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      Shared heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder

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          Abstract

          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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          Most cited references80

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          Structural variation of chromosomes in autism spectrum disorder.

          Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.
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            Association between microdeletion and microduplication at 16p11.2 and autism.

            Autism spectrum disorder is a heritable developmental disorder in which chromosomal abnormalities are thought to play a role. As a first component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), we used two novel algorithms to search for recurrent copy-number variations in genotype data from 751 multiplex families with autism. Specific recurrent de novo events were further evaluated in clinical-testing data from Children's Hospital Boston and in a large population study in Iceland. Among the AGRE families, we observed five instances of a de novo deletion of 593 kb on chromosome 16p11.2. Using comparative genomic hybridization, we observed the identical deletion in 5 of 512 children referred to Children's Hospital Boston for developmental delay, mental retardation, or suspected autism spectrum disorder, as well as in 3 of 299 persons with autism in an Icelandic population; the deletion was also carried by 2 of 18,834 unscreened Icelandic control subjects. The reciprocal duplication of this region occurred in 7 affected persons in AGRE families and 4 of the 512 children from Children's Hospital Boston. The duplication also appeared to be a high-penetrance risk factor. We have identified a novel, recurrent microdeletion and a reciprocal microduplication that carry substantial susceptibility to autism and appear to account for approximately 1% of cases. We did not identify other regions with similar aggregations of large de novo mutations. Copyright 2008 Massachusetts Medical Society.
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              Molecular genetics of attention-deficit/hyperactivity disorder.

              Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.
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                Author and article information

                Contributors
                +31-24-3512222 , +31-24-3512211 , n.lambregts-rommelse@psy.umcn.nl , j.buitelaar@psy.umcn.nl
                Journal
                Eur Child Adolesc Psychiatry
                European Child & Adolescent Psychiatry
                Springer-Verlag (Berlin/Heidelberg )
                1018-8827
                1435-165X
                11 February 2010
                11 February 2010
                March 2010
                : 19
                : 3
                : 281-295
                Affiliations
                [1 ]Department of Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Center, Reinier Postlaan 10, 6525 GC Nijmegen, The Netherlands
                [2 ]Karakter Child and Adolescent Psychiatry University Center Nijmegen, Nijmegen, The Netherlands
                [3 ]Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
                [4 ]Department of Psychonomics, University of Amsterdam, Amsterdam, The Netherlands
                [5 ]Dr Leo Kannerhuis, Amsterdam Clinic, Amsterdam, The Netherlands
                [6 ]Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
                Article
                92
                10.1007/s00787-010-0092-x
                2839489
                20148275
                387fb124-263a-482d-a7a9-0376e066f428
                © The Author(s) 2010
                History
                : 12 August 2009
                : 8 January 2010
                Categories
                Review
                Custom metadata
                © Springer-Verlag 2010

                Clinical Psychology & Psychiatry
                shared heritability,attention-deficit/hyperactivity disorder,autism spectrum disorder,molecular genetics

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