UM’s John P. Hussman Institute for Human Genomics (HIHG) is part of the AGP, an international autism genetics research consortium co-funded by Autism Speaks, the world’s largest autism science and advocacy organization, and an international public-private partnership.
“By pooling our resources with other institutions, we are able to find these genetic changes,” said Margaret Pericak-Vance, Ph.D., director of the HIHG. “These findings could eventually lead not only to more accurate diagnosis, but treatment for people with autism spectrum disorders. Without collaborating, we wouldn’t have achieved these findings.”
The HIHG’s research was led by Pericak-Vance and conducted by Michael L. Cuccaro, Ph.D., Susan Folstein, M.D., and John Gilbert, Ph.D. The HIHG researchers genotyped patients and analyzed data, which was pooled with data from the other institutions for the study.
Based on analysis of high-density genotyping data collected from 1,000 individuals with autism spectrum disorder (ASD) and 1,300 without ASD, the AGP reported that individuals with autism tend to carry more rare submicroscopic insertions and deletions called copy number variants (CNV) affected genes than controls. Some of these CNV appeared to be inherited, while others are considered de novo, or new, because they are found only in affected offspring and not in the parents. The causes of some of these CNV are unknown, but in individuals with ASD, more of them also tend to disrupt genes previously reported to be associated with autism or intellectual disabilities.
The new AGP study also identified new autism susceptibility genes including SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53–PTCHD1 locus. Some of these genes belong to synapse-related pathways, while others are involved in cellular proliferation, projection and motility, and intracellular signaling, functional targets that may lead to the development of new treatment approaches.
These findings further support an emerging consensus within the scientific community that autism is caused in part by many “rare variants” or genetic changes found in less than 1 percent of the population. While each of these variants may only account for a small fraction of the cases, collectively they are starting to account for a greater percentage of individuals in the autism community, as well as providing insights into possible common pathogenic mechanisms. The overlap between autism susceptibility genes and genes previously implicated in intellectual disabilities further supports the hypothesis that at least some genetic risk factors are shared by different psychiatric developmental disabilities. Finally, identification of these biological pathways points to new avenues of scientific investigation, as well as potential targets for the development of novel treatments.
The AGP consists of 120 scientists, representing 19 countries, who formed a first-of-its-kind autism genetics consortium. The AGP began in 2002 when researchers from around the world decided to come together and share their samples, data, and expertise to facilitate the identification of autism susceptibility genes. This continuing collaboration and its unique scientific assets (e.g., large sample set and multidisciplinary expertise) created scientific opportunities that otherwise would not exist. The AGP is well positioned to build on these extraordinary assets as the field of autism genetics further investigates rare variants, requiring larger sample sets to identify more CNV.
The research conducted at the HIHG for this study was supported by Autism Speaks, the National Institutes of Health and the John P. Hussman Foundation.