revolve around genetic mutations. Changes occur in our genetic code at a steady rate thanks to the error-prone processes that copy the code and other factors, and despite mechanisms bent on weeding out faulty code. Part of evolution, changes in the order of the ‘letters’ (base pairs) making up the instructions encoded in DNA are called mutations, with some inherited and others occurring when the egg or sperm are formed (de novo mutations).

Past studies looking at genetic autism risk focused only on de novo mutations that caused any key protein to stop working (loss-of-function mutations). The current study looked at both inherited and de novo loss-of-function mutations, along with de novo ‘missense’ mutations in affected children and their parents. Where loss-of-function mutations are blunt, causing the resultant protein to stop working, missense mutations may make a protein work slightly less well. Being more common and subtle, they are harder to spot, but the current study shows that they make a sizeable contribution to ASD risk.