Common genetic variants on 5p14.1 associate with autism spectrum disorders.

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.

Individual common variants exert weak effects on the risk for autism spectrum disorders.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.

Attentional modulation of the gap effect.

The gap effect refers to a reduction in the latency of saccades to peripherally appearing targets when the fixation point disappears a short time before target appearance. The effect has been attributed to a number of potential mechanisms that function to assist in the maintenance of fixation. One such mechanism, attention, has been the focus of some disagreement in the literature regarding the gap effect. In the present study, we had subjects attend to a portion of a complex fixation stimulus. On some trials the attended portion was removed prior to onset of a saccade target whereas on other trials an unattended portion was removed. Subjects were faster to initiate saccades when the attended portion was removed, thus establishing a role of attention in the gap effect. The results have important implications for our understanding of eye movements and the gap effect.

Strategies for Disseminating Information on Biomedical Research on Autism to Hispanic Parents.

Low income Hispanic families experience multiple barriers to accessing evidence-based information on Autism Spectrum Disorders (ASD). This study utilized a mixed-strategy intervention to create access to information in published bio-medical research articles on ASD by distilling the content into parent-friendly English- and Spanish-language ASD Science Briefs and presenting them to participants using two socially-oriented dissemination methods. There was a main effect for short-term knowledge gains associated with the Science Briefs but no effect for the dissemination method. After 5 months, participants reported utilizing the information learned and 90% wanted to read more Science Briefs. These preliminary findings highlight the potential benefits of distilling biomedical research articles on ASD into parent-friendly educational products for currently underserved Hispanic parents.

Changing the landscape of autism research: the autism genetic resource exchange.

Autism Speaks' Autism Genetic Resource Exchange (AGRE) represents the largest private collection of genetic and phenotype data for families with ASD that is made available to qualified researchers worldwide. The availability of large and comprehensive registries that include detailed phenotype and genetic information for individuals affected with an ASD and family members is crucial for the discovery of autism susceptibility genes and the development and application of biologically based approaches to diagnosis and treatment. The model that AGRE has developed can be applied broadly to other disorders with complex etiologies.