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      Genetic Insights Into ADHD Biology

      brief-report

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          Abstract

          ADHD is a neurobiological disorder with a large worldwide prevalence causing significant impairment in children, adolescents, and adults. While there is general agreement about genetic contributions toward the disorder, progress in leveraging genetics to learn more about the biology and risk factors for ADHD has been limited. In this perspective, we identified 105 genes from the literature showing at least nominal statistical significance in association with ADHD. We analyzed these genes for enrichment in biological pathways and in known interacting biological networks. We also analyzed the expression patterns of candidate genes across brain regions and across periods of human development. From our analysis, we identify 14 genes that cluster within an interactive gene network, with enrichment in nitric oxide synthase and alpha-1 adrenergic pathways. Furthermore, these genes show enrichment for expression in the cerebellum during childhood through young adulthood, and in the cortex in adolescence and young adulthood. Gene discovery holds great potential for elucidating the unknown biological underpinnings of ADHD. Genome-wide sequencing efforts are underway and are likely to provide important insights that can be leveraged for new treatments and interventions.

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          Most cited references63

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          The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies.

          This study examined the persistence of attention deficit hyperactivity disorder (ADHD) into adulthood. We analyzed data from published follow-up studies of ADHD. To be included in the analysis, these additional studies had to meet the following criteria: the study included a control group and it was clear from the methods if the diagnosis of ADHD included subjects who did not meet full criteria but showed residual and impairing signs of the disorder. We used a meta-analysis regression model to separately assess the syndromatic and symptomatic persistence of ADHD. When we define only those meeting full criteria for ADHD as having 'persistent ADHD', the rate of persistence is low, approximately 15% at age 25 years. But when we include cases consistent with DSM-IV's definition of ADHD in partial remission, the rate of persistence is much higher, approximately 65%. Our results show that estimates of ADHD's persistence rely heavily on how one defines persistence. Yet, regardless of definition, our analyses show that evidence for ADHD lessens with age. More work is needed to determine if this reflects true remission of ADHD symptoms or is due to the developmental insensitivity of diagnostic criteria for the disorder.
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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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              Prevalence and correlates of adult attention-deficit hyperactivity disorder: meta-analysis.

              In spite of the growing literature about adult attention-deficit hyperactivity disorder (ADHD), relatively little is known about the prevalence and correlates of this disorder. To estimate the prevalence of adult ADHD and to identify its demographic correlates using meta-regression analysis. We used the MEDLINE, PsycLit and EMBASE databases as well as hand-searching to find relevant publications. The pooled prevalence of adult ADHD was 2.5% (95% CI 2.1-3.1). Gender and mean age, interacting with each other, were significantly related to prevalence of ADHD. Meta-regression analysis indicated that the proportion of participants with ADHD decreased with age when men and women were equally represented in the sample. Prevalence of ADHD in adults declines with age in the general population. We think, however, that the unclear validity of DSM-IV diagnostic criteria for this condition can lead to reduced prevalence rates by underestimation of the prevalence of adult ADHD.
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                Author and article information

                Contributors
                Journal
                Front Psychiatry
                Front Psychiatry
                Front. Psychiatry
                Frontiers in Psychiatry
                Frontiers Media S.A.
                1664-0640
                07 June 2018
                2018
                : 9
                : 251
                Affiliations
                [1] 1Physiology Department, McGill University , Montreal, QC, Canada
                [2] 2Child Study Center, Department of Psychiatry, Yale University School of Medicine , New Haven, CT, United States
                Author notes

                Edited by: Hanna E. Stevens, University of Iowa, United States

                Reviewed by: Lin Sørensen, University of Bergen, Norway; Karen Muller Smith, University of Louisiana at Lafayette, United States

                *Correspondence: Thomas V. Fernandez thomas.fernandez@ 123456yale.edu

                This article was submitted to Child and Adolescent Psychiatry, a section of the journal Frontiers in Psychiatry

                Article
                10.3389/fpsyt.2018.00251
                5999780
                29930523
                06e225c8-029f-491b-a3f0-a2bbe3ca9dd2
                Copyright © 2018 Hayman and Fernandez.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 19 February 2018
                : 23 May 2018
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 80, Pages: 8, Words: 5813
                Categories
                Psychiatry
                Perspective

                Clinical Psychology & Psychiatry
                attention-deficit/hyperactivity disorder,gwas (genome-wide association study),copy number variation (cnv),candidate gene association,network analysis,pathway analysis,expression profiling,cerebellum

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