The genetic influence on autism is complex, with research suggesting that a combination of genes work together to render an individual susceptible. One way to address this complexity is for researchers to investigate a large collection of families with affected individuals in order to understand which genes likely contribute to autism risk.
In order to better describe the genetic influences in autism spectrum disorder, in 2004 Autism Speaks provided support to the Autism Genome Project. This project brought together 170 of the world's leading researchers to collaborate and build the largest dataset of DNA from families affected by autism. The researchers, who represented over 50 institutions worldwide, assembled a database of over 1400 families, 1168 of which contained at least two members affected with autism. This set represents a much greater sample size than has ever been studied previously.
Combining the expertise of these researchers, this project is the largest collaboration in the world to study the genetics of autism. Together, they used standardized cutting-edge and state-of-the-art technologies to detect the genes which are associated with this disorder, and then pooled their results across sites so that meaningful conclusions could be made. (Learn more about results from the first phase of the project).
The methods used by the AGP involved studying both the entire genome (all 23 pairs of chromosomes) as well as regions of interest within these chromosomes. A chromosome is an organized set of DNA which contains the genetic code of an individual. Each person has different DNA sequence and corresponding gene function and protein expression in the brain. Different DNA codes are part of what makes each of us different.
The investigators searched for clues in the pooled genetic database using a variety of techniques and by conducting linkage analysis. Linkage analysis is a technique that helps identify where genes are located in the human genome. It refers to the tendency of genetic markers, which are segments of DNA inherited from a person's parents, including those that may be associated with diseases, to be located together on a chromosome.
In this study, linkage analysis of individuals affected with autism yielded many areas of interest, including chromosome 11, specifically region 11p12-p13. Therefore, it is likely that these chromosomal regions harbor autism susceptibility genes.
Another way to address the genetic complexity of autism and to further define and describe genetic mutations is examination of copy number variations, or CNVs. CNVs are submicroscopic duplication, deletions, or rearrangements of genetic materials in the DNA. They can vary in length and position on the chromosome. Therefore, the presence of copy number variations in the DNA sequence has the potential to disrupt gene function and contribute to the disorder. Examination of copy number variation is sometimes missed in surveys or experiments of the genetic determinants of disease and the contribution of CNV's to some diseases is yet unknown.
The CNV analysis allowed researchers to make additional observations relevant to the genetics of autism. While some of the CNV's found were not related to autism spectrum disorder, others were found in siblings with autism spectrum disorder. Many of these specific copy number variations occurred in the same area of the chromosome. In addition, several of these CNVs were increased copy numbers located in chromosome 15 and were maternally inherited. While they add to the complexity of the data, these specific CNVs are enormously helpful in determining the nature of the genetic influence of autism.
As an example, a de novo CNV, that is a variation that wasn't transmitted by either parent, was found on a region of chromosome 2 called “2p16” in a pair of affected siblings. This CNV was a deletion in the gene that codes for a protein called neurexin or NRXN1. NRXN1 interacts with neuroligins, a class of cell adhesion molecules, or proteins which control how brain cells connect with each other. This neurexin-neuroligin interaction is important because this relationship guides axon signaling and mapping. That is, this interaction helps direct neurons to their proper target during development, and forms specific signaling pathways in the brain.
Changes in the expression of neuroligin have been previously associated with an increased risk of ASD and mental retardation. Moreover, the neurexin-neuroligin link is important for the functioning of synapses which control the release of a neurotransmitter called glutamate. Many scientists theorize aberrant glutamate function is involved in ASD.
Of the 168 genes involved in glutamate synthesis and functioning, several fall within linkage regions found in this study. Two in particular, SCL1A1, which maps to 9p24.2, and SCL1A2, which maps to 11q13-12, are especially promising candidates for future study.
The innovative combination of linkage and CNV analyses on the largest-ever collected cohort of families affected with autism offers new avenues of research to identify the genetic components of ASD. This research finding supports the influence of genetics on autism spectrum disorders and lays the foundation for later studies which will investigate the role of the environment with this genetic susceptibility. It also advances the possibility of biological diagnosis and of improved treatments targeted at specific symptoms.