Combining family- and population-based approaches sheds new light on the potential roles of both common and rare forms of human genetic variation
October 7, 2009
Boston, Mass. -- In one of the first studies of its kind, an international team of researchers has uncovered a single-letter change in the genetic code that is associated with autism. The finding, published in the October 8 issue of the journal Nature, implicates a neuronal gene not previously tied to the disorder and more broadly, underscores a role for common DNA variation. In addition, the new research highlights two other regions of the genome, which are likely to contain rare genetic differences that may also influence autism risk.
The study was conducted by The Gene Discovery Project of Johns Hopkins & the Autism Consortium, a large collaborative study involving multiple institutions, including the Broad Institute of Harvard and MIT, Massachusetts General Hospitaland Children’s Hospital Boston.
"These discoveries are an important step forward, but just one of many that are needed to fully dissect the complex genetics of this disorder, " said Mark Daly, one of the study's senior authors, a senior associate member at the Broad Institute of Harvard and MIT and an associate professor at the Center for Human Genetic Research at Massachusetts General Hospital (MGH). "The genomic regions we've identified help shed additional light on the biology of autism and point to areas that should be prioritized for further study."
"The biggest challenge to finding the genes that contribute to autism is having a large and well studied group of patients and their family members, both for primary discovery of genes and to test and verify the discovery candidates," said Aravinda Chakravarti, professor of medicine, pediatrics and molecular biology and genetics at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins, and one of the study's senior authors. "This latest finding would not have been possible without these many research groups and consortia pooling together their patient resources. Of course, they would not have been possible without the genomic scanning technologies either."
Autism is a common neurodevelopmental disorder characterized by impaired social, behavioral and communication abilities. Compared to other complex diseases, which are caused by a complicated mix of genetic, environmental and other factors, autism is highly heritable—roughly 90% of the disorder is thought to be genetic in origin. Yet the majority of autism cases cannot be attributed to known inherited causes.
The researchers' results highlight three regions of the human genome. These include parts of chromosomes 6 and 20, the top-scoring regions to emerge from the family-based linkage studies. Although further research is needed localize the exact causal changes and genes within these regions that contribute to autism, these findings can help guide future work.
The other major result, this one flowing from the population-based analyses, is a single-letter change in the genetic code known as a single nucleotide polymorphism, or SNP (pronounced "snip"). This common variant lies on chromosome 5 near a gene known as semaphorin 5A, which is thought to help guide the growth of neurons and their long projections called axons. Notably, the activity or "expression" of this gene appears to be reduced in the brains of autism patients compared to those without the disorder.
"These genetic findings give us important new leads to understand what's different in the developing autistic brain compared with typical neurodevelopment. We can now begin to explore the pathways in which this novel gene acts, expanding our knowledge of autism's biology," said co-lead author Lauren Weiss, a former postdoctoral fellow who collaborated with Daly and his colleagues at MGH and the Broad Institute. Weiss is now an assistant professor of psychiatry and human genetics at University of California, San Francisco (UCSF).
Although the Nature paper identifies a handful of new genes and genomic regions, the researchers emphasize that the findings are just one piece of a very large-—and mostly unfinished-—puzzle. Future studies involving larger patient cohorts and higher resolution genomic technologies, such as next-generation DNA sequencing, promise to yield a deeper understanding of autism and its complex genetic roots.
This work was supported by the Autism Consortium, the Nancy Lurie Marks Family Foundation, NARSAD, the National Center for Research Resources, the National Institute of Mental Health, the Simons Foundation as well as other funding agencies.
Broad Institute of MIT and Harvard
The Eli and Edythe L. Broad Institute of MIT and Harvard was founded in 2003 to empower this generation of creative scientists to transform medicine with new genome-based knowledge. The Broad Institute seeks to describe all the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.
Founded by MIT, Harvard and its affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide. For further information about the Broad Institute, go to www.broadinstitute.org.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 13 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 396-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School. For more information about the hospital and its research visit: www.childrenshospital.org/newsroom.