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      Genetic and Environmental Factors in Complex Neurodevelopmental Disorders

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          Abstract

          Complex neurodevelopmental disorders, such as schizophrenia, autism, attention deficit (hyperactivity) disorder, (manic) depressive illness and addiction, are thought to result from an interaction between genetic and environmental factors. Association studies on candidate genes and genome-wide linkage analyses have identified many susceptibility chromosomal regions and genes, but considerable efforts to replicate association have been surprisingly often disappointing. Here, we summarize the current knowledge of the genetic contribution to complex neurodevelopmental disorders, focusing on the findings from association and linkage studies. Furthermore, the contribution of the interaction of the genetic with environmental and epigenetic factors to the aetiology of complex neurodevelopmental disorders as well as suggestions for future research are discussed.

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          Epigenetic programming by maternal behavior.

          Ian Weaver, Nadia Cervoni, Frances Champagne … (2004)
          Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.
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            Global variation in copy number in the human genome.

            Richard Redon, Shumpei Ishikawa, Karen R Fitch … (2006)
            Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.
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              Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2.

              Ruthie Amir, Ignatia B Van den Veyver, Mimi Wan … (1999)
              Rett syndrome (RTT, MIM 312750) is a progressive neurodevelopmental disorder and one of the most common causes of mental retardation in females, with an incidence of 1 in 10,000-15,000 (ref. 2). Patients with classic RTT appear to develop normally until 6-18 months of age, then gradually lose speech and purposeful hand use, and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. As RTT occurs almost exclusively in females, it has been proposed that RTT is caused by an X-linked dominant mutation with lethality in hemizygous males. Previous exclusion mapping studies using RTT families mapped the locus to Xq28 (refs 6,9,10,11). Using a systematic gene screening approach, we have identified mutations in the gene (MECP2 ) encoding X-linked methyl-CpG-binding protein 2 (MeCP2) as the cause of some cases of RTT. MeCP2 selectively binds CpG dinucleotides in the mammalian genome and mediates transcriptional repression through interaction with histone deacetylase and the corepressor SIN3A (refs 12,13). In 5 of 21 sporadic patients, we found 3 de novo missense mutations in the region encoding the highly conserved methyl-binding domain (MBD) as well as a de novo frameshift and a de novo nonsense mutation, both of which disrupt the transcription repression domain (TRD). In two affected half-sisters of a RTT family, we found segregation of an additional missense mutation not detected in their obligate carrier mother. This suggests that the mother is a germline mosaic for this mutation. Our study reports the first disease-causing mutations in RTT and points to abnormal epigenetic regulation as the mechanism underlying the pathogenesis of RTT.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Curr Genomics
                Journal ID (publisher-id): CG
                Title: Current Genomics
                Publisher: Bentham Science Publishers Ltd.
                ISSN (Print): 1389-2029
                ISSN (Electronic): 1875-5488
                Publication date (Print): November 2007
                Volume: 8
                Issue: 7
                Pages: 429-444
                Affiliations
                []Department of Molecular Animal Physiology, Donders Institute for Neuroscience, Nijmegen Center for Molecular Life Sciences (NCMLS), Faculty of Science, Radboud University Nijmegen, Geert Grooteplein Zuid 28, 6525 GA Nijmegen, The Netherlands
                Author notes
                [* ]Address correspondence to this author at the Department of Molecular Animal Physiology, Donders Institute for Neuroscience and Nijmegen Center for Molecular Life Sciences (NCMLS), Radboud University Nijmegen, 193 RT, Geert Grooteplein Zuid 28, 6525 GA Nijmegen, The Netherlands; Tel: 31-24-3610564; Fax: 31-24-3615317; E-mail: g.martens@ 123456ncmls.ru.nl
                Article
                Publisher ID: CG-8-429
                DOI: 10.2174/138920207783591717
                PMC ID: 2647153
                PubMed ID: 19412416
                SO-VID: 8aa2d462-9b23-44ca-a0c7-a987e563b9cc
                Copyright © ©2007 Bentham Science Publishers Ltd.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.5/) which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 25 October 2007
                Date revision received : 7 November 2007
                Date accepted : 9 November 2007
                Categories
                Subject: Article

                ScienceOpen disciplines: Genetics
                Keywords: environmental factors,association studies,susceptibility genes,gene-environment interactions,linkage analysis.,neurodevelopmental disorders
                Data availability:
                ScienceOpen disciplines: Genetics
                Keywords: environmental factors, association studies, susceptibility genes, gene-environment interactions, linkage analysis., neurodevelopmental disorders

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