47 research outputs found
An approach to supporting young people with autism spectrum disorder and high anxiety to re-engage with formal education - the impact on young people and their families
School refusal is an important factor impacting upon poor outcomes for adolescents and youth. Individuals with autism spectrum disorder (ASD) experience characteristic difficulties regarding social interaction and communication, rigidity of thinking and sensory sensitivities. These difficulties, coupled with the heightened anxiety that many on the spectrum experience, place them at particular risk of school refusal. This study investigates activity undertaken in one UK local authority, where provision was developed to help such students to re-engage with formal education. Data were collected at three points through the first year of the provision’s existence. Findings show all students were successfully supported to attend the provision and re-engage with formal education. Factors supportive of re-engagement are presented and considered in the light of an ecological model of support for school refusers and what is considered as ‘good practice’ in autism education. It is suggested that the factors identified are indicative of good practice across both areas of activity
A genome-wide scan for common alleles affecting risk for autism
Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C
The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism
Although multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions
Mapping autism risk loci using genetic linkage and chromosomal rearrangements.
International audienceAutism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs
Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia.
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesOver the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15).We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls).We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23.This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4.National Institutes of Mental Health (NIMH, USA)
ACE Network
Autism Genetic Resource Exchange (AGRE) is a program of Autism Speaks (USA)
The Autism Genome Project (AGP) from Autism Speaks (USA)
Canadian Institutes of Health Research (CIHR), Genome Canada
Health Research Board (Ireland)
Hilibrand Foundation (USA)
Medical Research Council (UK)
National Institutes of Health (USA)
Ontario Genomics Institute
University of Toronto McLaughlin Centre
Simons Foundation
Johns Hopkins
Autism Consortium of Boston
NLM Family foundation
National Institute of Health grants
National Health Medical Research Council
Scottish Rite
Spunk Fund, Inc.
Rebecca and Solomon Baker Fund
APEX Foundation
National Alliance for Research in Schizophrenia and Affective Disorders (NARSAD)
endowment fund of the Nancy Pritzker Laboratory (Stanford)
Autism Society of America
Janet M. Grace Pervasive Developmental Disorders Fund
The Lundbeck Foundation
universities and university hospitals of Aarhus and Copenhagen
Stanley Foundation
Centers for Disease Control and Prevention (CDC)
Netherlands Scientific Organization
Dutch Brain Foundation
VU University Amsterdam
Trinity Centre for High Performance Computing through Science Foundation Ireland
Autism Genome Project (AGP) from Autism Speak
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
Autism spectrum disorder (ASD) risk is influenced by common polygenic and de novo variation. We aimed to clarify the influence of polygenic risk for ASD and to identify subgroups of ASD cases, including those with strongly acting de novo variants, in which polygenic risk is relevant. Using a novel approach called the polygenic transmission disequilibrium test and data from 6,454 families with a child with ASD, we show that polygenic risk for ASD, schizophrenia, and greater educational attainment is over-transmitted to children with ASD. These findings hold independent of proband IQ. We find that polygenic variation contributes additively to risk in ASD cases who carry a strongly acting de novo variant. Lastly, we show that elements of polygenic risk are independent and differ in their relationship with phenotype. These results confirm that the genetic influences on ASD are additive and suggest that they create risk through at least partially distinct etiologic pathways
A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder
Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data
New Interview and Observation Measures of the Broader Autism Phenotype: Description of Strategy and Reliability Findings for the Interview Measures
New interview and observation measures of the broader autism phenotype: Description of strategy and reliability findings for the interview measures
© 2015 International Society for Autism Research, Wiley Periodicals, Inc. Clinical genetic studies confirm the broader autism phenotype (BAP) in some relatives of individuals with autism, but there are few standardized assessment measures. We developed three BAP measures (informant interview, self-report interview, and impression of interviewee observational scale) and describe the development strategy and findings from the interviews. International Molecular Genetic Study of Autism Consortium data were collected from families containing at least two individuals with autism. Comparison of the informant and self-report interviews was restricted to samples in which the interviews were undertaken by different researchers from that site (251 UK informants, 119 from the Netherlands). Researchers produced vignettes that were rated blind by others. Retest reliability was assessed in 45 participants. Agreement between live scoring and vignette ratings was very high. Retest stability for the interviews was high. Factor analysis indicated a first factor comprising social-communication items and rigidity (but not other repetitive domain items), and a second factor comprised mainly of reading and spelling impairments. Whole scale Cronbach's alphas were high for both interviews. The correlation between interviews for factor 1 was moderate (adult items 0.50; childhood items 0.43); Kappa values for between-interview agreement on individual items were mainly low. The correlations between individual items and total score were moderate. The inclusion of several factor 2 items lowered the overall Cronbach's alpha for the total set. Both interview measures showed good reliability and substantial stability over time, but the findings were better for factor 1 than factor 2. We recommend factor 1 scores be used for characterising the BAP