Nijmeijer, Judith Simone

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Proceedings - University of Groningen

   University of GroningenASD symptoms in children with ADHDNijmeijer, Judith SimoneIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2011Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Nijmeijer, J. S. (2011). ASD symptoms in children with ADHD: familial and genetic underpinnings. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 03-06-2022Introduction1 |11The overall aim of this thesis is to study the causes of the frequent occurrence of autism spectrum disorder (ASD) symptoms in children with attention-deficit/hyperactivity disorder (ADHD). The hypothesis is tested that the occurrence of ASD symptoms in children with ADHD results from shared genetic risk factors. An introduction to this topic is provided in a review of studies on the co-occurrence of ASD and ADHD in the following chapter. This review is embedded in an elaborate description of the nature and consequences of problems in social interaction in children with ADHD, which may be the most salient ASD symptoms that children with ADHD display.  The most important risk factors for both ADHD and ASD are genetic in nature. Although this insight may be widely recognized today, it was not until the 20th century that it gained support. In 1902, George Still, a British paediatrician, made the first comprehensive description of children with ADHD, and also recognized the potential importance of biological causes for their behavior. Before, ADHD-like behavior was seen as moral failing, from either children or their parents. Unfortunately, although nowadays there is plenty of proof for the biological basis of ADHD, this view still persists. For ASD, recognition of the importance of genetic influences came not until the 1980’s. At least until the 1960’s, the psychodynamic theory was predominant. According to this theory, autism is caused by parents who lack warmth (‘refrigerator mums’) and provide an adverse family environment.  Today, both ADHD and ASD are seen as neurodevelopmental disorders, with a well-established, strong genetic background. Interestingly, recent studies on the common etiology of ADHD and ASD have shown that a substantial part of genetic influences are shared between ADHD and ASD. Moreover, genetic overlap is suggested by genetic linkage studies for ADHD and ASD, in which overlapping sets of suggestive disease loci have been identified.  Despite their high heritability, it has proven difficult to find genes underlying ADHD and ASD. It is now thought that these disorders are caused by multiple genes with small individual effects. Recent research suggests that an as yet unknown proportion of cases of both ASD and ADHD can also be caused by rare genetic variants, e.g., Copy Number Variations (CNVs), with rather strong effect sizes. Adding to the complexity of the etiology of ADHD and ASD, environmental factors also contribute to the pathogenesis of both disorders, possibly in interaction with genetic factors. The most consistently replicated environmental risk factors for ADHD are maternal smoking during pregnancy and low birth weight, which are autism risk factors as well. Other factors that complicate the search for ADHD and ASD risk genes are the clinical and genetic heterogeneity of both disorders. One way to reduce clinical heterogeneity is to specify the disease phenotype, for instance by focussing on specific symptoms. For ADHD, co-occurring ASD symptoms could possibly fulfil this role. introduction112 Molecular genetic study methods to investigate the origin of ASD symptoms in children with ADHD include genetic linkage and association approaches. Both methods are based on the transmission of disease related genetic variants from generation to generation. In general, a disease variant will be transmitted together with surrounding DNA, with smaller transmitted areas every subsequent generation due to recombination during meiosis. DNA variants close to a disease variant are associated or in ‘linkage disequilibrium’ with the mutation, and can be used as genetic markers. Single nucleotide polymorphisms (SNPs) are the most commonly used markers to date. Linkage analysis is a hypothesis free method to investigate the whole genome for regions that may contain risk genes, and is based on the assumption that siblings with similar disease phenotypes inherit the same disease related mutation as well as the same genetic marker allele associated with that mutation. In association or candidate gene studies, allele frequencies of genetic markers in genes that are selected for their possible role in the pathophysiology of a disease, or for their position in previously identified chromosomal regions, are compared in cases and controls. In the present thesis, both linkage and association are employed. A well-defined sample of children with ADHD and their siblings for whom both phenotypic and genetic data were available was used to investigate the nature and causes of ASD symptoms in children with ADHD. All children were participants of the International Multicenter ADHD Genetics (IMAGE) project, a collaborative study in eight European countries that at aims to identify genes that increase the risk of ADHD using linkage and association strategies. In this thesis, we used data from the larger, international IMAGE sample, as well as from the Dutch IMAGE subsample, for which an extended dataset was collected. To assess ASD symptoms, two instruments were available: one designed as a screening instrument for autism, i.e., the Social Communication Questionnaire (SCQ), and the other developed to investigate ASD symptoms across a wider range of severity, i.e., the Children’s Social Behavior Questionnaire (CSBQ). Chapter 3 presents a study on symptoms of ASD in sibling pairs with at least one child affected with ADHD. We investigated whether we could confirm previous findings of elevated ASD symptom levels in children with ADHD, and whether ASD symptoms are familial. In the studies presented in the subsequent chapters, we explored the genetics underlying the occurrence of ASD symptoms in children with ADHD. Chapter 4 reports on the association between ASD symptoms in children with ADHD and two candidate genes, namely catechol o-methyltransferase (COMT ) and the serotonin transporter gene (SLC6A4/SERT/5-HTT ), as well as the interaction between these genes and perinatal risk factors. In chapters 5 and 6, two whole genome linkage analyses are presented, which were aimed at discovering risk loci for ASD symptoms in children with ADHD. More stringent ASD symptoms are studied in chapter 5, whereas chapter 6 focuses on subtle ASD symptoms. Furthermore, in chapter 6, linkage analysis was followed by association analysis in all significant and suggestive linkage regions. chapter 113In chapter 7, the studies in this thesis are summarized and discussed. Lastly, the implications of our findings for clinical practice are briefly described. introduction1

ASD symptoms in children with ADHD:familial and genetic underpinnings

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ASD symptoms in children with ADHD:familial and genetic underpinnings

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