Common risk factor for autism identified
Largest genetic study in autism to date
Many research sites joined together to work on autism genetics and two significant findings were published in the journal Nature. The unprecedented collaborative nature of the studies allowed the researchers to study a huge sample, ultimately including over 10,000 individuals-and resulted in the first genome-wide, replicated association of a common variant with increased risk for development of autism.
The researchers (including many from the Seaver Autism Center at Mount Sinai School of Medicine) were looking for genetic factors across the human genome that contribute to autism risk. In the first phase, ten research groups joined forces to create the Autism Case Control (ACC) cohort. Using over half a million markers spread throughout the human genome, the ACC sample was analyzed in two ways. First, they looked for small deletions and duplications (genomic imbalances) in the genome. They found new, rare genomic imbalances that contribute to the development of autism in genes involved in protein degradation (ubiquitin) and neuronal cell-adhesion proteins and confirmed these findings in the AGRE (Autism Genetic Resource Exchange). Second, they looked at markers that are more common in the population that contribute to increased risk for autism. For the first time ever, the study identified good evidence for such a marker --- found on chromosome 5 --- on a genome-wide level. In order to validate this finding the researchers then joined with additional groups to analyze this marker in a total sample that included over 10,000 individuals. The population attributable risk (a measure based on both frequency and the risk associated with the variant) for this variant was estimated at over 15%, which means that a significant proportion of risk for autism was explained by this variant. In this particular case, a large proportion of the study group has this common variant in their genome, but possession of it increases risk for autism by only a small amount (perhaps 10-20%). Both of these major findings implicate genes for synaptic proteins and cell adhesion molecules in the pathogenesis of autism-possibly as a result of both structural and functional disconnection of brain regions. These results will ultimately help us to develop novel treatments for autism and related conditions.
Joseph D Buxbaum, PhD
Director, Seaver Autism Center
Professor, Mount Sinai School of Medicine
www.seaverautismcenter.org
For more information see:
1. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H. Nature. 2009 Apr 28. [Epub ahead of print] PMID: 19404257
2. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PM, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A, Owley T, Sweeney JA, Brune CW, Cantor RM, Bernier R, Gilbert JR, Cuccaro ML, McMahon WM, Miller J, State MW, Wassink TH, Coon H, Levy SE, Schultz RT, Nurnberger JI, Haines JL, Sutcliffe JS, Cook EH, Minshew NJ, Buxbaum JD, Dawson G, Grant SF, Geschwind DH, Pericak-Vance MA, Schellenberg GD, Hakonarson H. Nature. 2009 Apr 28. [Epub ahead of print] PMID: 19404256