1. Bauman MD, Iosif AM, Ashwood P, Braunschweig D, Lee A, Schumann CM, Van de Water J, Amaral DG. {{Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey}}. {Transl Psychiatry};2013;3:e278.
Antibodies directed against fetal brain proteins of 37 and 73 kDa molecular weight are found in approximately 12% of mothers who have children with autism spectrum disorder (ASD), but not in mothers of typically developing children. This finding has raised the possibility that these immunoglobulin G (IgG) class antibodies cross the placenta during pregnancy and impact brain development, leading to one form of ASD. We evaluated the pathogenic potential of these antibodies by using a nonhuman primate model. IgG was isolated from mothers of children with ASD (IgG-ASD) and of typically developing children (IgG-CON). The purified IgG was administered to two groups of female rhesus monkeys (IgG-ASD; n=8 and IgG-CON; n=8) during the first and second trimesters of pregnancy. Another control group of pregnant monkeys (n=8) was untreated. Brain and behavioral development of the offspring were assessed for 2 years. Behavioral differences were first detected when the macaque mothers responded to their IgG-ASD offspring with heightened protectiveness during early development. As they matured, IgG-ASD offspring consistently deviated from species-typical social norms by more frequently approaching familiar peers. The increased approach was not reciprocated and did not lead to sustained social interactions. Even more striking, IgG-ASD offspring displayed inappropriate approach behavior to unfamiliar peers, clearly deviating from normal macaque social behavior. Longitudinal magnetic resonance imaging analyses revealed that male IgG-ASD offspring had enlarged brain volume compared with controls. White matter volume increases appeared to be driving the brain differences in the IgG-ASD offspring and these differences were most pronounced in the frontal lobes.
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2. Braunschweig D, Krakowiak P, Duncanson P, Boyce R, Hansen RL, Ashwood P, Hertz-Picciotto I, Pessah IN, Van de Water J. {{Autism-specific maternal autoantibodies recognize critical proteins in developing brain}}. {Transl Psychiatry};2013;3:e277.
Autism spectrum disorders (ASDs) are neurodevelopmental in origin, affecting an estimated 1 in 88 children in the United States. We previously described ASD-specific maternal autoantibodies that recognize fetal brain antigens. Herein, we demonstrate that lactate dehydrogenase A and B (LDH), cypin, stress-induced phosphoprotein 1 (STIP1), collapsin response mediator proteins 1 and 2 (CRMP1, CRMP2) and Y-box-binding protein to comprise the seven primary antigens of maternal autoantibody-related (MAR) autism. Exclusive reactivity to specific antigen combinations was noted in 23% of mothers of ASD children and only 1% of controls. ASD children from mothers with specific reactivity to LDH, STIP1 and CRMP1 and/or cypin (7% vs 0% in controls; P<0.0002; odds ratios of 24.2 (95% confidence interval: 1.45-405)) had elevated stereotypical behaviors compared with ASD children from mothers lacking these antibodies. We describe the first panel of clinically significant biomarkers with over 99% specificity for autism risk thereby advancing our understanding of the etiologic mechanisms and therapeutic possibilities for MAR autism.
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3. Cocks G, Curran S, Gami P, Uwanogho D, Jeffries AR, Kathuria A, Lucchesi W, Wood V, Dixon R, Ogilvie C, Steckler T, Price J. {{The utility of patient specific induced pluripotent stem cells for the modelling of Autistic Spectrum Disorders}}. {Psychopharmacology (Berl)};2013 (Jul 10)
Until now, models of psychiatric diseases have typically been animal models. Whether they were to be used to further understand the pathophysiology of the disorder, or as drug discovery tools, animal models have been the choice of preference in mimicking psychiatric disorders in an experimental setting. While there have been cellular models, they have generally been lacking in validity. This situation is changing with the advent of patient-specific induced pluripotent stem cells (iPSCs). In this article, we give a methodological evaluation of the current state of the iPS technology with reference to our own work in generating patient-specific iPSCs for the study of autistic spectrum disorder (ASD). In addition, we will give a broader perspective on the validity of this technology and to what extent it can be expected to complement animal models of ASD in the coming years.
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4. Estes A, Vismara L, Mercado C, Fitzpatrick A, Elder L, Greenson J, Lord C, Munson J, Winter J, Young G, Dawson G, Rogers S. {{The Impact of Parent-Delivered Intervention on Parents of Very Young Children with Autism}}. {J Autism Dev Disord};2013 (Jul 10)
This study investigated the impact of a parent-coaching intervention based on the Early Start Denver Model (P-ESDM) on parenting-related stress and sense of competence. This was part of a multisite, randomized trial comparing P-ESDM (n = 49) with community intervention (n = 49) for children aged 12 and 24 months. The P-ESDM group reported no increase in parenting stress, whereas the Community group experienced an increase over the same 3-month period. Parental sense of competence did not differ. Number of negative life events was a significant predictor of parenting stress and sense of competence across both groups. This suggests that a parent-coaching intervention may help maintain parental adjustment directly after a child is diagnosed with ASD.
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5. Faucher MA. {{FOLIC ACID SUPPLEMENTATION BEFORE AND IN EARLY PREGNANCY MAY DECREASE RISK FOR AUTISM}}. {J Midwifery Womens Health};2013 (Jul 9)
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6. Galle SA, Courchesne V, Mottron L, Frasnelli J. {{Olfaction in the autism spectrum}}. {Perception};2013;42(3):341-355.
The autism spectrum (AS) is characterised by enhanced perception in vision and audition, described by the enhanced perceptual functioning (EPF) model. This model predicts enhanced low-level (discrimination of psychophysical dimensions), and mid- and high-level (pattern detection and identification) perception. The EPF model is here tested for olfaction by investigating olfactory function in autistic and Asperger participants. Experiment 1 targeted higher-order olfactory processing by assessing olfactory identification in nine Asperger, ten autistic, and eleven typically developed individuals. Experiment 2 focused on low-level olfactory processing; we assessed odour detection thresholds and odour discrimination in five Asperger, five autistic, and five typically developed males. Olfactory identification was impaired in autistic participants relative to control and Asperger participants. Typical performance in low-level olfactory processing suggests that neural mechanisms involved in the perceptual phenotype of AS do not affect structures implicated in olfactory processing. Reduced olfactory identification is limited to autistic participants who displayed speech delay and may be due to a reduced facility to use verbal labels. The apparent absence of enhanced olfactory perception of AS participants distinguishes the olfactory system from the other sensory modalities and might be caused by the absence of an obligatory thalamic relay.
7. Ghezzo A, Visconti P, Abruzzo PM, Bolotta A, Ferreri C, Gobbi G, Malisardi G, Manfredini S, Marini M, Nanetti L, Pipitone E, Raffaelli F, Resca F, Vignini A, Mazzanti L. {{Oxidative Stress and Erythrocyte Membrane Alterations in Children with Autism: Correlation with Clinical Features}}. {PLoS One};2013;8(6):e66418.
It has been suggested that oxidative stress may play a role in the pathogenesis of Autism Spectrum Disorders (ASD), but the literature reports somewhat contradictory results. To further investigate the issue, we evaluated a high number of peripheral oxidative stress parameters, and some related issues such as erythrocyte membrane functional features and lipid composition. Twenty-one autistic children (Au) aged 5 to 12 years, were gender and age-matched with 20 typically developing children (TD). Erythrocyte thiobarbituric acid reactive substances, urinary isoprostane and hexanoyl-lysine adduct levels were elevated in Au, thus confirming the occurrence of an imbalance of the redox status of Au, whilst other oxidative stress markers or associated parameters (urinary 8-oxo-dG, plasma radical absorbance capacity and carbonyl groups, erythrocyte superoxide dismutase and catalase activities) were unchanged. A very significant reduction of Na+/K+-ATPase activity (-66%, p<0.0001), a reduction of erythrocyte membrane fluidity and alteration in erythrocyte fatty acid membrane profile (increase in monounsaturated fatty acids, decrease in EPA and DHA-omega3 with a consequent increase in omega6/omega3 ratio) were found in Au compared to TD, without change in membrane sialic acid content. Some Au clinical features appear to be correlated with these findings; in particular, hyperactivity score appears to be related with some parameters of the lipidomic profile and membrane fluidity. Oxidative stress and erythrocyte membrane alterations may play a role in the pathogenesis of ASD and prompt the development of palliative therapeutic protocols. Moreover, the marked decrease in NKA could be potentially utilized as a peripheral biomarker of ASD.
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8. Guevara-Campos J, Gonzalez-Guevara L, Puig-Alcaraz C, Cauli O. {{Autism spectrum disorders associated to a deficiency of the enzymes of the mitochondrial respiratory chain}}. {Metab Brain Dis};2013 (Jul 10)
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders characterized by a combination of reciprocal social deficits, communication impairment, and rigid ritualistic interest and stereotypies. The etiology is generally multifactorial, including genetic, immunological and/or environmental factors. A group of ASD has been linked to mitochondrial dysfunction with subsequent deficiency in energy production. Patients with ASD and mitochondrial disease often show signs and symptoms uncommon to idiopathic ASD such as cardiac, pancreatic or liver dysfunction, cardiac, growth retardation, fatigability, but in some cases semiology is different. We show two clinical cases of ASD associated to a deficiency of the mitochondrial respiratory chain (complex I+III and IV) with different clinical presentations. In one case, signs and symptoms of mitochondrial disorder were mild and the second diagnosis was attained many years after that of ASD. These findings support the recent growing body of evidence that ASD can be associated with mitochondrial disorder. Children with ASD and abnormal neurologic or systemic findings should be evaluated for mitochondrial disorder.
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9. Horder J, Lavender T, Mendez MA, O’Gorman R, Daly E, Craig MC, Lythgoe DJ, Barker GJ, Murphy DG. {{Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [(1)H]MRS study}}. {Transl Psychiatry};2013;3:e279.
Dysfunctional glutamatergic neurotransmission has been implicated in autism spectrum disorder (ASD). However, relatively few studies have directly measured brain glutamate in ASD adults, or related variation in glutamate to clinical phenotype. We therefore set out to investigate brain glutamate levels in adults with an ASD, comparing these to healthy controls and also comparing results between individuals at different points on the spectrum of symptom severity. We recruited 28 adults with ASD and 14 matched healthy controls. Of those with ASD, 15 fulfilled the ‘narrowly’ defined criteria for typical autism, whereas 13 met the ‘broader phenotype’. We measured the concentration of the combined glutamate and glutamine signal (Glx), and other important metabolites, using proton magnetic resonance spectroscopy in two brain regions implicated in ASD-the basal ganglia (including the head of caudate and the anterior putamen) and the dorsolateral prefrontal cortex-as well as in a parietal cortex ‘control’ region. Individuals with ASD had a significant decrease (P<0.001) in concentration of Glx in the basal ganglia, and this was true in both the ‘narrow’ and ‘broader’ phenotype. Also, within the ASD sample, reduced basal ganglia Glx was significantly correlated with increased impairment in social communication (P=0.013). In addition, there was a significant reduction in the concentration of other metabolites such as choline, creatine (Cr) and N-acetylaspartate (NAA) in the basal ganglia. In the dorsolateral prefrontal cortex, Cr and NAA were reduced (P<0.05), although Glx was not. There were no detectable differences in Glx, or any other metabolite, in the parietal lobe control region. There were no significant between-group differences in age, gender, IQ, voxel composition or data quality. In conclusion, individuals across the spectrum of ASD have regionally specific abnormalities in subcortical glutamatergic neurotransmission that are associated with variation in social development.
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10. Huang YP, Chang MY, Chi YL, Lai FC. {{Health-related quality of life in fathers of children with or without developmental disability: the mediating effect of parental stress}}. {Qual Life Res};2013 (Jul 10)
PURPOSE: The aims of this study were to compare parental stress and health-related quality of life (HRQOL) between Taiwanese fathers of children with and without developmental disabilities (DDs) and to examine the mediating effect of parental stress on the association between having a child with DD and paternal HRQOL within Chinese culture. METHOD: This cross-sectional, prospective, unmatched case-control study included 206 fathers of children with DDs and 207 fathers of healthy children. HRQOL was assessed by the SF-36 short-form questionnaire, and parental stress was assessed by the Chinese version Parental Stress Scale. RESULTS: Fathers of children with DDs experienced poorer mental and physical HRQOL and higher parental stress than fathers of healthy children. Parental stress acted as a complete mediator for paternal physical HRQOL, while parental stress had a partial mediating effect on the relationship between having a child with DD and paternal mental HRQOL. Having a child with DD also directly affected paternal mental HRQOL. CONCLUSIONS: Fathers of children with DDs should be monitored for parental stress and HRQOL, and interventions should be provided to empower them with the knowledge and skills to reduce their stress and to enhance their HRQOL.
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11. Kelemen O, Kovacs T, Keri S. {{Contrast, motion, perceptual integration, and neurocognition in schizophrenia: The role of fragile-X related mechanisms}}. {Prog Neuropsychopharmacol Biol Psychiatry};2013 (Jul 6)
Recent studies demonstrated a reduced expression of Fragile X Mental Retardation Protein (FMRP), an RNA binding protein and translation regulator, in the brain and peripheral lymphocytes of patients with schizophrenia. Low FMRP levels may be related to impaired neurodevelopmental processes and synaptic plasticity. Here, we studied the relationship between peripheral FMRP level, visual perception (contrast sensitivity, perceptual integration, motion/form perception), and neuropsychological functions in schizophrenia as measured with the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Results revealed that patients with schizophrenia displayed lower FMRP levels in peripheral lymphocytes as compared to control individuals. We found significant correlations between FMRP levels and contrast sensitivity at low spatial and high temporal frequencies, perceptual integration, and motion perception. The relationship between FMRP level and neuropsychological functions was less pronounced than that seen in the case of visual perception, with the greatest effect for RBANS attention. FMRP level was not related to contrast sensitivity at high spatial and low temporal frequencies and form perception. This pattern of data is reminiscent to that observed in patients with Fragile X Syndrome (FXS). These results suggest that FMRP may be implicated in the pathogenesis of schizophrenia, possibly via the regulation of neurodevelopment, plasticity, GABA-ergic, and glutamatergic neurotransmission.
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12. Mazur-Kolecka B, Cohen IL, Gonzalez M, Jenkins EC, Kaczmarski W, Brown WT, Flory M, Frackowia J. {{Autoantibodies against neuronal progenitors in sera from children with autism}}. {Brain Dev};2013 (Jul 6)
The pathological role of autoantibodies in development of CNS disorders is a new idea with growing interest among neuroscientists. The involvement of autoimmune response in the pathogenesis of autism spectrum disorders (ASD) has been suggested by the presence of multiple brain-specific autoantibodies in children with ASD and in their mothers. The possibility of the effect of autoimmunity on neurogenesis and postnatal brain plasticity has not been determined. The presence of autoantibodies against human neuronal progenitor cells (NPCs) stimulated for neuronal differentiation in culture was tested in sera from children with autism (n=20) and age-matched controls (n=18) by immunoblotting and immunocytochemistry. Immunoreactivity against multiple NPCs proteins of molecular sizes of approximately 55kDa, 105kDa, 150kDa, and 210kDa in sera from individuals with autism had a higher incidence and was stronger than in control sera which immunoreacted mainly with a 150kDa protein. The sera from children with autism immunoreacted the strongest with NPCs expressing neuronal markers Tuj1 and doublecortin, but not astrocyte marker GFAP. The epitopes recognized by antibodies from sera were not human-specific because they detected also NPCs in situ in murine hippocampus. The autoimmune reactions against NPCs suggest an impaired tolerance to neural antigens in autism. These autoantibodies may be symptomatic for autism and furthermore, their presence suggests that autoimmunity may affect postnatal neuronal plasticity particularly after impairment of blood-brain barrier. Future studies will determine the diagnostic value of the presence of autoantibodies in autism and the therapeutic value of prevention of autoimmunity in autism.
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13. Ruble L, McGrew JH. {{Teacher and Child Predictors of Achieving IEP Goals of Children with Autism}}. {J Autism Dev Disord};2013 (Jul 10)
It is encouraging that children with autism show a strong response to early intervention, yet more research is needed for understanding the variability in responsiveness to specialized programs. Treatment predictor variables from 47 teachers and children who were randomized to receive the COMPASS intervention (Ruble et al. in The collaborative model for promoting competence and success for students with ASD. Springer, New York, 2012a) were analyzed. Predictors evaluated against child IEP goal attainment included child, teacher, intervention practice, and implementation practice variables based on an implementation science framework (Dunst and Trivette in J Soc Sci 8:143-148, 2012). Findings revealed one child (engagement), one teacher (exhaustion), two intervention quality (IEP quality for targeted and not targeted elements), and no implementation quality variables accounted for variance in child outcomes when analyzed separately. When the four significant variables were compared against each other in a single regression analysis, IEP quality accounted for one quarter of the variance in child outcomes.
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14. Shen MD, Nordahl CW, Young GS, Wootton-Gorges SL, Lee A, Liston SE, Harrington KR, Ozonoff S, Amaral DG. {{Early brain enlargement and elevated extra-axial fluid in infants who develop autism spectrum disorder}}. {Brain};2013 (Jul 9)
Prospective studies of infants at risk for autism spectrum disorder have provided important clues about the early behavioural symptoms of autism spectrum disorder. Diagnosis of autism spectrum disorder, however, is not currently made until at least 18 months of age. There is substantially less research on potential brain-based differences in the period between 6 and 12 months of age. Our objective in the current study was to use magnetic resonance imaging to identify any consistently observable brain anomalies in 6-9 month old infants who would later develop autism spectrum disorder. We conducted a prospective infant sibling study with longitudinal magnetic resonance imaging scans at three time points (6-9, 12-15, and 18-24 months of age), in conjunction with intensive behavioural assessments. Fifty-five infants (33 ‘high-risk’ infants having an older sibling with autism spectrum disorder and 22 ‘low-risk’ infants having no relatives with autism spectrum disorder) were imaged at 6-9 months; 43 of these (27 high-risk and 16 low-risk) were imaged at 12-15 months; and 42 (26 high-risk and 16 low-risk) were imaged again at 18-24 months. Infants were classified as meeting criteria for autism spectrum disorder, other developmental delays, or typical development at 24 months or later (mean age at outcome: 32.5 months). Compared with the other two groups, infants who developed autism spectrum disorder (n = 10) had significantly greater extra-axial fluid at 6-9 months, which persisted and remained elevated at 12-15 and 18-24 months. Extra-axial fluid is characterized by excessive cerebrospinal fluid in the subarachnoid space, particularly over the frontal lobes. The amount of extra-axial fluid detected as early as 6 months was predictive of more severe autism spectrum disorder symptoms at the time of outcome. Infants who developed autism spectrum disorder also had significantly larger total cerebral volumes at both 12-15 and 18-24 months of age. This is the first magnetic resonance imaging study to prospectively evaluate brain growth trajectories from infancy in children who develop autism spectrum disorder. The presence of excessive extra-axial fluid detected as early as 6 months and the lack of resolution by 24 months is a hitherto unreported brain anomaly in infants who later develop autism spectrum disorder. This is also the first magnetic resonance imaging evidence of brain enlargement in autism before age 2. These findings raise the potential for the use of structural magnetic resonance imaging to aid in the early detection of children at risk for autism spectrum disorder or other neurodevelopmental disorders.
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15. Singh SK, Eroglu C. {{Neuroligins provide molecular links between syndromic and nonsyndromic autism}}. {Sci Signal};2013;6(283):re4.
Autism is a common and heritable neuropsychiatric disorder that can be categorized into two types: syndromic and nonsyndromic, the former of which are associated with other neurological disorders or syndromes. Molecular and functional links between syndromic and nonsyndromic autism genes were lacking until studies aimed at understanding the role of trans-synaptic adhesion molecule neuroligin, which is associated with nonsyndromic autism, provided important connections. Here, we integrate data from these studies into a model of how neuroligin functions to control synaptic connectivity in the central nervous system and how neuroligin dysfunction may participate in the pathophysiology of autism. Understanding the complex functional interactions between neuroligins and other autism-associated proteins at the synapse is crucial to understand the pathology of autism. This understanding might bring us closer to development of therapeutic approaches for autism.
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16. Sticozzi C, Belmonte G, Pecorelli A, Cervellati F, Leoncini S, Signorini C, Ciccoli L, De Felice C, Hayek J, Valacchi G. {{Scavenger receptor B1 post-translational modifications in Rett syndrome}}. {FEBS Lett};2013 (Jul 11);587(14):2199-2204.
The modulation of the HDL receptor scavenger receptor B1 (SRB1) was evaluated in skin fibroblasts isolated from patients with Rett syndrome (RTT), a genetic form of infantile autism. Patients showed an altered plasma lipid profile, while their skin fibroblasts showed a dramatic reduction in SRB1 (immunogold, Western blot and immunohistochemistry). The decreased SRB1 levels were demonstrated to be the consequence of its binding with 4-hydroxy-2-nonenal (4HNE), a product of lipid peroxidation, and its increased ubiquitination. Our findings show for the first time a loss of SRB1 in RTT cells and its relationship with a chronic oxidative stress status.
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17. Talebizadeh Z, Aldenderfer R, Wen Chen X. {{A proof-of-concept study: exon-level expression profiling and alternative splicing in autism using lymphoblastoid cell lines}}. {Psychiatr Genet};2013 (Jul 3)
OBJECTIVE: Autism is a complex, heterogeneous neurobehavioral disorder with many causes and varying degrees of severity. Some genetic implications related to autism may involve gene-regulatory processes such as alternative splicing. Here, we assess the feasibility of profiling exon-level gene expression in autism using the Affymetrix Human exon 1.0 ST array. METHODS: We examined lymphoblastoid cell line-derived RNAs from five subjects with autism compared with five controls. RESULTS: Analysis of variance and Bonferroni multiple test correction identified 57 genes exhibiting differential exon-level expression, suggesting potential changes in the resultant alternatively spliced transcripts in autism compared with controls. Genes with differentially expressed exons included CYFIP1, a previously reported autism susceptibility gene. Furthermore, several genes recently reported to have deregulated alternative splicing in autism brain samples showed differential exon expression in our autism group. CONCLUSION: The paucity of autism brain samples and extensive phenotypic heterogeneity of autism demands finding ways to also identify autism-related genomic events in accessible nonbrain resources, which may contribute in biomarker identifications. This proof-of-concept study shows that the analysis of alternative splicing in lymphoblastoid cell line samples has a potential to reveal at least a subset of brain-related deregulation of splicing machinery that might be implicated in autism.
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18. Talebizadeh Z, Arking DE, Hu VW. {{A Novel Stratification Method in Linkage Studies to Address Inter- and Intra-Family Heterogeneity in Autism}}. {PLoS One};2013;8(6):e67569.
Most genome linkage scans for autism spectrum disorders (ASDs) have failed to be replicated. Recently, a new ASD phenotypic sub-classification method was developed which employed cluster analyses of severity scores from the Autism Diagnostic Interview-Revised (ADI-R). Here, we performed linkage analysis for each of the four identified ADI-R stratified subgroups. Additional stratification was also applied to reduce intra-family heterogeneity and to investigate the impact of gender. For the purpose of replication, two independent sets of single nucleotide polymorphism markers for 392 families were used in our study. This deep subject stratification protocol resulted in 16 distinct group-specific datasets for linkage analysis. No locus reached significance for the combined non-stratified cohort. However, study-wide significant (P = 0.02) linkage scores were reached for chromosomes 22q11 (LOD = 4.43) and 13q21 (LOD = 4.37) for two subsets representing the most severely language impaired individuals with ASD. Notably, 13q21 has been previously linked to autism with language impairment, and 22q11 has been separately associated with either autism or language disorders. Linkage analysis on chromosome 5p15 for a combination of two stratified female-containing subgroups demonstrated suggestive linkage (LOD = 3.5), which replicates previous linkage result for female-containing pedigrees. A trend was also found for the association of previously reported 5p14-p15 SNPs in the same female-containing cohort. This study demonstrates a novel and effective method to address the heterogeneity in genetic studies of ASD. Moreover, the linkage results for the stratified subgroups provide evidence at the gene scan level for both inter- and intra-family heterogeneity as well as for gender-specific loci.
