ABSTRACT
BACKGROUND: Recent studies point to overlap between neuropsychiatric disorders in symptomatology and genetic aetiology. AIMS: To systematically investigate genomics overlap between childhood and adult attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and major depressive disorder (MDD). METHOD: Analysis of whole-genome blood gene expression and genetic risk scores of 318 individuals. Participants included individuals affected with adult ADHD (n = 93), childhood ADHD (n = 17), MDD (n = 63), ASD (n = 51), childhood dual diagnosis of ADHD-ASD (n = 16) and healthy controls (n = 78). RESULTS: Weighted gene co-expression analysis results reveal disorder-specific signatures for childhood ADHD and MDD, and also highlight two immune-related gene co-expression modules correlating inversely with MDD and adult ADHD disease status. We find no significant relationship between polygenic risk scores and gene expression signatures. CONCLUSIONS: Our results reveal disorder overlap and specificity at the genetic and gene expression level. They suggest new pathways contributing to distinct pathophysiology in psychiatric disorders and shed light on potential shared genomic risk factors.
Subject(s)
Attention Deficit Disorder with Hyperactivity/genetics , Autism Spectrum Disorder/genetics , Depressive Disorder, Major/genetics , Gene Expression Profiling , Adult , Attention Deficit Disorder with Hyperactivity/complications , Autism Spectrum Disorder/complications , Case-Control Studies , Child , Female , Genetic Predisposition to Disease/genetics , Humans , Male , Middle Aged , Young AdultABSTRACT
Increased oxidative stress has been postulated to contribute to the pathogenesis of autism spectrum disorder (ASD). However, reports of alterations in oxidation markers including glutathione (GSH), the major endogenous antioxidant, are indirect, coming from blood plasma level measurements and postmortem studies. Therefore we used in-vivo 3 Tesla proton magnetic resonance spectroscopy ([1H]MRS) to directly measure GSH concentrations in the basal ganglia (BG) and the dorsomedial prefrontal cortex of 21 normally intelligent adult males with ASD and 29 controls who did not differ in age or IQ. There was no difference in brain GSH between patients and controls in either brain area; neither did GSH levels correlate with measures of clinical severity in patients. Thus [1H]MRS measures of cortical and subcortical GSH are not a biomarker for ASD in intellectually able adult men.
Subject(s)
Autism Spectrum Disorder/metabolism , Basal Ganglia/metabolism , Glutathione/metabolism , Prefrontal Cortex/metabolism , Adolescent , Adult , Autism Spectrum Disorder/diagnostic imaging , Basal Ganglia/diagnostic imaging , Brain Mapping/methods , Humans , Magnetic Resonance Spectroscopy , Male , Middle Aged , Prefrontal Cortex/diagnostic imaging , Protons , Young AdultABSTRACT
Sensory processing abnormalities are common in autism spectrum disorders (ASD), and now form part of the Diagnostic and Statistical Manual 5th Edition (DSM-5) diagnostic criteria, but it is unclear whether they characterize the 'broader phenotype' of the disorder. We recruited adults (n = 772) with and without an ASD and administered the Autism Quotient (AQ) along with the Adult/Adolescent Sensory Profile (AASP), the Cardiff Anomalous Perceptions Scale (CAPS), and the Glasgow Sensory Questionnaire (GSQ), all questionnaire measures of abnormal sensory responsivity. Autism traits were significantly correlated with scores on all three sensory scales (AQ/GSQ r = 0.478; AQ/AASP r = 0.344; AQ/CAPS r = 0.333; all p < 0.001). This relationship was linear across the whole range of AQ scores and was true both in those with, and without, an ASD diagnosis. It survived correction for anxiety trait scores, and other potential confounds such as mental illness and migraine.
Subject(s)
Anxiety/diagnosis , Child Development Disorders, Pervasive/physiopathology , Sensation Disorders/diagnosis , Adolescent , Adult , Anxiety/psychology , Child Development Disorders, Pervasive/diagnosis , Child Development Disorders, Pervasive/psychology , Female , Humans , Male , Perception , Phenotype , Sensation Disorders/psychology , Surveys and Questionnaires , Young AdultABSTRACT
Autism spectrum disorders (ASDs) are neurodevelopmental syndromes characterised by repetitive behaviours and restricted interests, impairments in social behaviour and relations, and in language and communication. These symptoms are also observed in a number of developmental disorders of known origin, including Fragile X Syndrome, Rett Syndrome, and Foetal Anticonvulsant Syndrome. While these conditions have diverse etiologies, and poorly understood pathologies, emerging evidence suggests that they may all be linked to dysfunction in particular aspects of GABAergic inhibitory signalling in the brain. We review evidence from genetics, molecular neurobiology and systems neuroscience relating to the role of GABA in these conditions. We conclude by discussing how these deficits may relate to the specific symptoms observed.
