$6 million autism gene hunt

ALLENTOWN, PA — A major expansion of the collaborative effort to identify genes linked to autism is about to start with a $6 million grant awarded by the US National Institute of Mental Health (NIMH). The five-year grant will support the addition of about 300 families to the Autism Genetic Resource Exchange (AGRE) gene bank and enable genetic analysis of the newly deposited DNA samples. "Within the five-year period, our goal is to identify autism susceptibility genes," explained Daniel Geschwind, co-principal investigator of the collaborative project that includes researchers from the University of California, Los Angeles, the University of Chicago, and Columbia University, in partnership with Cure Autism Now (CAN), the citizens group that created AGRE. Since being established nearly four years ago, AGRE has added about 400 autism families to its genetic repository, which is maintained by the NIMH Human Genetics Initiative. Unusual in terms of its public accessibility, AGRE makes both its DNA sample collection and the information gathered on those samples available to the research community. "We believe this is the way things should be done, rather than have biomaterials and data sequestered by individual researchers," said Geschwind.Autism, a neuropsychiatric disorder that begins in early childhood, is caused by abnormalities in brain structure or function. These abnormalities impair the ability to think, feel, use language, and relate to others. Genetic factors appear to be important in autism, based on studies of twins and evidence suggesting that parents who have a child with autism have a slightly increased risk of having a second child with the condition. Further support of a hereditary basis for autism came from the discovery by Andres of the genes that cause two monogenic disorders — tuberous sclerosis and fragile-X — both of which are associated with autism (Brain Res Bull 2002, 57:109-119). "Autistic disorder is one of the most genetic neuropsychiatric diseases," explained Andres. "The relative risk of first relatives is about 100-fold higher than the risk in the normal population and the concordance in monozygotic twins is about 60%."Geschwind believes that many genes are likely to be involved in making a child more susceptible to developing autism. The likelihood of multiple 'vulnerability genes' present on more than one chromosome, and the potential for interaction between these as yet undiscovered genes makes for quite a scientific challenge. Autism is a very difficult genetic nut to crack largely because of the heterogeneity of the disorder. It has a social, language/communication, and behavioral component, and the symptoms associated with each of these may be present in varying degrees in any one patient. Different combinations of genetic factors may cause the various presentations of the disorder. In early 2002, Silverman and colleagues at the Department of Psychiatry at the Mount Sinai School of Medicine, New York, who are part of the AGRE Consortium, reported further evidence to support familiality in autism based on similarities among affected siblings (who either had autism or autism-related symptoms) in the areas of language deficits and repetitive behaviors (Am J Med Genet 2002, 114:64-73).Genetic linkage studies have implicated the long arm of chromosome 7 — called 7q — in autism, and it is thought that genes in this chromosomal region might also be associated with language development. Brandberg and colleagues in the Department of Genetics and Pathology at Uppsala University have reported on a child who had autism disorder and a balanced reciprocal translocation involving the long arm of chromosome 7. The International Molecular Genetic Study of Autism Consortium (IMGSAC), reporting on the results of the first whole genome screen in autism families, identified the autism susceptibility locus AUTS1 on chromosome 7q.In addition to genetic causes of autism, factors associated with pregnancy and fetal brain development are also being investigate for associations with autism. Furthermore, certain environmental factors have been suspected of having a causal effect in autism. In particular, significant controversy has focused on childhood vaccination and, more specifically, on the measles, mumps, rubella, or MMR vaccine and its role in the development of autism. However, the National Institutes of Health, the Centers for Disease Control and Prevention, and the British Committee on Safety of Medicines have all concluded that current scientific evidence does not support the hypothesis (proposed by Wakefield and colleagues in 1998) that the MMR vaccine contributes to the development of autism. Studies have shown no clustering of cases after vaccination, no noteworthy increase in the prevalence of autism after the introduction of the MMR vaccine, and no link between the age at diagnosis of autism and age at vaccination. "Genetics doesn't mean that environment does not play a role," said Geschwind. "To really understand the environmental influences, which are so complex and so variable, the genetics will give a basis for future studies." For example, it is possible that a particular gene may make a child more susceptible to developing autism following medical treatment, such as vaccination. If that were the case, "by understanding the genetics, we will be able to identify those people."AGRE is a resource for the study of autism and pervasive developmental disorder (PDD). DNA samples are housed at the Human Biological Data Interchange (HBDI) at Rutgers University. Genome scans are performed using advanced genetic analysis techniques, including Single Nucleotide Polymorphism (SNP) genotyping and polymorphic marker studies. The genotype results for at least 188 autism families are available to researchers on the web, and cousin genotyping will soon become available.The pedigrees of the more than 400 families already recruited for AGRE are available online and in catalog format; they include information on affectation status and phenotypic features such as language delay. Phenotypic evaluations include two examinations: the Autism Diagnostic Interview-Revised (ADI-R), and the Autism Diagnostic Observational Schedule (ADOS). Designated researchers have access to the ADI data and a subset of the ADOS data online.In a recent review of the genetics of autism, Edwin Cook proposed: "If there is an advantage to autism being a complex rather than monogenetic disorder, it is that the nature of multiplicative or interacting genetic risk means that prevention or treatment directed to any of the identified genetic risks may be sufficient to break a chain of pathophysiology. More genes increase the chance that one or more will have implications for treatment development sooner."

$6 million autism gene hunt

A major initiative is launched to try and identify the genetic basis of autism.

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