ORCID Profile
0000-0001-9462-2836
Current Organisations
The Hospital for Sick Children Department of Psychiatry
,
Royal College of Psychiatrists
,
Centre for Addiction and Mental Health
,
University of Toronto
,
University of Dublin Trinity College
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Publications
Oxytocin receptor (OXTR) does not play a major role in the aetiology of autism: Genetic and molecular studies
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.NEULET.2010.03.035
Abstract: 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 s les 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 s le or in a combined s le (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 s les.
Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders
Publisher: Springer Science and Business Media LLC
Date: 15-10-2013
DOI: 10.1038/MP.2013.127
Abstract: Schizophrenia (SZ) and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders that may share an underlying pathology suggested by shared genetic risk variants. We sequenced the exonic regions of 215 genes in 147 ASD cases, 273 SZ cases and 287 controls, to identify rare risk mutations. Genes were primarily selected for their function in the synapse and were categorized as: (1) Neurexin and Neuroligin Interacting Proteins, (2) Post-synaptic Glutamate Receptor Complexes, (3) Neural Cell Adhesion Molecules, (4) DISC1 and Interactors and (5) Functional and Positional Candidates. Thirty-one novel loss-of-function (LoF) variants that are predicted to severely disrupt protein-coding sequence were detected among 2 861 rare variants. We found an excess of LoF variants in the combined cases compared with controls (P=0.02). This effect was stronger when analysis was limited to singleton LoF variants (P=0.0007) and the excess was present in both SZ (P=0.002) and ASD (P=0.001). As an in idual gene category, Neurexin and Neuroligin Interacting Proteins carried an excess of LoF variants in cases compared with controls (P=0.05). A de novo nonsense variant in GRIN2B was identified in an ASD case adding to the growing evidence that this is an important risk gene for the disorder. These data support synapse formation and maintenance as key molecular mechanisms for SZ and ASD.
The Autism Simplex Collection: an international, expertly phenotyped autism sample for genetic and phenotypic analyses
Publisher: Springer Science and Business Media LLC
Date: 2014
Virtual Ontogeny of Cortical Growth Preceding Mental Illness
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.BIOPSYCH.2022.02.959
Abstract: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre erinatal periods may be reflected in in idual variations in cortical surface area later in life. Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 in iduals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed. Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre erinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth. Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.
Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity
Publisher: Springer Science and Business Media LLC
Date: 29-06-2017
DOI: 10.1038/S41598-017-03054-8
Abstract: Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS , which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1 , BBS9 , GNAS , MKKS , CLOCK and ANGPTL6 . The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10 −3 ), highlighting the challenges of testing rare variant associations and the need for very large s le sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.
Preferential Transmission of Paternal Alleles at Risk Genes in Attention-Deficit/Hyperactivity Disorder
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1086/498174
Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets
Publisher: Springer Science and Business Media LLC
Date: 31-10-2019
DOI: 10.1038/S41467-019-13005-8
Abstract: Altered structural brain asymmetry in autism spectrum disorder (ASD) has been reported. However, findings have been inconsistent, likely due to limited s le sizes. Here we investigated 1,774 in iduals with ASD and 1,809 controls, from 54 independent data sets of the ENIGMA consortium. ASD was significantly associated with alterations of cortical thickness asymmetry in mostly medial frontal, orbitofrontal, cingulate and inferior temporal areas, and also with asymmetry of orbitofrontal surface area. These differences generally involved reduced asymmetry in in iduals with ASD compared to controls. Furthermore, putamen volume asymmetry was significantly increased in ASD. The largest case-control effect size was Cohen’s d = −0.13, for asymmetry of superior frontal cortical thickness. Most effects did not depend on age, sex, IQ, severity or medication use. Altered lateralized neurodevelopment may therefore be a feature of ASD, affecting widespread brain regions with erse functions. Large-scale analysis was necessary to quantify subtle alterations of brain structural asymmetry in ASD.
The phenotypic manifestations of rare genic CNVs in autism spectrum disorder
Publisher: Springer Science and Business Media LLC
Date: 25-11-2014
DOI: 10.1038/MP.2014.150
Atypical Visuospatial Processing in Autism: Insights from Functional Connectivity Analysis
Publisher: Wiley
Date: 04-08-2012
DOI: 10.1002/AUR.1245
Abstract: 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 in idually 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.
Disruption at the PTCHD1 Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability
Publisher: American Association for the Advancement of Science (AAAS)
Date: 15-09-2010
DOI: 10.1126/SCITRANSLMED.3001267
Abstract: Mutations of the X-linked gene PTCHD1 are associated with autism spectrum disorders and intellectual disability.
Lack of association between markers in the ITGA3, ITGAV, ITGA6 and ITGB3 and autism in an Irish sample
Publisher: Wiley
Date: 12-2010
DOI: 10.1002/AUR.157
Abstract: 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 s le. 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 s le the integrin genes tested here do not play an important role in the aetiology of autism.
Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure
Publisher: Wiley
Date: 18-05-2020
DOI: 10.1002/HBM.25029
Abstract: Neuroimaging has been extensively used to study brain structure and function in in iduals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small s le sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA‐ADHD and ENIGMA‐ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA‐ADHD and ‐ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case–control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case–control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow‐up analyses continue that include more imaging modalities (diffusion MRI and resting‐state functional MRI), collaborations with other large databases, and s les with dual diagnoses.
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
Publisher: Springer Science and Business Media LLC
Date: 22-05-2017
Whole-genome sequence-based analysis of thyroid function
Publisher: Springer Science and Business Media LLC
Date: 06-03-2015
DOI: 10.1038/NCOMMS6681
Abstract: Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project ( N =2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 ( N =16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P =6.15 × 10 −9 ) and a new independent variant in PDE8B (MAF=10.4%, P =5.94 × 10 −14 ). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P =1.27 × 10 −9 ) tagging a rare TTR variant (MAF=0.4%, P =2.14 × 10 −11 ). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants (MAF %) using sequence kernel association testing reveals a novel association with FT4 in NRG1. Our results demonstrate that increased coverage in whole-genome sequence association studies identifies novel variants associated with thyroid function.
The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism
Publisher: Springer Science and Business Media LLC
Date: 13-06-2014
DOI: 10.1038/NCOMMS5074
Abstract: 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.
Protein kinase C-beta 1 gene variants are not associated with autism in the Irish population
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2007
CNVs leading to fusion transcripts in individuals with autism spectrum disorder
Publisher: Springer Science and Business Media LLC
Date: 02-05-2012
DOI: 10.1038/EJHG.2012.73
A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder
Publisher: Springer Science and Business Media LLC
Date: 14-10-2011
Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia
Publisher: Elsevier BV
Date: 05-2019
The UK10K project identifies rare variants in health and disease
Publisher: Springer Science and Business Media LLC
Date: 14-09-2015
DOI: 10.1038/NATURE14962
Low-frequency variation in TP53 has large effects on head circumference and intracranial volume
Publisher: Springer Science and Business Media LLC
Date: 21-01-2019
DOI: 10.1038/S41467-018-07863-X
Abstract: Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53 , with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.
Synaptic, transcriptional and chromatin genes disrupted in autism
Publisher: Springer Science and Business Media LLC
Date: 29-10-2014
DOI: 10.1038/NATURE13772
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
Publisher: Elsevier BV
Date: 02-2020
A Genetics-First Approach to Dissecting the Heterogeneity of Autism: Phenotypic Comparison of Autism Risk Copy Number Variants
Publisher: Cold Spring Harbor Laboratory
Date: 16-01-2020
DOI: 10.1101/2020.01.14.20017426
Abstract: Certain copy number variants (CNVs) greatly increase risk of autism. We conducted a genetics-first study to investigate whether heterogeneity in the clinical presentation of autism is underpinned by specific genotype-phenotype relationships. This international study included 547 in iduals (12.3 years (SD=4.2), 54% male) who were ascertained on the basis of having a genetic diagnosis of a rare CNV associated with high risk of autism (82 16p11.2 deletion carriers, 50 16p11.2 duplication carriers, 370 22q11.2 deletion carriers and 45 22q11.2 duplication carriers), as well as 2027 in iduals (9.1 years (SD=4.9), 86% male) with autism of heterogeneous aetiology. The Autism Diagnostic Interview-Revised (ADI-R) and IQ testing were conducted. The four genetic variant groups differed in autism severity, autism subdomain profile as well as IQ profile. However, we found substantial variability in phenotypic outcome within in idual genetic variant groups (74% to 97% of the variance depending on the trait), whereas variability between groups was low (1% to 21% depending on trait). We compared CNV carriers who met autism criteria, to in iduals with heterogeneous autism, and a range of profile differences were identified. Using clinical cut-offs, we found that 54% of in iduals with one of the 4 CNVs who did not meet full autism diagnostic criteria nonetheless had elevated levels of autistic traits. Many CNV carriers do not meet full diagnostic criteria for autism, but nevertheless meet clinical cut-offs for autistic traits. Although we find profile differences between variants, there is considerable variability in clinical symptoms within the same variant.
A review of neuropsychological and neuroimaging research in autistic spectrum disorders: Attention, inhibition and cognitive flexibility
Publisher: Elsevier BV
Date: 2008
Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism
Publisher: Cold Spring Harbor Laboratory
Date: 30-11-2018
DOI: 10.1101/484113
Abstract: We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n=35,584 total s les, 11,986 with ASD). Using an enhanced Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in in iduals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in in iduals ascertained for ASD comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.
The phenotypic manifestations of rare CNVs in schizophrenia
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1016/J.SCHRES.2014.06.016
Abstract: 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 s le 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.
Molecular Pathways in Autistic Spectrum Disorders
Publisher: S. Karger AG
Date: 2015
DOI: 10.1159/000363593
Subcortical brain volume, regional cortical thickness and cortical surface area across attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorde
Publisher: Cold Spring Harbor Laboratory
Date: 18-06-2019
DOI: 10.1101/673012
Abstract: Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders. Structural T1-weighted whole-brain MRI of controls ( n =5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures). We found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippoc al volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed. Our findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippoc al alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders.
Fine mapping and association studies in a candidate region for autism on chromosome 2q31–q32
Publisher: Wiley
Date: 07-10-2008
DOI: 10.1002/AJMG.B.30854
Abstract: 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 )(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 s le 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 s le (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 s les, 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 s le (OR = 1.2 P = 0.067) and haplotypes at the 3' end of ITGA4 was observed in the AGRE s le. The VT s le showed association with markers and haplotypes across the gene, but no association with the rs12690517 marker or its surrounding haplotypes. The combined s le 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.
White Matter and Visuospatial Processing in Autism: A Constrained Spherical Deconvolution Tractography Study
Publisher: Wiley
Date: 18-03-2013
DOI: 10.1002/AUR.1290
Abstract: 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 in iduals with ASD. In addition, poorer visuospatial processing was associated in in iduals 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.
Disrupted Functional Connectivity in Dorsal and Ventral Attention Networks During Attention Orienting in Autism Spectrum Disorders
Publisher: Wiley
Date: 26-11-2014
DOI: 10.1002/AUR.1430
Abstract: Attention orienting is a cognitive process that facilitates the movement of attention focus from one location to another: this may be impaired in autism spectrum disorder (ASD). Dorsal and ventral attention networks (DAN and VAN) sub-serve the process of attention orienting. This study investigated the functional connectivity of attention orienting in these networks in ASD using the Posner Cueing Task. Twenty-one adolescents with ASD and 21 age and IQ matched controls underwent functional magnetic resonance imaging. A psychophysical interaction (PPI) analysis was implemented to investigate task-dependent functional connectivity, measuring synchronicity of brain regions during the task. Regions of interest (ROI) were selected to explore functional connectivity in the DAN during cue-only conditions and in the VAN during invalid and valid trials. Behaviourally, the ASD and control groups performed the task in a similar manner. Functional MRI results indicated that the ASD and control groups activated similar brain regions. During invalid trials (VAN), the ASD group showed significant positive functional connectivity to multiple brain regions, whilst the control group demonstrated negative connectivity. During valid trials (VAN), the two groups also showed contrasting patterns of connectivity. In the cue-only conditions (DAN), the ASD group showed weaker functional connectivity. The DAN analysis suggests that the ASD group has weaker coherence between brain areas involved in goal-driven, endogenous attention control. The strong positive functional connectivity exhibited by the ASD group in the VAN during the invalid trials suggests that in iduals with ASD may generate compensatory mechanisms to achieve neurotypical behaviour. These results support the theory of abnormal cortical connectivity in autism.
A genome-wide investigation into parent-of-origin effects in autism spectrum disorder identifies previously associated genes including SHANK3
Publisher: Springer Science and Business Media LLC
Date: 23-11-2016
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism
Publisher: Elsevier BV
Date: 2019
DOI: 10.2139/SSRN.3371405
TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport
Publisher: Springer Science and Business Media LLC
Date: 05-06-2015
DOI: 10.1038/NCOMMS8074
Abstract: The analysis of in iduals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas , accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.
Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium
Publisher: Springer Science and Business Media LLC
Date: 08-02-2022
DOI: 10.1038/S41380-022-01452-7
Abstract: Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in in iduals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 in iduals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium’s ASD Working Group, to assess hemispheric asymmetries of intra-in idual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD s le showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined s le. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.
Abnormal functional connectivity during visuospatial processing is associated with disrupted organisation of white matter in autism
Publisher: Frontiers Media SA
Date: 2013
Functionality of promoter microsatellites of arginine vasopressin receptor 1A (AVPR1A): implications for autism
Publisher: Springer Science and Business Media LLC
Date: 2011
Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders
Publisher: Springer Science and Business Media LLC
Date: 15-05-2017
DOI: 10.1038/NG.3863
Subcortical Brain Volume, Regional Cortical Thickness, and Cortical Surface Area Across Disorders: Findings From the ENIGMA ADHD, ASD, and OCD Working Groups
Publisher: American Psychiatric Association Publishing
Date: 09-2020
No evidence that common genetic risk variation is shared between schizophrenia and autism
Publisher: Wiley
Date: 28-11-2012
DOI: 10.1002/AJMG.B.32121
Abstract: 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.
Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders
Publisher: Elsevier BV
Date: 05-2014
Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs
Publisher: Springer Science and Business Media LLC
Date: 11-08-2202
DOI: 10.1038/NG.2711
Related Organisations
The Hospital For Sick Children Department Of Psychiatry
Location: Canada
Royal College Of Psychiatrists
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Louise Gallagher.