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      Neurodevelopmental hypothesis of schizophrenia

      other
      , PhD FRCPsych, , PhD FRCPsych, , PhD FRCPsych, , PhD FRCPsych
      The British Journal of Psychiatry
      The Royal College of Psychiatrists

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          Abstract

          The neurodevelopmental hypothesis of schizophrenia provided a valuable framework that allowed a condition that usually presents with frank disorder in adolescence or early adulthood to be understood at least in part as a consequence of events occurring early in development. However, the implications of the neurodevelopmental hypothesis for nosological conceptions of the disorder can only now be fully appreciated. Recent research indicates genetic overlap between schizophrenia and syndromes in which psychopathology is manifest in childhood and that are often grouped together as ‘ neurodevelopmental disorders’ such as autism-spectrum disorders, intellectual disability and attention-deficit hyperactivity disorder. These findings challenge the aetiological basis of current diagnostic categories and, together with evidence for frequent comorbidity, suggest that we should view the functional psychoses as members of a group of related and overlapping syndromes that result in part from a combination of genetic and environmental effects on brain development and that are associated with specific and general impairments of cognitive function. This has important implications for future research and for the configuration of psychiatric services.

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          Most cited references25

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          Genome-wide association studies: theoretical and practical concerns.

          To fully understand the allelic variation that underlies common diseases, complete genome sequencing for many individuals with and without disease is required. This is still not technically feasible. However, recently it has become possible to carry out partial surveys of the genome by genotyping large numbers of common SNPs in genome-wide association studies. Here, we outline the main factors - including models of the allelic architecture of common diseases, sample size, map density and sample-collection biases - that need to be taken into account in order to optimize the cost efficiency of identifying genuine disease-susceptibility loci.
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            Shared heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder

            Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders. Evidence indicates both disorders co-occur with a high frequency, in 20–50% of children with ADHD meeting criteria for ASD and in 30-80% of ASD children meeting criteria for ADHD. This review will provide an overview on all available studies [family based, twin, candidate gene, linkage, and genome wide association (GWA) studies] shedding light on the role of shared genetic underpinnings of ADHD and ASD. It is concluded that family and twin studies do provide support for the hypothesis that ADHD and ASD originate from partly similar familial/genetic factors. Only a few candidate gene studies, linkage studies and GWA studies have specifically addressed this co-occurrence, pinpointing to some promising pleiotropic genes, loci and single nucleotide polymorphisms (SNPs), but the research field is in urgent need for better designed and powered studies to tackle this complex issue. We propose that future studies examining shared familial etiological factors for ADHD and ASD use a family-based design in which the same phenotypic (ADHD and ASD), candidate endophenotypic, and environmental measurements are obtained from all family members. Multivariate multi-level models are probably best suited for the statistical analysis.
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              Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis

              Summary Background Large, rare chromosomal deletions and duplications known as copy number variants (CNVs) have been implicated in neurodevelopmental disorders similar to attention-deficit hyperactivity disorder (ADHD). We aimed to establish whether burden of CNVs was increased in ADHD, and to investigate whether identified CNVs were enriched for loci previously identified in autism and schizophrenia. Methods We undertook a genome-wide analysis of CNVs in 410 children with ADHD and 1156 unrelated ethnically matched controls from the 1958 British Birth Cohort. Children of white UK origin, aged 5–17 years, who met diagnostic criteria for ADHD or hyperkinetic disorder, but not schizophrenia and autism, were recruited from community child psychiatry and paediatric outpatient clinics. Single nucleotide polymorphisms (SNPs) were genotyped in the ADHD and control groups with two arrays; CNV analysis was limited to SNPs common to both arrays and included only samples with high-quality data. CNVs in the ADHD group were validated with comparative genomic hybridisation. We assessed the genome-wide burden of large (>500 kb), rare (<1% population frequency) CNVs according to the average number of CNVs per sample, with significance assessed via permutation. Locus-specific tests of association were undertaken for test regions defined for all identified CNVs and for 20 loci implicated in autism or schizophrenia. Findings were replicated in 825 Icelandic patients with ADHD and 35 243 Icelandic controls. Findings Data for full analyses were available for 366 children with ADHD and 1047 controls. 57 large, rare CNVs were identified in children with ADHD and 78 in controls, showing a significantly increased rate of CNVs in ADHD (0·156 vs 0·075; p=8·9×10−5). This increased rate of CNVs was particularly high in those with intellectual disability (0·424; p=2·0×10−6), although there was also a significant excess in cases with no such disability (0·125, p=0·0077). An excess of chromosome 16p13.11 duplications was noted in the ADHD group (p=0·0008 after correction for multiple testing), a finding that was replicated in the Icelandic sample (p=0·031). CNVs identified in our ADHD cohort were significantly enriched for loci previously reported in both autism (p=0·0095) and schizophrenia (p=0·010). Interpretation Our findings provide genetic evidence of an increased rate of large CNVs in individuals with ADHD and suggest that ADHD is not purely a social construct. Funding Action Research; Baily Thomas Charitable Trust; Wellcome Trust; UK Medical Research Council; European Union.

                Author and article information

                Journal
                Br J Psychiatry
                Br J Psychiatry
                bjprcpsych
                The British Journal of Psychiatry
                The Royal College of Psychiatrists
                0007-1250
                1472-1465
                March 2011
                : 198
                : 3
                : 173-175
                Affiliations
                MRC Centre for Neuropsychiatric Genetics and Genomics and the Neuroscience and Mental Health Research Institute, Cardiff University, Cardiff, UK
                Author notes
                Correspondence: Michael J. Owen, MRC Centre for Neuropsychiatric Genetics and Genomics, Henry Wellcome Building, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK. Email: owenmj@ 123456cardiff.ac.uk
                Article
                0173
                10.1192/bjp.bp.110.084384
                3764497
                21357874
                8803a581-3a68-4d87-8919-773610b37e46
                © 2011 Royal College of Psychiatrists
 This paper accords with the Wellcome Trust Open Access policy and is governed by the licence available at http://www.rcpsych.ac.uk/pdf/Wellcome%20Trust%20licence.pdf
                History
                : 17 November 2010
                : 26 July 2010
                : 15 November 2010
                Categories
                Reappraisal
                Custom metadata
                173
                Reappraisal

                Clinical Psychology & Psychiatry
                Clinical Psychology & Psychiatry

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