The genetic architecture of autism spectrum disorder involves the interplay of common and rare variants and their impact on hundreds of genes. Using exome sequencing, here we show that analysis of rare coding variation in 3,871 autism cases and 9,937 ancestry-matched or parental controls implicates 22 autosomal genes at a false discovery rate (FDR) < 0.05, plus a set of 107 autosomal genes strongly enriched for those likely to affect risk (FDR < 0.30). These 107 genes, which show unusual evolutionary constraint against mutations, incur de novo loss-of-function mutations in over 5% of autistic subjects. Many of the genes implicated encode proteins for synaptic formation, transcriptional regulation and chromatin-remodelling pathways. These include voltage-gated ion channels regulating the propagation of action potentials, pacemaking and excitability-transcription coupling, as well as histone-modifying enzymes and chromatin remodellers-most prominently those that mediate post-translational lysine methylation/demethylation modifications of histones.
Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ?3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
Impaired face perception in autism spectrum disorders is thought to reflect a perceptual style characterized by componential rather than configural processing of faces. This study investigated face processing in adolescents with autism spectrum disorders using the Thatcher illusion, a perceptual phenomenon exhibiting 'inversion effects' that characterize typical face processing. While previous studies used a limited range of face orientations, we measured perception of normality/grotesqueness of faces at seven orientations ranging from upright to inverted to allow for a detailed comparison of both reaction time and error by orientation profiles. We found that, like their typically developing peers, adolescents with autism spectrum disorders show strong inversion effects whereby reaction times were longer and error rates greater at inverted when compared to upright orientations. Additionally, the adolescents with autism spectrum disorders, like their peers in the typically developing group, show a marked nonlinearity in the error by orientation profile. Error is roughly constant out to 90° and then increases steeply, indicating a sudden shift from configural to local processing that reflects experience with faces in their typical orientations. These findings agree with recent reports that face perception is qualitatively similar in autistic and neurotypical groups.
There is compelling evidence for the role of copy number variants (CNVs) in schizophrenia susceptibility, and it has been estimated that up to 2-3% of schizophrenia cases may carry rare CNVs. Despite evidence that these events are associated with an increased risk across categorical neurodevelopmental disorders, there is limited understanding of the impact of CNVs on the core features of disorders like schizophrenia. Our objective was to evaluate associations between rare CNVs in differentially brain expressed (BE) genes and the core features and clinical correlates of schizophrenia. The sample included 386 cases of Irish ancestry with a diagnosis of schizophrenia, at least one rare CNV impacting any gene, and a core set of phenotypic measures. Statistically significant associations between deletions in differentially BE genes were found for family history of mental illness (decreased prevalence of all CNVs and deletions, unadjusted and adjusted) and for paternal age (increase in deletions only, unadjusted, among those with later ages at birth of patient). The strong effect of a lack of a family history on BE genes suggests that CNVs may comprise one pathway to schizophrenia, whereas a positive family history could index other genetic mechanisms that increase schizophrenia vulnerability. To our knowledge, this is the first investigation of the association between genome-wide CNVs and risk factors and sub-phenotypic features of schizophrenia beyond cognitive function.
This study aims to establish whether children of an immigrant maternal population presented with a higher rate of autism than the indigenous population and to explore their presentation with regard to severity of symptoms, demographics and ethnicity. It is a retrospective case note analysis of 366 children who presented to the paediatric developmental service in the Adelaide and Meath incorporating the National Childrens Hospital, Tallaght, Ireland between 2007 and 2009. During the study period, 366 children presented. Fifty-eight children (16 %) had mothers who were born in Africa and 53 (14 %) were born to mothers originating from a wider variety of countries. Two hundred and forty-eight children (68 %) had mothers born in Ireland. Maternal origin was not identified for seven children (2 %). An autistic spectrum disorder (ASD) was diagnosed in 131 children and speech and language delay in 132. Of the children with an ASD diagnosis, a higher proportion of the African cohort 13/18 (72.2 %) presented with moderate/severe cognitive disability compared to the Irish group 9/55(16.3 %), and the children in the African cohort showed a higher heritability with 36.9 % having a positive family history of autism reported compared to 26.3 % of the Irish cohort with an ASD diagnosis. Conclusion: This study highlights an observation of increased rates of ASD among a migrant population derived particularly from children born to mothers originating in Sub-Saharan Africa. This cohort is more severely affected. Further validation in an epidemiological sample is warranted, which if replicated, may help to identify possible aetiological risk factors.
Autism spectrum disorders (ASDs) are associated with a marked disturbance of neural functional connectivity, which may arise from disrupted organization of white matter. The aim of this study was to use constrained spherical deconvolution (CSD)-based tractography to isolate and characterize major intrahemispheric white matter tracts that are important in visuospatial processing. CSD-based tractography avoids a number of critical confounds that are associated with diffusion tensor tractography, and to our knowledge, this is the first time that this advanced diffusion tractography method has been used in autism research. Twenty-five participants with ASD and aged 25, intelligence quotient-matched controls completed a high angular resolution diffusion imaging scan. The inferior fronto-occipital fasciculus (IFOF) and arcuate fasciculus were isolated using CSD-based tractography. Quantitative diffusion measures of white matter microstructural organization were compared between groups and associated with visuospatial processing performance. Significant alteration of white matter organization was present in the right IFOF in individuals with ASD. In addition, poorer visuospatial processing was associated in individuals with ASD with disrupted white matter in the right IFOF. Using a novel, advanced tractography method to isolate major intrahemispheric white matter tracts in autism, this research has demonstrated that there are significant alterations in the microstructural organization of white matter in the right IFOF in ASD. This alteration was associated with poorer visuospatial processing performance in the ASD group. This study provides an insight into structural brain abnormalities that may influence atypical visuospatial processing in autism.
Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohns disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Disruption of structural and functional neural connectivity has been widely reported in Autism Spectrum Disorder (ASD) but there is a striking lack of research attempting to integrate analysis of functional and structural connectivity in the same study population, an approach that may provide key insights into the specific neurobiological underpinnings of altered functional connectivity in autism. The aims of this study were (1) to determine whether functional connectivity abnormalities were associated with structural abnormalities of white matter (WM) in ASD and (2) to examine the relationships between aberrant neural connectivity and behavior in ASD. Twenty-two individuals with ASD and 22 age, IQ-matched controls completed a high-angular-resolution diffusion MRI scan. Structural connectivity was analysed using constrained spherical deconvolution (CSD) based tractography. Regions for tractography were generated from the results of a previous study, in which 10 pairs of brain regions showed abnormal functional connectivity during visuospatial processing in ASD. WM tracts directly connected 5 of the 10 region pairs that showed abnormal functional connectivity; linking a region in the left occipital lobe (left BA19) and five paired regions: left caudate head, left caudate body, left uncus, left thalamus, and left cuneus. Measures of WM microstructural organization were extracted from these tracts. Fractional anisotropy (FA) reductions in the ASD group relative to controls were significant for WM connecting left BA19 to left caudate head and left BA19 to left thalamus. Using a multimodal imaging approach, this study has revealed aberrant WM microstructure in tracts that directly connect brain regions that are abnormally functionally connected in ASD. These results provide novel evidence to suggest that structural brain pathology may contribute (1) to abnormal functional connectivity and (2) to atypical visuospatial processing in ASD.
Abnormalities in frontostriatal circuitry potentially underlie the two core deficits in Autism Spectrum Disorder (ASD); social interaction and communication difficulties and restricted interests and repetitive behaviors. Whilst a few studies have examined connectivity within this circuitry in ASD, no previous study has examined both functional and structural connectivity within the same population. The present study provides the first exploration of both functional and structural frontostriatal connectivity in ASD. Twenty-eight right-handed Caucasian male ASD (17.28 ± 3.57 years) and 27 right-handed male, age and IQ matched controls (17.15 ± 3.64 years) took part in the study. Resting state functional connectivity was carried out on 21 ASD and control participants, and tractography was carried out on 22 ASD and 24 control participants, after excluding subjects for excessive motion and poor data quality. Functional connectivity analysis was carried out between the frontal cortex and striatum after which tractography was performed between regions that showed significant group differences in functional connectivity. The ASD group showed increased functional connectivity between regions in the frontal cortex [anterior cingulate cortex (ACC), middle frontal gyrus (MFG), paracingulate gyrus (Pcg) and orbitofrontal cortex (OFC)], and striatum [nucleus accumbens (NAcc) and caudate]. Increased functional connectivity between ACC and caudate was associated with deactivation to social rewards in the caudate, as previously reported in the same participants. Greater connectivity between the right MFG and caudate was associated with higher restricted interests and repetitive behaviors and connectivity between the bilateral Pcg and NAcc, and the right OFC and NAcc, was negatively associated with social and communicative deficits. Although tracts were reliably constructed for each subject, there were no group differences in structural connectivity. Results are in keeping with previously reported increased corticostriatal functional connectivity in ASD.
Increasing worldwide use of chemicals, including heavy metals used in industry and pesticides used in agriculture, may produce increases in chronic diseases in children unless steps are taken to manage the production, use, trade, and disposal of chemicals. In 2020 the developing world will account for 33 percent of global chemical demand and 31 percent of production, compared with 23 percent and 21 percent, respectively, in 1995. We describe present and potential costs of environmental exposures and discuss policy options to protect future generations of children in a sustainable development context. Specifically, we describe the principles of sound chemicals management, as follows: precaution, or the use of cost-effective measures to prevent potentially hazardous exposures before scientific understanding is complete; the right to know, or informing the public--especially vulnerable groups--in a timely fashion about the safe use of chemicals and any releases of chemicals into the environment; pollution prevention, or preventing the use of hazardous chemicals and the production of pollutants, rather than focusing on managing wastes; internalization of environmental and health costs, or ensuring that the consequences of exposures are reflected in the price of chemicals through such approaches as "polluter pays"; and use of best available scientific information in making decisions such as what chemicals to allow into the market. We recommend that industrializing nations in particular employ these principles to prevent disease among their populations while at the same time minimizing the risk to their own economic development.
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.
Recent genome-wide association studies (GWAS) have implicated a range of genes from discrete biological pathways in the aetiology of autism. However, despite the strong influence of genetic factors, association studies have yet to identify statistically robust, replicated major effect genes or SNPs. We apply the principle of the SNP ratio test methodology described by ODushlaine et al to over 2100 families from the Autism Genome Project (AGP). Using a two-stage design we examine association enrichment in 5955 unique gene-ontology classifications across four groupings based on two phenotypic and two ancestral classifications. Based on estimates from simulation we identify excess of association enrichment across all analyses. We observe enrichment in association for sets of genes involved in diverse biological processes, including pyruvate metabolism, transcription factor activation, cell-signalling and cell-cycle regulation. Both genes and processes that show enrichment have previously been examined in autistic disorders and offer biologically plausibility to these findings.
Arginine vasopressin (AVP) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. The arginine vasopressin receptor 1A gene (AVPR1A) is widely expressed in the brain and is considered to be a key receptor for regulation of social behaviour. Moreover, genetic variation at AVPR1A has been reported to be associated with autism. Evidence from non-human mammals implicates variation in the 5-flanking region of AVPR1A in variable gene expression and social behaviour.
Human social behavior develops under the influence of genetic, environmental, and cultural factors. Social cognition comprises our ability to understand and respond appropriately to other peoples social approaches or responses. The concept embraces self-knowledge and theory of mind, or the ability to think about emotions and behavior from the perspective of another person. The neuropeptides oxytocin (OT) and vasopressin (AVP) are now known to play an important role, affecting individual differences in parenting behavior, social recognition, and affiliative behaviors. The processes of social cognition are also supported by reward circuitry, underpinned by the dopaminergic neurotransmitter system. Reward processes build social relationships, in parenting and pair-bonding, and influence social interactions that require trust, or display altruism. The impact of emotional regulation upon social behavior, including mood and anxiety, is also mediated through the serotonergic system. Variation in activity of serotonergic networks in the brain influences emotional responsivity, including subjective feelings, physiological responses, emotional expressions, and the tendency to become engaged in action as a consequence of a feeling state. Genetic variation in the receptors associated with OT, AVP, dopamine, and serotonin has been intensively studied in humans and animal models. Recent findings are building an increasingly coherent picture of regulatory mechanisms.
In the analysis of genome-wide association (GWA) data, the aim is to detect statistical associations between single nucleotide polymorphisms (SNPs) and the disease or trait of interest. These SNPs, or the particular regions of the genome they implicate, are then considered for further study. We demonstrate through a comprehensive simulation study that the inclusion of additional, biologically relevant information through a 2-level empirical Bayes hierachical model framework offers a more robust method of detecting associated SNPs. The empirical Bayes approach is an objective means of analyzing the data without the need for the setting of subjective parameter estimates. This framework gives more stable estimates of effects through a reduction of the variability in the usual effect estimates. We also demonstrate the consequences of including additional information that is not informative and examine power and false-positive rates. We apply the methodology to a number of genome-wide association (GWA) data sets with the inclusion of additional biological information. Our results agree with previous findings and in the case of one data set (Crohns disease) suggest an additional region of interest.
Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, although the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability. A 167-kilobase microdeletion spanning exon 1 was found in two brothers, one with ASD and the other with a learning disability and ASD features; a 90-kilobase microdeletion spanning the entire gene was found in three males with intellectual disability in a second family. In 900 probands with ASD and 208 male probands with intellectual disability, we identified seven different missense changes (in eight male probands) that were inherited from unaffected mothers and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5 flanking region of PTCHD1 that disrupted a complex noncoding RNA and potential regulatory elements; equivalent changes were not found in male control individuals. Thus, our systematic screen of PTCHD1 and its 5 flanking regions suggests that this locus is involved in ~1% of individuals with ASD and intellectual disability.
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 winners 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.
Autism is a neurodevelopmental disorder characterized by impairments in three core areas--language, social interaction and restricted/repetitive behaviours. It is generally accepted that genetics plays a large role in the aetiology of autism, but the exact mechanism is still unknown. We recently published evidence of an association between autism and the ITGA4 gene [Conroy et al., 2008]. Two genomic regions have shown evidence of linkage to autism in multiple studies--2q31-q33 and 17q21-q22. Both of these regions harbour multiple integrin subunit genes. We tested markers in ITGA3, ITGA6, ITGAV and ITGB3 for association with autism in the Irish autism sample. No markers in ITGA3, ITGA6, ITGAV and ITGB3 were found to be associated with autism. Three 3-marker haplotypes in ITGAV, ITGA3 and ITGA6 were found to be nominally associated (0.01 < P < 0.05) and to have unremarkable findings. Our data indicates that in the Irish autism sample the integrin genes tested here do not play an important role in the aetiology of autism.
The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviours. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability. Although ASDs are known to be highly heritable ( approximately 90%), the underlying genetic determinants are still largely unknown. Here we analysed the genome-wide characteristics of rare (<1% frequency) copy number variation in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic copy number variants (CNVs) (1.19 fold, P = 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P = 3.4 x 10(-4)). Among the CNVs there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes such as SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene sets involved in cellular proliferation, projection and motility, and GTPase/Ras signalling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
Oxytocin (OXT) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. It is postulated that OXT reduces activation of the amygdala, inhibiting social anxiety, indicating a neural mechanism for the effects of OXT in social cognition. Genetic variation at the oxytocin receptor gene (OXTR) has been reported to be associated with autism. We examined 18 SNPs at the OXTR gene for association in three independent autism samples from Ireland, Portugal and the United Kingdom. We investigated cis-acting genetic effects on OXTR expression in lymphocytes and amygdala region of the brain using an allelic expression imbalance (AEI) assay and by investigating the correlation between RNA levels and genotype in the amygdala region. No marker survived multiple correction for association with autism in any sample or in a combined sample (n=436). Results from the AEI assay performed in the lymphoblast cell lines highlighted two SNPs associated with relative allelic abundance in OXTR (rs237897 and rs237895). Two SNPs were found to be effecting cis-acting variation through AEI in the amygdala. One was weakly correlated with total gene expression (rs13316193) and the other was highlighted in the lymphoblast cell lines (rs237895). Data presented here does not support the role of common genetic variation in OXTR in the aetiology of autism spectrum disorders in Caucasian samples.
Autism Spectrum Disorders (ASD) are characterised by social and communication impairment, yet evidence for deficits in the ability to recognise facial expressions of basic emotions is conflicting. Many studies reporting no deficits have used stimuli that may be too simple (with associated ceiling effects), for example, 100% full-blown expressions. In order to investigate subtle deficits in facial emotion recognition, 21 adolescent males with high-functioning Austism Spectrum Disorders (ASD) and 16 age and IQ matched typically developing control males completed a new sensitive test of facial emotion recognition which uses dynamic stimuli of varying intensities of expressions of the six basic emotions (Emotion Recognition Test; Montagne et al., 2007). Participants with ASD were found to be less accurate at processing the basic emotional expressions of disgust, anger and surprise; disgust recognition was most impaired--at 100% intensity and lower levels, whereas recognition of surprise and anger were intact at 100% but impaired at lower levels of intensity.
Autism (OMIM %209850) is a neurodevelopmental disorder with a strong genetic component. We previously reported a de novo rearrangement of chromosome 2q31 in a patient with autism [Gallagher et al. (2003); J Autism Dev Disord 33(1):105-108]. Further cytogenetic analysis revealed this to be a 46,XY, t(9;2)(q31.1;q32.2q31.3) translocation. Association mapping with microsatellite and SNP markers of this translocated region on 2q revealed association with markers in Integrin alpha-4 (ITGA4; GeneID 3676). ITGA4 was tested for association in a sample of 179 trio-based families. SNP markers in exons 16 and 17 showed evidence of association. Mutation screening revealed a G to A synonymous variation in the last nucleotide of exon 16 (rs12690517), significantly associated with autism in the Irish sample (OR = 1.6; P = 0.04). The location of this SNP at a putative splice donor site may affect the splicing of the ITGA4 protein. Haplotype analysis showed significant overtransmission of haplotypes surrounding this marker. These markers were investigated in two additional samples, 102 families from Vanderbilt University (VT) (n = 102), and AGRE (n = 267). A non-significant trend towards overtransmission of the associated allele of rs12690517 in the Irish sample (OR = 1.2; P = 0.067) and haplotypes at the 3 end of ITGA4 was observed in the AGRE sample. The VT sample showed association with markers and haplotypes across the gene, but no association with the rs12690517 marker or its surrounding haplotypes. The combined sample showed evidence of association with rs12690517 (OR = 1.3; P = 0.008) and surrounding haplotypes. The findings indicate some evidence for the role of ITGA4 as candidate gene for autism.
Copy-number variation (CNV) is the most prevalent type of structural variation in the human genome. There is emerging evidence that copy-number variants (CNVs) provide a new vista on understanding susceptibility to neuropsychiatric disorders. Some challenges in the interpretation of current CNV studies include the use of overlapping samples, differing phenotypic definitions, an absence of population norms for CNVs and a lack of consensus in methods for CNV detection and analysis. Here, we review current CNV association study methods and results in autism spectrum disorders (ASD) and schizophrenia, and provide suggestions for design approaches to future studies that might maximize the translation of this work to etiological understanding.
Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 x 10(-5), OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 x 10(-7)), bipolar disorder (P = 0.017) and autism (P = 1.9 x 10(-7)). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 x 10(-13)). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).
A well-mapped set of brain regions is dedicated to social cognition. It is responsive to social cues, engaged in moral decision-making and makes predictions about the likely behaviour of other people. Recent studies of affiliation, using animal models, have revealed that specific neurotransmitters and hormones influence the neural circuits of the social brain. There is converging evidence that the interface between the neuropeptides oxytocin and vasopressin and dopaminergic reward circuits is of particular importance. In the context of recent research, we discuss emerging evidence for the impact of these neuropeptides on the regulation of the social brain. We also examine the putative role of allelic variation in candidate genes on individual differences in social cognitive processing and associated social behaviour.
In the present work, we provide further evidence for the involvement of the integrin alpha-4 precursor gene (ITGA4) in the etiology of autism, by replicating previous findings of a genetic association with autism in various independent populations. The ITGA4 gene maps to the autism linkage region on 2q31-33 and is therefore a plausible positional candidate. We tested eight single nucleotide polymorphisms (SNPs) in the ITGA4 gene region for association with autism in a sample of 164 nuclear families. Evidence for association was found for the rs155100 marker (P = 0.019) and for a number of specific marker haplotypes containing this SNP (0.00053 < P < 0.022). alpha4 integrins are known to play a key role in neuroinflammatory processes, which are hypothesized to contribute to autism. In this study, an association was found between the ITGA4 rs1449263 marker and levels of a serum autoantibody directed to brain tissue, which was previously shown to be significantly more frequent in autistic patients than in age-matched controls in our population. This result suggests that the ITGA4 gene could be involved in a neuroimmune process thought to occur in autistic patients and, together with previous findings, offers a new perspective on the role of integrins in the etiology of autism to which little attention has been paid so far.
This review aimed to find relevant published studies on the co-morbidity of autism and Aspergers syndrome with psychotic, anxiety and/or mood disorders, assess them, synthesize the findings, present an overview and make recommendations for future research.
The purpose of this study was to develop and evaluate an advanced practice nurse case-management intervention programme in a US senior citizen community centre. Researchers Louise Gallagher, Marie Truglio-Londrigan and Rona Levin used a participatory action research method and found that a number of themes emerged to guide nursing interventions.
The impact of medications on the physiology of swallowing has received much attention in dysphagia literature. This article reviews the potential effects of medications commonly prescribed in an adult continuing care and rehabilitation facility on swallowing. An audit of medications prescribed to 153 adults accessing age-related respiratory, neurology, and learning disability services was performed. This was followed by an investigation of relevant sources to identify the potential side effects of these medications. One side effect, namely, xerostomia, which our investigations revealed could be a side effect of 24.8% of the medications used at our institution, was further investigated. The prevalence of xerostomia was then investigated in a randomly selected sample of ten subjects whose dysphagia had been confirmed by videofluoroscopy. It was found that six of the ten dysphagic clients displayed xerostomia. Review of the medications of these ten subjects indicated that all were using from three to nine drugs that could cause xerostomia. This article highlights the need for health-care professionals to consider the potential effects of these medications on swallowing and, indeed, the general presentation of clients.
The similarity between aspects of the clinical presentation of schizophrenia and autism spectrum disorders (ASD) suggests that elements of the biological etiology may also be shared between these two disorders. Recently, an increasing number of rare, mostly structural genetic variants are reported to increase the risk of both schizophrenia and ASD. We hypothesized that given this evidence for a shared genetic background based on rare genetic variants, common risk alleles may also be shared between ASD and schizophrenia. To test this hypothesis, the polygenic score, which summarizes the collective effect of a large number of common risk alleles, was used. We examined whether the polygenic score derived from a schizophrenia case-control dataset, previously reported by Purcell et al., was able to differentiate ASD cases from controls. The results demonstrate that the schizophrenia-derived polygenic score is not different between ASD cases and controls, indicating that there is no important sharing of common risk alleles between the two neuropsychiatric disorders. Possibly, common risk alleles are less important in ASD in comparison to their more prominent role in schizophrenia and bipolar disorders. These findings provide important novel insights into shared and distinct elements of the genetic architecture of autism and schizophrenia.
Atypical visuospatial processing is commonly described in autism spectrum disorders (ASDs); however the specific neurobiological underpinnings of this phenomenon are poorly understood. Given the extensive evidence suggesting ASDs are characterized by abnormal neural connectivity, this study aimed to investigate network connectivity during visuospatial processing in ASD. Twenty-two males with ASD without intellectual disability and 22 individually matched controls performed a mental rotation task during functional magnetic resonance imaging (MRI) in which two rotated stimuli were judged to be same ("Same Trials") or mirror-imaged ("Mirror Trials"). Behavioral results revealed a relative advantage of mental rotation in the ASD group-controls were slower responding to the more difficult Mirror Trials than Same Trials whereas the ASD group completed Mirror Trials and Same-trials at similar speeds. In the ASD group, brain activity was reduced in frontal, temporal, occipital, striatal, and cerebellar regions and, consistent with previous literature, functional connectivity between a number of brain regions was reduced. However, some connections appeared to be conserved and were recruited in a qualitatively different way by the two groups. As task difficulty increased (on Mirror Trials), controls tended to increase connections between certain brain regions, whereas the ASD group appeared to suppress connections between these regions. There was an interesting exception to this pattern in the visual cortex, a finding that may suggest an advantage in early visual perceptual processing in ASD. Overall, this study has identified a relative advantage in mental rotation in ASD that is associated with aberrant neural connectivity and that may stem from enhanced visual perceptual processing.
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.
Non-progressive congenital ataxias (NPCA) with or without intellectual disability (ID) are clinically and genetically heterogeneous conditions. As a consequence, the identification of the genes responsible for these phenotypes remained limited.
There is strong evidence that rare copy number variants (CNVs) have a role in susceptibility to autism spectrum disorders (ASDs). Much research has focused on how CNVs mediate a phenotypic effect by altering gene expression levels. We investigated an alternative mechanism whereby CNVs combine the 5 and 3 ends of two genes, creating a fusion gene. Any resulting mRNA with an open reading frame could potentially alter the phenotype via a gain-of-function mechanism. We examined 2382 and 3096 rare CNVs from 996 individuals with ASD and 1287 controls, respectively, for potential to generate fusion transcripts. There was no increased burden in individuals with ASD; 122/996 cases harbored at least one rare CNV of this type, compared with 179/1287 controls (P=0.89). There was also no difference in the overall frequency distribution between cases and controls. We examined specific examples of such CNVs nominated by case-control analysis and a candidate approach. Accordingly, a duplication involving REEP1-POLR1A (found in 3/996 cases and 0/1287 controls) and a single occurrence CNV involving KIAA0319-TDP2 were tested. However, no fusion transcripts were detected by RT-PCR. Analysis of additional samples based on cell line availability resulted in validation of a MAPKAPK5-ACAD10 fusion transcript in two probands. However, this variant was present in controls at a similar rate and is unlikely to influence ASD susceptibility. In summary, although we find no evidence that fusion-gene generating CNVs lead to ASD susceptibility, discovery of a MAPKAPK5-ACAD10 transcript with an estimated frequency of ~1/200 suggests that gain-of-function mechanisms should be considered in future CNVs studies.
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