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The genetics of attention deficit/hyperactivity disorder in adults, a review

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      Abstract

      The adult form of attention deficit/hyperactivity disorder (aADHD) has a prevalence of up to 5% and is the most severe long-term outcome of this common neurodevelopmental disorder. Family studies in clinical samples suggest an increased familial liability for aADHD compared with childhood ADHD (cADHD), whereas twin studies based on self-rated symptoms in adult population samples show moderate heritability estimates of 30–40%. However, using multiple sources of information, the heritability of clinically diagnosed aADHD and cADHD is very similar. Results of candidate gene as well as genome-wide molecular genetic studies in aADHD samples implicate some of the same genes involved in ADHD in children, although in some cases different alleles and different genes may be responsible for adult versus childhood ADHD. Linkage studies have been successful in identifying loci for aADHD and led to the identification of LPHN3 and CDH13 as novel genes associated with ADHD across the lifespan. In addition, studies of rare genetic variants have identified probable causative mutations for aADHD. Use of endophenotypes based on neuropsychology and neuroimaging, as well as next-generation genome analysis and improved statistical and bioinformatic analysis methods hold the promise of identifying additional genetic variants involved in disease etiology. Large, international collaborations have paved the way for well-powered studies. Progress in identifying aADHD risk genes may provide us with tools for the prediction of disease progression in the clinic and better treatment, and ultimately may help to prevent persistence of ADHD into adulthood.

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      Most cited references 226

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      Finding the missing heritability of complex diseases.

      Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
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        Next-generation DNA sequencing.

        DNA sequence represents a single format onto which a broad range of biological phenomena can be projected for high-throughput data collection. Over the past three years, massively parallel DNA sequencing platforms have become widely available, reducing the cost of DNA sequencing by over two orders of magnitude, and democratizing the field by putting the sequencing capacity of a major genome center in the hands of individual investigators. These new technologies are rapidly evolving, and near-term challenges include the development of robust protocols for generating sequencing libraries, building effective new approaches to data-analysis, and often a rethinking of experimental design. Next-generation DNA sequencing has the potential to dramatically accelerate biological and biomedical research, by enabling the comprehensive analysis of genomes, transcriptomes and interactomes to become inexpensive, routine and widespread, rather than requiring significant production-scale efforts.
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          The endophenotype concept in psychiatry: etymology and strategic intentions.

          Endophenotypes, measurable components unseen by the unaided eye along the pathway between disease and distal genotype, have emerged as an important concept in the study of complex neuropsychiatric diseases. An endophenotype may be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological (including configured self-report data) in nature. Endophenotypes represent simpler clues to genetic underpinnings than the disease syndrome itself, promoting the view that psychiatric diagnoses can be decomposed or deconstructed, which can result in more straightforward-and successful-genetic analysis. However, to be most useful, endophenotypes for psychiatric disorders must meet certain criteria, including association with a candidate gene or gene region, heritability that is inferred from relative risk for the disorder in relatives, and disease association parameters. In addition to furthering genetic analysis, endophenotypes can clarify classification and diagnosis and foster the development of animal models. The authors discuss the etymology and strategy behind the use of endophenotypes in neuropsychiatric research and, more generally, in research on other diseases with complex genetics.
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            Author and article information

            Affiliations
            [1 ]simpleDepartment of Human Genetics, Radboud University Nijmegen Medical Centre , Nijmegen, The Netherlands
            [2 ]simpleDepartment of Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre , Nijmegen, The Netherlands
            [3 ]simpleDepartments of Psychiatry and of Neuroscience and Physiology, State University of New York Upstate Medical University , Syracuse, NY, USA
            [4 ]simpleMRC Social Genetic and Developmental Psychiatry, Institute of Psychiatry, Kings College London, London, UK
            [5 ]simpleDepartment of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre , Nijmegen, The Netherlands
            [6 ]simpleDepartment of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul , Porto Alegre, RS, Brazil
            [7 ]simpleAdult ADHD Outpatient Clinic, Hospital de Clínicas de Porto Alegre , Porto Alegre, RS, Brazil
            [8 ]simpleDepartment of Psychiatry, Hospital Universitari Vall d'Hebron, CIBERSAM, and Department of Psychiatry and Legal Medicine, Universitat Autónoma de Barcelona , Barcelona, Catalonia, Spain
            [9 ]simpleQuantitative Health Sciences, University of Massachusetts Medical School , Worcester, MA, USA
            [10 ]simpleCenter for Medical Genetics and Molecular Medicine, Haukeland University Hospital , Bergen, Norway
            [11 ]simpleDepartment of Biomedicine, KG Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen , Bergen, Norway
            [12 ]simpleDepartment of Psychiatry, Haukeland University Hospital , Bergen, Norway
            [13 ]simpleLaboratory of Translational Neuroscience, ADHD Clinical Research Network, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg , Wuerzburg, Germany
            [14 ]simpleDepartment of Neuroscience, School of Mental Health and Neuroscience (MHENS), Maastricht University , Maastricht, The Netherlands
            [15 ]simpleDepartment of Genetics, Faculty of Biology, University of Barcelona , Catalonia, Spain
            [16 ]simpleBiomedical Network Research Centre on Rare Diseases (CIBERER) , Barcelona, Catalonia, Spain
            [17 ]simpleInstitut de Biomedicina de la Universitat de Barcelona (IBUB) , Catalonia, Spain
            [18 ]simpleDepartment of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg , Würzburg, Germany
            Author notes
            [* ]simpleDepartment of Human Genetics (855), Radboud University Nijmegen Medical Centre, PO Box 9101 , 6500 HB Nijmegen, The Netherlands. E-mail: b.franke@ 123456antrg.umcn.nl
            Journal
            Mol Psychiatry
            Mol. Psychiatry
            Molecular Psychiatry
            Nature Publishing Group
            1359-4184
            1476-5578
            October 2012
            22 November 2011
            : 17
            : 10
            : 960-987
            3449233
            22105624
            mp2011138
            10.1038/mp.2011.138
            Copyright © 2012 Macmillan Publishers Limited

            This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

            Categories
            Feature Review

            Molecular medicine

            impact, endophenotype, heritability, molecular genetics, persistent adhd

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