TY - THES A1 - Lüffe, Teresa Magdalena T1 - Behavioral and pharmacological validation of genetic zebrafish models for ADHD T1 - Pharmakologische und verhaltensbasierte Validierung genetischer Zebrafischmodelle für ADHS N2 - Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder described in psychiatry today. ADHD arises during early childhood and is characterized by an age-inappropriate level of inattention, hyperactivity, impulsivity, and partially emotional dysregulation. Besides, substantial psychiatric comorbidity further broadens the symptomatic spectrum. Despite advances in ADHD research by genetic- and imaging studies, the etiopathogenesis of ADHD remains largely unclear. Twin studies suggest a heritability of 70-80 % that, based on genome-wide investigations, is assumed to be polygenic and a mixed composite of small and large, common and rare genetic variants. In recent years the number of genetic risk candidates is continuously increased. However, for most, a biological link to neuropathology and symptomatology of the patient is still missing. Uncovering this link is vital for a better understanding of the disorder, the identification of new treatment targets, and therefore the development of a more targeted and possibly personalized therapy. The present thesis addresses the issue for the ADHD risk candidates GRM8, FOXP2, and GAD1. By establishing loss of function zebrafish models, using CRISPR/Cas9 derived mutagenesis and antisense oligonucleotides, and studying them for morphological, functional, and behavioral alterations, it provides novel insights into the candidate's contribution to neuropathology and ADHD associated phenotypes. Using locomotor activity as behavioral read-out, the present work identified a genetic and functional implication of Grm8a, Grm8b, Foxp2, and Gad1b in ADHD associated hyperactivity. Further, it provides substantial evidence that the function of Grm8a, Grm8b, Foxp2, and Gad1b in activity regulation involves GABAergic signaling. Preliminary indications suggest that the three candidates interfere with GABAergic signaling in the ventral forebrain/striatum. However, according to present and previous data, via different biological mechanisms such as GABA synthesis, transmitter release regulation, synapse formation and/or transcriptional regulation of synaptic components. Intriguingly, this work further demonstrates that the activity regulating circuit, affected upon Foxp2 and Gad1b loss of function, is involved in the therapeutic effect mechanism of methylphenidate. Altogether, the present thesis identified altered GABAergic signaling in activity regulating circuits in, presumably, the ventral forebrain as neuropathological underpinning of ADHD associated hyperactivity. Further, it demonstrates altered GABAergic signaling as mechanistic link between the genetic disruption of Grm8a, Grm8b, Foxp2, and Gad1b and ADHD symptomatology like hyperactivity. Thus, this thesis highlights GABAergic signaling in activity regulating circuits and, in this context, Grm8a, Grm8b, Foxp2, and Gad1b as exciting targets for future investigations on ADHD etiopathogenesis and the development of novel therapeutic interventions for ADHD related hyperactivity. Additionally, thigmotaxis measurements suggest Grm8a, Grm8b, and Gad1b as interesting candidates for prospective studies on comorbid anxiety in ADHD. Furthermore, expression analysis in foxp2 mutants demonstrates Foxp2 as regulator of ADHD associated gene sets and neurodevelopmental disorder (NDD) overarching genetic and functional networks with possible implications for ADHD polygenicity and comorbidity. Finally, with the characterization of gene expression patterns and the generation and validation of genetic zebrafish models for Grm8a, Grm8b, Foxp2, and Gad1b, the present thesis laid the groundwork for future research efforts, for instance, the identification of the functional circuit(s) and biological mechanism(s) by which Grm8a, Grm8b, Foxp2, and Gad1b loss of function interfere with GABAergic signaling and ultimately induce hyperactivity. N2 - Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) ist mit einer weltweiten Prävalenz von rund 5 % die am häufigsten vorkommende Neuroentwicklungsstörung. Das Krankheitsbild, das zumeist im Kindesalter auftritt und bis ins Erwachsenenalter bestehen kann, zeigt sich im Wesentlichen durch eine Beeinträchtigung der Aufmerksamkeit, der Aktivität, der Impuls-kontrolle und zum Teil durch emotionale Dysregulation. Darüber hinaus führt das vermehrte Auftreten von psychischen Begleiterkrankungen (so genannte Komorbiditäten) zu einer komplexen Symptomatik vieler Betroffener, die über die klassischen Merkmale von ADHS hinausgeht. Während das Krankheitsbild vielfach beschrieben wurde, ist die Ätiopathogenese trotz intensiver wissenschaftlicher Bemühungen bis heute weitestgehend ungeklärt. Zwillingsstudien weisen darauf hin, dass ADHS zu 70-80 % erblich bedingt ist. Aufgrund mehrerer Genom-Studien wird vermutet, dass es sich dabei um eine polygene Vererbbarkeit handelt und sowohl kleine (SNPs), verhältnismäßig häufig auftretende, als auch große (CNVs) verhältnismäßig seltene Genpolymorphismen beteiligt sind. Die Anzahl der potenziellen Risikogene für ADHS ist in den letzten Jahren kontinuierlich gestiegen, jedoch ist es nach wie vor unklar, inwiefern und durch welche biologischen Prozesse die meisten zur Neuropathologie und Symptomatik von ADHS Patienten beitragen. Diese Prozesse zu identifizieren ist von zentraler Bedeutung für ein besseres Verständnis der Erkrankung, der Identifizierung neuer Angriffsziele und somit, der Entwicklung gezielterer und möglicherweise personalisierter Behandlungsmöglichkeiten. Die vorliegende Arbeit befasst sich mit diesen Prozessen am Beispiel der potenziellen Risikogene GRM8, FOXP2 und GAD1. Durch die Etablierung und Validierung entsprechender (geneti-scher) Knockout und Knockdown Zebrafischmodelle und der anschließenden Untersuchung auf Verhaltens-, morphologische und funktionelle Veränderungen liefert die vorliegende Dissertation wichtige Erkenntnisse über die funktionelle Relevanz der einzelnen Kandidaten für die Neuropathologie und die Symptomatik von ADHS. Beispielsweise zeigen die erfassten Aktivitätsdaten von Knockdown und Knockout Larven, dass Grm8a, Grm8b, Foxp2 und Gad1b an der Regulation von Bewegungsaktivität beteiligt sind und dass dies, die korrekte Funktion GABAerger Prozesse bedarf. Des Weiteren liefert die Arbeit Hinweise, dass der Effekt im Subpallium/Striatum verankert ist. Jedoch ist aufgrund vorliegender und bereits publizierter Daten anzunehmen, dass im Falle der einzelnen Kandidaten, zum Teil unterschiedliche Me-chanismen wie die Transmittersynthese, die Transmitterfreisetzung, die Synapsenbildung und die Expression synaptischer Komponenten betroffen sind. Interessanterweise scheinen die durch die Kandidaten betroffenen Signalwege außerdem, laut erhobener Daten, am Wirkmechanismus von Methylphenidat beteiligt zu sein. Kurzum, die vorliegende Dissertation identifiziert die Beeinträchtigung GABAerger Signalübertragung eines, mutmaßlich subpallialen/striatalen aktivitäts-regulierenden neuronalen Netzwerks als neurobiologische Grundlage ADHS-assoziierter Hyperaktivität. Gleichzeitig präsentiert die Arbeit diese Prozesse als funktionelles Bindeglied zwischen der genetischen Veränderung von GRM8, FOXP2 und GAD1 und Hyperaktivität in ADHS. Folglich sind die entwicklungs- und neurobiologischen Mechanismen rund um die GABAerge Übertragung in diesem Netzwerk, und in diesem Zusammenhang die Funktion von Grm8a, (Grm8b), Foxp2 und Gad1b, spannende Ziele für zukünftige Projekte zur Erforschung der Ätiopathogenese und der Entwicklung neuer Therapien von Hyperakti-vität in ADHS. Neben der Rolle in ADHS-assoziierter Hyperaktivität, präsentieren die erhobenen Verhaltensdaten Grm8a, Grm8b und Gad1b außerdem, als interessante Kandidaten für die Erforschung komorbider Angststörung in ADHS. Foxp2 dagegen, wurde mit Hilfe einer Genexpressionsanalyse als Regulator zahlreicher ADHS Risikogene und Entwicklungsstörungs-übergreifenden genetischen und funktionellen Netzwerken, mit möglicher Relevanz für die Polygenie und Komorbidität von ADHS, identifiziert. Im Allgemeinen schafft die vorliegende Dissertation mit der Bestimmung der Genexpressionsmuster und Etablierung und Validierung der (genetischen) Zebrafischmodelle für Grm8a, Grm8b, Foxp2 und Gad1b die Grundlage, diese und weitere Aspekte in zukünftigen Forschungsprojekten zu untersuchen. Beispielsweise die Identifizierung der Netzwerke und Mechanismen, mit dessen Hilfe Grm8a, (Grm8b), Foxp2 und Gad1b in die GABAerge Signalübertragung eingreifen und so letztlich die Aktivität beeinflussen. KW - ADHD KW - Zebrafish KW - FOXP2 KW - GRM8 KW - GAD1 KW - Genetic etiology KW - Animal model KW - Thigmotaxis KW - Locomotor activity KW - Hyperactivity Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257168 ER - TY - THES A1 - Peters, Katharina T1 - Biological Substrates of Waiting Impulsivity in Children and Adolescents with and without ADHD T1 - Biologische Substrate der Warte-Impulsivität bei Kindern und Jugendlichen mit und ohne ADHS N2 - Focus of the present work were the questions whether and how the concept of waiting impulsivity (WI), defined as the ability to regulate a response in anticipation of reward and measured by the 4-choice serial reaction time task (4-CSRTT), may contribute to our understanding of Attention-Deficit/Hyperactivity Disorder (ADHD) and its neurobiological underpinnings. To address this topic, two studies were conducted: in a first study, the relationship be-tween 4-CSRTT behavioral measures, neural correlates and ADHD symptom domains, i.e. inattention (IA) and hyperactivity/impulsivity (H/I) was explored in a pooled sample of 90 children and adolescents with (n=44) and without (n=46) ADHD diagnosis. As ex-pected, IA was associated with dorsolateral prefrontal brain regions linked with executive functions and attentional control, which was evident on the structural and the functional level. Higher levels of both IA and H/I covaried with decreased activity in the right ven-trolateral prefrontal cortex (PFC), a central structure for response inhibition. Moderation analyses revealed that H/I-related decreased activation in this region did not map linearly on difficulties on the behavioral level: brain activation was a significant predictor of task accuracy only, when H/I symptoms were low/absent but not for clinically relevant ADHD symptoms. Further, H/I was implicated in dysfunctional top-down control of reward eval-uation. Both symptom domains correlated positively with hippocampus (HC) activity in anticipation of reward. In addition, for high H/I symptoms, greater activation in the HC was found to correlate with higher motivation on the behavioral level, indicating that rein-forcement-learning and/or contingency awareness may contribute to altered reward pro-cessing in ADHD patients. In a second study, the possible serotonergic modulation of WI and the ADHD-WI relation-ship was addressed in a sub-sample comprising 86 children and adolescents of study I. The effects of a functional variant in the gene coding for the rate-limiting enzyme in the synthesis of brain serotonin on behavior and structure or function of the WI-network was investigated. Moderation analyses revealed that on the behavioral level, a negative corre-lation between accuracy and IA was found only in GG-homozygotes, whereas no signifi-cant relationship emerged for carriers of the T-allele. This is in line with previous reports of differential effects of serotonergic modulation on attentional performance depending on the presence of ADHD symptoms. A trend-wise interaction effect of genotype and IA for regional volume of the right middle frontal gyrus was interpreted as a hint towards an involvement of the PFC in this relationship, although a more complex mechanism includ-ing developmental effects can be assumed. In addition, interaction effects of genotype and IA were found for brain activation in the amygdala (AMY) und HC during perfor-mance of the 4-CSRTT, while another interaction was found for H/I symptoms and geno-type for right AMY volume. These findings indicate a serotonergic modulation of coding of the emotional value of reward during performance of the 4-CSRTT that varies de-pending on the extent of psychopathology-associated traits. Taken together, it was shown that the 4-CSRTT taps distinct domains of impulsivity with relevance to ADHD symptomatology: (proactive) response inhibition difficulties in relation with anticipation of reward. Furthermore, the two symptom domains, IA and H/I, contrib-ute differently to WI, which emphasizes the need to distinguish both in the research of ADHD. The results of study II emphasized the relevance of serotonergic transmission especially for attentional control and emotional processing. Although the present findings need replication and further refinement in more homogenous age groups, the use of the 4-CSRTT with a dimensional approach is a very promising strategy, which will hopefully extend our understanding of impulsivity-related mental disorders in the future. N2 - Im Mittelpunkt der vorliegenden Arbeit steht das Konzept der Warte-Impulsivität (WI), definiert als die Fähigkeit der Antwort-Inhibition, während eine Belohnung erwartet wird, welche mittels des 4-choice serial reaction time task (4-CSRTT) erfasst werden kann. Es sollte untersucht werden ob und auf welche Weise WI und der 4-CSRTT genutzt werden können, um die neurobiologischen Grundlagen der Aufmerksamkeits-Defizit/Hyperaktivitäts-Störung (ADHS) besser zu verstehen. Es wurden zwei Studien durchgeführt: In einer ersten Studie wurde der Zusammenhang zwischen 4-CSRTT Verhaltensmaßen, ihren neuronalen Korrelaten und den ADHS Kern-Symptomen, Unaufmerksamkeit (IA) und Hyperaktivität/Impulsivität (H/I), überprüft. Es wurden 90 Kinder und Jugendliche mit (n=44) und ohne (n=46) ADHS-Diagnose unter-sucht. Erwartungsgemäß war IA, auf funktioneller und struktureller Ebene, mit dorsolate-ralen präfrontalen Hirnregionen assoziiert, die für Exekutivfunktionen und die Aufmerk-samkeitskontrolle zuständig sind. Stärkere Ausprägungen von IA und H/I gingen mit ver-ringerter Aktivität im rechten ventrolateralen präfrontalen Cortex (PFC), einer zentralen Struktur für die Inhibition von Antworten, einher. Moderationsanalysen ergaben, dass diese H/I-assoziierte geringere Aktivität nicht direkt mit Einschränkungen auf Verhaltens-ebene zusammenhing: Die Hirnaktivierung war nur in Abwesenheit von H/I Symptomen ein signifikanter Prädiktor der Sorgfaltsleistung, was bei stärkerer ADHS-Symptomatik nicht der Fall war. Darüber hinaus wiesen die Ergebnisse auf einen Zusammenhang zwi-schen H/I und dysfunktionaler Belohnungsverarbeitung hin. Beide Symptombereiche korrelierten während der Belohnungserwartung positiv mit Aktivität im Hippocampus (HC). Zusätzlich zeigte sich, dass bei stark ausgeprägten H/I-Symptomen eine höhere HC-Aktivierung mit höherer Motivation auf Verhaltensebene einher ging. Dies deutet da-rauf hin, dass Lernprozesse und ein Bewusstsein für Kontingenz bei der Verarbeitung von Belohnungen bei ADHS eine Rolle spielen könnten. In einer zweiten Studie wurde eine mögliche serotonerge Modulation von WI und dem WI-ADHS Zusammenhang betrachtet. Eine Teilstichprobe von 86 Probanden aus Studie I wurde untersucht. Eine funktionelle Genvariante des Enzyms, welches den entschei-denden Schritt in der Serotonin-Synthese im Gehirn katalysiert, wurde bezüglich seiner Effekte auf WI-Verhalten sowie Struktur und Funktion des WI-Netzwerks getestet. Mode-rationsanalysen zeigten, dass auf Verhaltensebene eine negative Korrelation zwischen IA und der Sorgfaltsleistung bei GG-Homozygoten, aber kein signifikanter Zusammenhang für Träger des T-Allels bestand. Unterschiedliche Effekte von serotonerger Modulation auf die Aufmerksamkeitsleistung in Abhängigkeit von ADHS-Symptomatik wurden be-reits in der Literatur berichtet. Ein Trend-Effekt für die Interaktion zwischen Genotyp und IA und dem Volumen des rechten Gyrus frontalis medius wurde als Hinweis auf eine Be-teiligung des PFC in diesem Zusammenhang interpretiert. Auf Grund möglicher Entwick-lungseffekte, ist aber ein komplexeres Zusammenspiel der verschiedenen Faktoren an-zunehmen. Interaktionseffekte von Genotyp und IA für Aktivität der Amygdala (AMY) und dem HC sowie für H/I und Genotyp bezüglich des Volumens der rechten AMY könn-ten auf eine serotonerge Modulation der emotionalen Bewertung von Belohnung hindeu-ten, die je nach ADHS-Symptomatik unterschiedlich ausfällt. Zusammenfassend zeigte sich, dass mittels des 4-CSRTT ADHS-relevante Aspekte von Impulsivität untersucht werden können: Schwierigkeiten der Antwortinhibition im Kontext von Belohnungserwartung. Sowohl IA als auch H/I hatten unterschiedlichen Einfluss auf WI. Sie sollten in der ADHS-Forschung differenziert betrachtet werden. Die Ergebnisse der zweiten Studie verdeutlichen, dass die serotonerge Transmission bei ADHS beson-ders bei Aufmerksamkeitsprozessen und emotionaler Verarbeitung eine Rolle spielt. Die vorliegenden Befunde sollten in homogeneren Alterskohorten überprüft werden. Sie ma-chen jedoch Hoffnung, dass mittels des 4-CSRTT und dimensionaler Forschungsansätze psychiatrische Störungen der Impulskontrolle besser verstanden werden können. KW - Aufmerksamkeitsdefizit-Syndrom KW - Impulsivität KW - ADHD KW - Waiting Impulsivity Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246368 ER - TY - JOUR A1 - Fernàndez-Castillo, Noèlia A1 - Cabana-Domínguez, Judit A1 - Kappel, Djenifer B. A1 - Torrico, Bàrbara A1 - Weber, Heike A1 - Lesch, Klaus-Peter A1 - Lao, Oscar A1 - Reif, Andreas A1 - Cormand, Bru T1 - Exploring the contribution to ADHD of genes involved in Mendelian disorders presenting with hyperactivity and/or inattention JF - Genes N2 - Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders. KW - ADHD KW - rare mendelian disorders KW - genetic variants Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252346 SN - 2073-4425 VL - 13 IS - 1 ER - TY - JOUR A1 - Ziegler, Georg C. A1 - Ehlis, Ann-Christine A1 - Weber, Heike A1 - Vitale, Maria Rosaria A1 - Zöller, Johanna E. M. A1 - Ku, Hsing-Ping A1 - Schiele, Miriam A. A1 - Kürbitz, Laura I. A1 - Romanos, Marcel A1 - Pauli, Paul A1 - Kalisch, Raffael A1 - Zwanzger, Peter A1 - Domschke, Katharina A1 - Fallgatter, Andreas J. A1 - Reif, Andreas A1 - Lesch, Klaus-Peter T1 - A Common CDH13 Variant is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD JF - Genes N2 - The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD. KW - ADHD KW - CDH13 KW - neurodevelopment KW - executive functions KW - working memory KW - Big Five KW - agreeableness Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245220 SN - 2073-4425 VL - 12 IS - 9 ER - TY - THES A1 - Mortimer, Niall Patrick T1 - ADHD Genetics in Mouse and Man T1 - ADHS Genetik bei Maus und Mensch T1 - Genética del TDAH en ratón y hombre N2 - Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with an estimated heritability of around 70%. In order to fully understand ADHD biology it is necessary to incorporate multiple different types of research. In this thesis, both human and animal model research is described as both lines of research are required to elucidate the aetiology of ADHD and development new treatments. The role of a single gene, Adhesion G protein-coupled receptor L3 (ADGRL3) was investigated using a knockout mouse model. ADGRL3 has putative roles in neuronal migration and synapse function. Various polymorphisms in ADGRL3 have been linked with an increased risk of attention deficit/hyperactivity disorder (ADHD) in human studies. Adgrl3-deficient mice were examined across multiple behavioural domains related to ADHD: locomotive activity, visuospatial and recognition memory, gait impulsivity, aggression, sociability and anxiety-like behaviour. The transcriptomic alterations caused by Adgrl3-depletion were analysed by RNA-sequencing of three ADHD-relevant brain regions: prefrontal cortex (PFC), hippocampus and striatum. Increased locomotive activity in Adgrl3-/- mice was observed across all tests with the specific gait analysis revealing subtle gait abnormalities. Spatial memory and learning domains were also impaired in these mice. Increased levels of impulsivity and sociability accompanying decreased aggression were also detected. None of these alterations were observed in Adgrl3+/- mice. The numbers of genes found to exhibit differential expression was relatively small in all brain regions sequenced. The absence of large scale gene expression dysregulation indicates a specific pathway of action, rather than a broad neurobiological perturbation. The PFC had the greatest number of differentially expressed genes and gene-set analysis of differential expression in this brain region detected a number of ADHD-relevant pathways including dopaminergic synapses as well as cocaine and amphetamine addiction. The most dysregulated gene in the PFC was Slc6a3 which codes for the dopamine transporter, a molecule vital to current pharmacological treatment of ADHD. The behavioural and transcriptomic results described in this thesis further validate Adgrl3 constitutive knockout mice as an experimental model of ADHD and provide neuroanatomical targets for future studies involving ADGRL3 modified animal models. The study of ADHD risk genes such as ADGRL3 requires the gene to be first identified using human studies. These studies may be genome based such as genome wide association studies (GWAS) or transcriptome based using microarray or RNA sequencing technology. To explore ADHD biology in humans the research described in this thesis includes both GWAS and trancriptomic data. A two-step transcriptome profiling was performed in peripheral blood mononuclear cells (PBMCs) of 143 ADHD subjects and 169 healthy controls. We combined GWAS and expression data in an expression-based Polygenic Risk Score (PRS) analysis in a total sample of 879 ADHD cases and 1919 controls from three different datasets. Through this exploratory study we found eight differentially expressed genes in ADHD and no support for the genetic background of the disorder playing a role in the aberrant expression levels identified. These results highlight promising candidate genes and gene pathways for ADHD and support the use of peripheral tissues to assess gene expression signatures for ADHD. This thesis illustrates how both human and animal model research is required to increase our understanding of ADHD. The animal models provide biological insight into the targets identified in human studies and may themselves provide further relevant gene targets. Only by combining research from disparate sources can we develop the thorough understanding on ADHD biology required for treatment development, which is the ultimate goal of translational science research. N2 - Die Aufmerksamkeitsdefizit- / Hyperaktivitätsstörung (ADHS) ist eine neurologische Entwicklungsstörung mit einer geschätzten Erblichkeit von etwa 70%. Um die ADHS-Biologie vollständig verstehen zu können, müssen verschiedene Forschungsansätze verfolgt werden. In dieser Dissertation werden sowohl Forschungsansätze am Menschen als auch im Tiermodell beschrieben, da beide Forschungsansätze erforderlich sind, um die Ätiologie von ADHS aufzuklären und neue Therapien zu entwickeln. Die Rolle eines einzelnen Gens, des Adhesion G-Protein-gekoppelten Rezeptors L3 (ADGRL3), wurde unter Verwendung eines Knockout-Mausmodells untersucht. ADGRL3 spielt eine mutmaßliche Rolle bei der neuronalen Migration und der Synapsenfunktion. Verschiedene Polymorphismen in ADGRL3 wurden in Studien an Menschen mit einem erhöhten Risiko für Aufmerksamkeitsdefizit- / Hyperaktivitätsstörung (ADHS) in Verbindung gebracht. Adgrl3-defiziente Mäuse wurden in mehreren Verhaltensbereichen im Zusammenhang mit ADHS untersucht: Bewegungsaktivität, visuelles und Erkennungsgedächtnis, Gangimpulsivität, Aggression, Umgänglichkeit und angstartiges Verhalten. Die durch Adgrl3-Depletion verursachten transkriptomischen Veränderungen wurden durch RNA-Sequenzierung von drei ADHS-relevanten Hirnregionen analysiert: präfrontaler Cortex (PFC), Hippocampus und Striatum. Bei allen Tests wurde eine erhöhte Aktivität der Lokomotive bei Adgrl3 - / - Mäusen beobachtet, wobei die spezifische Ganganalyse subtile Gangstörungen aufdeckte. Das räumliche Gedächtnis und die Lerndomänen waren bei diesen Mäusen ebenfalls beeinträchtigt. Es wurde auch ein erhöhtes Maß an Impulsivität und Umgänglichkeit festgestellt, begleitet von verminderter Aggression. Keine dieser Veränderungen wurde bei Adgrl3 +/- Mäusen beobachtet. Die Anzahl der Gene, bei denen eine unterschiedliche Expression festgestellt wurde, war in allen sequenzierten Hirnregionen relativ gering. Das Fehlen einer Dysregulation der Genexpression in großem Maßstab weist eher auf einen spezifischen Wirkmechanismus als auf eine breite neurobiologische Störung hin. Die PFC hatte die größte Anzahl differentiell exprimierter Gene, und eine Gen-Set-Analyse der differentiellen Expression in dieser Hirnregion ergab eine Reihe von ADHS-relevanten Signalwegen, einschließlich dopaminerger Synapsen sowie Kokain- und Amphetaminsucht. Das am stärksten dysregulierte Gen in der PFC war Slc6a3, das für den Dopamintransporter kodiert.Dieses Gen ist bei der derzeitigen pharmakologischen Behandlung von ADHS von entscheidender Bedeutung. Die in dieser Arbeit beschriebenen Verhaltens- und Transkriptomergebnisse bestätigen die konstitutiven Adgrl3-Knockout-Mäuse als experimentelles Modell für ADHS und liefern neuroanatomische Zielstrukturen für zukünftige Studien mit ADGRL3-modifizierten Tiermodellen. Die Untersuchung von ADHS-Risikogenen wie ADGRL3 erfordert zunächst, dass das Gen in Studien im Menschen identifiziert wird. Diese Studien können genombasiert sein, z.B. wie genomweite Assoziationsstudie (GWAS), oder transkriptombasiert unter Verwendung von Microarray- oder RNA-Sequenzierungstechnologie. Um die ADHS-Biologie beim Menschen zu erforschen, umfassen die in dieser Arbeit beschriebenen Forschungsansätze sowohl GWAS- als auch trankriptomische Daten. Ein zweistufiges Transkriptom-Profiling wurde in mononukleären Zellen des peripheren Blutes (PBMCs) von 143 ADHS-Patienten und 169 gesunden Kontrollpersonen durchgeführt. Wir kombinierten GWAS- und Expressionsdaten in einer Expressions-basierten PRS-Analyse (Polygenic Risk Score) in einer Gesamtstichprobe von 879 ADHS-Fällen und 1919 Kontrollen aus drei verschiedenen Datensätzen. Durch diese Untersuchungen fanden wir acht differentiell exprimierte Gene bei ADHS und keinen Hinweis darauf, dass der genetische Hintergrund der Störung eine Rolle bei den identifizierten aberranten Expressionsniveaus spielt. Diese Ergebnisse weisen auf vielversprechende Kandidatengene und Genwege für ADHS hin und unterstützen die Verwendung peripherer Gewebe zur Beurteilung der Genexpressionssignaturen für ADHS. Diese Arbeit zeigt, dass sowohl Forschungsansätze am Menschen als auch Tiermodelle erforderlich sind, um unser Verständnis von ADHS zu verbessern. Die Tiermodelle bieten biologische Einblicke in die in Studien an Menschen identifizierten Ziele und können selbst weitere relevante Genziele liefern. Nur durch die Kombination von Forschungsansätzen aus unterschiedlichen Quellen können wir ein tiefes Verständnis der ADHS-Biologie entwickeln, das für die Entwicklung von Behandlungsstrategien erforderlich ist. Dies ist das ultimative Ziel der translationalen wissenschaftlichen Forschung. N2 - El trastorno por déficit de atención con hiperactividad (TDAH) es un trastorno del desarrollo neural con una heredabilidad estimada de alrededor de un 70%. Para poder comprender plenamente la biología del TDAH, es necesario incorporar diversos tipos de investigación. En esta tesis, se describe la investigación en modelos tanto humanos como animales, ya que se requieren ambas líneas de investigación para aclarar la etiología del TDAH y poder desarrollar nuevos tratamientos. El papel de un solo gen, el receptor L3 acoplado a la proteína de adhesión G (ADGRL3) se ha investigado utilizando un modelo de ratón knock-out. El ADGRL3 tiene efectos putativos en la migración neuronal y en la función de la sinapsis. Varios polimorfismos en ADGRL3 se han relacionado con un mayor riesgo de trastorno por déficit de atención/ hiperactividad (TDAH) en estudios en humanos. Adicionalmente se han examinado ratones deficientes en ADGRL3 en varios ámbitos conductuales relacionados con el TDAH tales como la actividad locomotriz, la memoria visoespacial y de reconocimiento, la impulsividad de la marcha, la agresividad, la sociabilidad y los comportamientos similares a la ansiedad. Las modificaciones trabscriptómicas causadas por el agotamiento de ADGRL3 se han analizado por secuenciación del ARN de tres regiones del cerebro relevantes al TDAH: la corteza prefrontal (CPF), el hipocampo, y el estriado. Se ha observado una mayor actividad locomotriz en ratones ADGRL3 -/- en todas las pruebas con el análisis específico de la marcha que revela anomalías sutiles de la marcha. La memoria espacial y los dominios de aprendizaje también se han visto afectados en estos mismos ratones. También se detectaron niveles aumentados de impulsividad y sociabilidad que acompañan a la disminución de la agresividad. Ninguno de estos cambios se han observado en ratones ADGRL3 +/-. El número de genes encontrados que exhibieron una expresión diferencial ha sido relativamente bajo en todas las regiones del cerebro secuenciadas. La ausencia de desregulación de expresión génica a gran escala indica una vía de acción específica, en vez de una perturbación neurobiológica amplia. La corteza prefrontal tenía el mayor número de genes expresados diferencialmente y el análisis de conjuntos de genes de expresión diferencial en esta región del cerebro ha mostrado una serie de vías relevantes para el TDAH, incluyendo las sinapsis dopaminérgicas así como la adicción a la cocaína y a las anfetaminas. El gen más desregulado en la corteza prefrontal fue el Slc6a3, que codifica para el transportador de dopamina, una molécula esencial para el tratamiento farmacológico actual del TDAH. Los resultados conductuales y transcriptómicos descritos en esta tesis dan aún más validez a los ratones knock-out constitutivos de Adgrl3 como modelo experimental de TDAH y ofrecen objetivos neuroanatómicos para estudios futuros con modelos animales modificados con ADGRL3. El estudio de genes de riesgo de TDAH como el ADGRL3 requiere que el gen se identifique primero mediante estudios en humanos. Estos estudios pueden basarse en el genoma, como GWAS (estudio extenso de asociación en todo el genoma) o en transcriptoma, usando microarrays o tecnología de secuenciación de ARN. Para explorar la biología del TDAH en humanos, la investigación descrita en esta tesis incluye datos GWAS y trancriptómicos. Se ha realizado un perfil de transcriptoma de dos fases en células mononucleares de sangre periférica (CMSP) de 143 sujetos con TDAH y 169 controles sanos. Hemos combinado GWAS y datos de expresión en un análisis de puntuación de riesgo poligénico con sede en expression genica en una muestra total de 879 casos de TDAH y 1919 controles de tres conjuntos de datos distintos. A través de este estudio exploratorio, hemos encontrado ocho genes expresados diferencialmente en el TDAH y además que no existe indicio de que el fondo genético del trastorno tiene un papel en los niveles de expresión aberrantes identificados. Estos resultados subrayan genes candidatos prometedores y vías genéticas para el TDAH y además apoyan el uso de tejidos periféricos para evaluar las firmas de expresión génica para el TDAH Esta tesis muestra cómo se requiere la investigación en modelos humanos y animales para aumentar nuestra comprensión del TDAH. Los modelos animales proporcionan información biológica sobre los objetivos identificados en estudios en humanos y pueden proporcionar objetivos genéticos relevantes adicionales. Solo mediante la combinación de las investigaciones de fuentes dispares podemos desarrollar la comprensión exhaustiva de la biología del TDAH necesaria para el desarrollo del tratamiento, lo que es el objetivo principal de la investigación científica traslacional. KW - ADGRL3 KW - Neuroscience KW - Genetics KW - ADHD KW - Mouse Model KW - Human Transcriptome Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236265 ER - TY - JOUR A1 - Capetian, Philipp A1 - Roessner, Veit A1 - Korte, Caroline A1 - Walitza, Susanne A1 - Riederer, Franz A1 - Taurines, Regina A1 - Gerlach, Manfred A1 - Moser, Andreas T1 - Altered urinary tetrahydroisoquinoline derivatives in patients with Tourette syndrome: reflection of dopaminergic hyperactivity? JF - Journal of Neural Transmission N2 - Tetrahydroisoquinolines (TIQs) such as salsolinol (SAL), norsalsolinol (NSAL) and their methylated derivatives N-methyl-norsalsolinol (NMNSAL) and N-methyl-salsolinol (NMSAL), modulate dopaminergic neurotransmission and metabolism in the central nervous system. Dopaminergic neurotransmission is thought to play an important role in the pathophysiology of chronic tic disorders, such as Tourette syndrome (TS). Therefore, the urinary concentrations of these TIQ derivatives were measured in patients with TS and patients with comorbid attention-deficit/hyperactivity disorder (TS + ADHD) compared with controls. Seventeen patients with TS, 12 with TS and ADHD, and 19 age-matched healthy controls with no medication took part in this study. Free levels of NSAL, NMNSAL, SAL, and NMSAL in urine were measured by a two-phase chromatographic approach. Furthermore, individual TIQ concentrations in TS patients were used in receiver-operating characteristics (ROC) curve analysis to examine the diagnostic value. NSAL concentrations were elevated significantly in TS [434.67 ± 55.4 nmol/l (standard error of mean = S.E.M.), two-way ANOVA, p < 0.0001] and TS + ADHD patients [605.18 ± 170.21 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] compared with controls [107.02 ± 33.18 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] and NSAL levels in TS + ADHD patients were elevated significantly in comparison with TS patients (two-way ANOVA, p = 0.017). NSAL demonstrated an AUC of 0.93 ± 0.046 (S.E.M) the highest diagnostic value of all metabolites for the diagnosis of TS. Our results suggest a dopaminergic hyperactivity underlying the pathophysiology of TS and ADHD. In addition, NSAL concentrations in urine may be a potential diagnostic biomarker of TS. KW - Tourette syndrome KW - ADHD KW - tics KW - biomarkers KW - tetrahydroisoquinoline derivates Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235771 SN - 0300-9564 VL - 128 ER - TY - JOUR A1 - Grimm, Oliver A1 - Weber, Heike A1 - Kittel-Schneider, Sarah A1 - Kranz, Thorsten M. A1 - Jacob, Christian P. A1 - Lesch, Klaus-Peter A1 - Reif, Andreas T1 - Impulsivity and Venturesomeness in an Adult ADHD Sample: Relation to Personality, Comorbidity, and Polygenic Risk JF - Frontiers in Psychiatry N2 - While impulsivity is a basic feature of attention-deficit/hyperactivity disorder (ADHD), no study explored the effect of different components of the Impulsiveness (Imp) and Venturesomeness (Vent) scale (IV7) on psychiatric comorbidities and an ADHD polygenic risk score (PRS). We used the IV7 self-report scale in an adult ADHD sample of 903 patients, 70% suffering from additional comorbid disorders, and in a subsample of 435 genotyped patients. Venturesomeness, unlike immediate Impulsivity, is not specific to ADHD. We consequently analyzed the influence of Imp and Vent also in the context of a PRS on psychiatric comorbidities of ADHD. Vent shows a distinctly different distribution of comorbidities, e.g., less anxiety and depression. PRS showed no effect on different ADHD comorbidities, but correlated with childhood hyperactivity. In a complementary analysis using principal component analysis with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD criteria, revised NEO Personality Inventory, Imp, Vent, and PRS, we identified three ADHD subtypes. These are an impulsive–neurotic type, an adventurous–hyperactive type with a stronger genetic component, and an anxious–inattentive type. Our study thus suggests the importance of adventurousness and the differential consideration of impulsivity in ADHD. The genetic risk is distributed differently between these subtypes, which underlines the importance of clinically motivated subtyping. Impulsivity subtyping might give insights into the organization of comorbid disorders in ADHD and different genetic background. KW - impulsivity KW - ADHD KW - polygenic risk score KW - venturesomeness KW - substance abuse disorder KW - attention KW - hyperactivity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219751 SN - 1664-0640 VL - 11 ER - TY - JOUR A1 - Palladino, Viola Stella A1 - Chiocchetti, Andreas G. A1 - Frank, Lukas A1 - Haslinger, Denise A1 - McNeill, Rhiannon A1 - Radtke, Franziska A1 - Till, Andreas A1 - Haupt, Simone A1 - Brüstle, Oliver A1 - Günther, Katharina A1 - Edenhofer, Frank A1 - Hoffmann, Per A1 - Reif, Andreas A1 - Kittel-Schneider, Sarah T1 - Energy metabolism disturbances in cell models of PARK2 CNV carriers with ADHD JF - Journal of Clinical Medicine N2 - The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics. KW - ADHD KW - hiPSC KW - PARK2 KW - mitochondria KW - disease modelling Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220074 SN - 2077-0383 VL - 9 IS - 12 ER - TY - JOUR A1 - Baader, Anna A1 - Kiani, Behnaz A1 - Brunkhorst-Kanaan, Nathalie A1 - Kittel-Schneider, Sarah A1 - Reif, Andreas A1 - Grimm, Oliver T1 - A within-sample comparison of two innovative neuropsychological tests for assessing ADHD JF - Brain Sciences N2 - New innovative neuropsychological tests in attention deficit hyperactivity disorder ADHD have been proposed as objective measures for diagnosis and therapy. The current study aims to investigate two different commercial continuous performance tests (CPT) in a head-to-head comparison regarding their comparability and their link with clinical parameters. The CPTs were evaluated in a clinical sample of 29 adult patients presenting in an ADHD outpatient clinic. Correlational analyses were performed between neuropsychological data, clinical rating scales, and a personality-based measure. Though inattention was found to positively correlate between the two tests (r = 0.49, p = 0.01), no association with clinical measures and inattention was found for both tests. While hyperactivity did not correlate between both tests, current ADHD symptoms were positively associated with Nesplora Aquarium's motor activity (r = 0.52 to 0.61, p < 0.05) and the Qb-Test's hyperactivity (r = 0.52 to 0.71, p < 0.05). Conclusively, the overall comparability of the tests was limited and correlation with clinical parameters was low. While our study shows some interesting correlation between clinical symptoms and sub-scales of these tests, usage in clinical practice is not recommended. KW - ADHD KW - neuropsychology KW - continuous performance test KW - Qb-Test KW - Nesplora Aquarium KW - attention KW - hyperactivity KW - GHQ-28 KW - UPPS KW - impulsivity Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220089 SN - 2076-3425 VL - 11 IS - 1 ER - TY - JOUR A1 - Biere, Silvia A1 - Kranz, Thorsten M. A1 - Matura, Silke A1 - Petrova, Kristiyana A1 - Streit, Fabian A1 - Chiocchetti, Andreas G. A1 - Grimm, Oliver A1 - Brum, Murielle A1 - Brunkhorst-Kanaan, Natalie A1 - Oertel, Viola A1 - Malyshau, Aliaksandr A1 - Pfennig, Andrea A1 - Bauer, Michael A1 - Schulze, Thomas G. A1 - Kittel-Schneider, Sarah A1 - Reif, Andreas T1 - Risk Stratification for Bipolar Disorder Using Polygenic Risk Scores Among Young High-Risk Adults JF - Frontiers in Psychiatry N2 - Objective: Identifying high-risk groups with an increased genetic liability for bipolar disorder (BD) will provide insights into the etiology of BD and contribute to early detection of BD. We used the BD polygenic risk score (PRS) derived from BD genome-wide association studies (GWAS) to explore how such genetic risk manifests in young, high-risk adults. We postulated that BD-PRS would be associated with risk factors for BD. Methods: A final sample of 185 young, high-risk German adults (aged 18–35 years) were grouped into three risk groups and compared to a healthy control group (n = 1,100). The risk groups comprised 117 cases with attention deficit hyperactivity disorder (ADHD), 45 with major depressive disorder (MDD), and 23 help-seeking adults with early recognition symptoms [ER: positive family history for BD, (sub)threshold affective symptomatology and/or mood swings, sleeping disorder]. BD-PRS was computed for each participant. Logistic regression models (controlling for sex, age, and the first five ancestry principal components) were used to assess associations of BD-PRS and the high-risk phenotypes. Results: We observed an association between BD-PRS and combined risk group status (OR = 1.48, p < 0.001), ADHD diagnosis (OR = 1.32, p = 0.009), MDD diagnosis (OR = 1.96, p < 0.001), and ER group status (OR = 1.7, p = 0.025; not significant after correction for multiple testing) compared to healthy controls. Conclusions: In the present study, increased genetic risk for BD was a significant predictor for MDD and ADHD status, but not for ER. These findings support an underlying shared risk for both MDD and BD as well as ADHD and BD. Improving our understanding of the underlying genetic architecture of these phenotypes may aid in early identification and risk stratification. KW - polygenic risk score KW - bipolar disorder KW - genetic phenotypes KW - depression KW - ADHD KW - early recognition Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214976 VL - 11 ER - TY - JOUR A1 - McNeill, Rhiannon V. A1 - Ziegler, Georg C. A1 - Radtke, Franziska A1 - Nieberler, Matthias A1 - Lesch, Klaus‑Peter A1 - Kittel‑Schneider, Sarah T1 - Mental health dished up — the use of iPSC models in neuropsychiatric research JF - Journal of Neural Transmission N2 - Genetic and molecular mechanisms that play a causal role in mental illnesses are challenging to elucidate, particularly as there is a lack of relevant in vitro and in vivo models. However, the advent of induced pluripotent stem cell (iPSC) technology has provided researchers with a novel toolbox. We conducted a systematic review using the PRISMA statement. A PubMed and Web of Science online search was performed (studies published between 2006–2020) using the following search strategy: hiPSC OR iPSC OR iPS OR stem cells AND schizophrenia disorder OR personality disorder OR antisocial personality disorder OR psychopathy OR bipolar disorder OR major depressive disorder OR obsessive compulsive disorder OR anxiety disorder OR substance use disorder OR alcohol use disorder OR nicotine use disorder OR opioid use disorder OR eating disorder OR anorexia nervosa OR attention-deficit/hyperactivity disorder OR gaming disorder. Using the above search criteria, a total of 3515 studies were found. After screening, a final total of 56 studies were deemed eligible for inclusion in our study. Using iPSC technology, psychiatric disease can be studied in the context of a patient’s own unique genetic background. This has allowed great strides to be made into uncovering the etiology of psychiatric disease, as well as providing a unique paradigm for drug testing. However, there is a lack of data for certain psychiatric disorders and several limitations to present iPSC-based studies, leading us to discuss how this field may progress in the next years to increase its utility in the battle to understand psychiatric disease. KW - hiPSC KW - iPSC KW - stem cells KW - mental disorders KW - affective disorders KW - ADHD Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235666 SN - 0300-9564 VL - 127 ER - TY - THES A1 - Kiser, Dominik Pascal T1 - Gene x Environment Interactions in Cdh13-deficient Mice: CDH13 as a Factor for Adaptation to the Environment T1 - Gen x Umwelt-Interaktionen in Cdh13-defizienten Mäusen: CDH13 als ein Faktor für Umweltanpassung N2 - Neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are disorders of mostly unknown etiopathogenesis, for which both genetic and environmental influences are expected to contribute to the phenotype observed in patients. Changes at all levels of brain function, from network connectivity between brain areas, over neuronal survival, synaptic connectivity and axonal growth, down to molecular changes and epigenetic modifications are suspected to play a key roles in these diseases, resulting in life-long behavioural changes. Genome-wide association as well as copy-number variation studies have linked cadherin-13 (CDH13) as a novel genetic risk factor to neuropsychiatric and neurodevelopmental disorders. CDH13 is highly expressed during embryonic brain development, as well as in the adult brain, where it is present in regions including the hippocampus, striatum and thalamus (among others) and is upregulated in response to chronic stress exposure. It is however unclear how CDH13 interacts with environmentally relevant cues, including stressful triggers, in the formation of long-lasting behavioural and molecular changes. It is currently unknown how the environment influences CDH13 and which long term changes in behaviour and gene expression are caused by their interaction. This work therefore investigates the interaction between CDH13 deficiency and neonatal maternal separation (MS) in mice with the aim to elucidate the function of CDH13 and its role in the response to early-life stress (ELS). For this purpose, mixed litters of wild-type (Cdh13+/+), heterozygous (Cdh13+/-) and homozygous knockout (Cdh13-/-) mice were maternally separated from postnatal day 1 (PN1) to postnatal day 14 (PN14) for 3 hours each day (180MS; PN1-PN14). In a first series of experiments, these mice were subjected to a battery of behavioural tests starting at 8 weeks of age in order to assess motor activity, memory functions as well as measures of anxiety. Subsequently, expression of RNA in various brain regions was measured using quantitativ real-time polymerase chain reaction (qRT-PCR). A second cohort of mice was exposed to the same MS procedure, but was not behaviourally tested, to assess molecular changes in hippocampus using RNA sequencing. Behavioural analysis revealed that MS had an overall anxiolytic-like effect, with mice after MS spending more time in the open arms of the elevated-plus-maze (EPM) and the light compartment in the light-dark box (LDB). As a notable exception, Cdh13-/- mice did not show an increase of time spent in the light compartment after MS compared to Cdh13+/+ and Cdh13+/- MS mice. During the Barnes-maze learning task, mice of most groups showed a similar ability in learning the location of the escape hole, both in terms of primary latency and primary errors. Cdh13-/- control (CTRL) mice however committed more primary errors than Cdh13-/- MS mice. In the contextual fear conditioning (cFC) test, Cdh13-/- mice showed more freezing responses during the extinction recall, indicating a reduced extinction of fear memory. In the step-down test, an impulsivity task, Cdh13-/- mice had a tendency to wait longer before stepping down from the platform, indicative of more hesitant behaviour. In the same animals, qRT-PCR of several brain areas revealed changes in the GABAergic and glutamatergic systems, while also highlighting changes in the gatekeeper enzyme Glykogensynthase-Kinase 3 (Gsk3a), both in relation to Cdh13 deficiency and MS. Results from the RNA sequencing study and subsequent gene-set enrichment analysis revealed changes in adhesion and developmental genes due to Cdh13 deficiency, while also highlighting a strong link between CDH13 and endoplasmatic reticulum function. In addition, some results suggest that MS increased pro-survival pathways, while a gene x environment analysis showed alterations in apoptotic pathways and migration, as well as immune factors and membrane metabolism. An analysis of the overlap between gene and environment, as well as their interaction, highlighted an effect on cell adhesion factors, underscoring their importance for adaptation to the environment. Overall, the stress model resulted in increased stress resilience in Cdh13+/+ and Cdh13+/- mice, a change absent in Cdh13-/- mice, suggesting a role of CDH13 during programming and adaptation to early-life experiences, that can results in long-lasting consequences on brain functions and associated behaviours. These changes were also visible in the RNA sequencing, where key pathways for cell-cell adhesion, neuronal survival and cell-stress adaptation were altered. In conclusion, these findings further highlight the role of CDH13 during brain development, while also shedding light on its function in the adaptation and response during (early life) environmental challenges. N2 - Neuronale Entwicklungsstörungen (NES), wie Aufmerksamkeitsdefizit-Hyperaktivitätssyndrom (ADHS) oder Autismus Spektrums Störung (ASS), haben eine größtenteils unbekannte Krankheitsentwicklung, deren klinisches Erscheinungsbild bei dem Patienten durch die individuelle Genetik und Umwelt beieinflusst wird. Veränderungen in allen funktionellen Ebenen des Gehirns, von Netzwerkaktivität zwischen unterschiedlichen Gehirnregionen, über synaptischer Verschaltung, axonalem Wachstum und den Überlebenschancen einzelner Neuronen, bis hin zu molekularen und epigenetischen Modifikationen werden als Schlüsselrollen in NES betrachtet, welche schlussendlich zu langfristigen Verhaltensauffälligkeiten führen. Genome-weite-Assoziations und genomische Kopiezahlvariations Studien haben Cadherin 13 (CDH13) als neuartiges Risikogen für neuropsychiatrische und neuronale Entwicklungsstörungen identifizieren können. CDH13 wird sowohl während der embryonalen Entwicklung, als auch im adulten Gehirn, stark exprimiert und kann dort in Regionen wie dem Hippocampus, Striatum und Thalamus gefunden werden. Darüber hinaus wird es als Reaktion auf akuten (physiologischen und psychologischen) Stress exprimiert. Gegenwärtig ist jedoch nicht bekannt, wie Umwelteinflüsse mit CDH13 interagieren und langanhaltende Veränderungen im Verhalten und der Gene Expression im Gehirn herbeiführen. Die vorliegende Arbeit untersucht daher die Interaktion zwischen CDH13 und Stress während eines frühen Lebensabschnitts. Hierfür wurden Würfe mit wildtyp (Cdh13+/+), heterozygoten (Cdh13+/-) und homozygoten knockout (Cdh13-/-) Mäusen zwischen dem ersten und vierzehnten Tag nach der Geburt für jeweils 3 Stunden von ihren Müttern getrennt (englisch: maternal separation, MS). In einem ersten Experiment wurden diese Mäuse dann im Alter von 8 Wochen in einer Reihe von Verhaltensversuchen auf ihre motorischen Fähigkeiten und Gedächtnisleistung getestet. Im Anschluss daran wurde mittels der quantitativen Polymerase Kettenreaktion (qPCR) verschiedene Gehirnregionen dieser Tiere auf Expressionsunterschiede in Faktoren für Neurotransmittersysteme, Neurogenese und DNA Methylierungsmechanismen hin analysiert. Das Hippocampus-Gewebe einer zweiten gleich aufgebauten Versuchsgruppe wurde mittels RNA Sequenzierung untersucht. Die Verhaltensanalyse zeigt das MS einen überwiegend angst-lindernden Einfluss auf die Mäuse hatte. Im Vergleich zu Mäusen ohne MS verbrachten MS-Mäuse mehr Zeit auf dem offenen Arm eines erhöhten Plus-Labyrinths, so wie in der hell-erleuchteten Seite einer Hell-Dunkel Box (HDB). Eine auffallende Ausnahme stellten jedoch die Cdh13-/- Mäuse dar, welche in der HDB keinen Zeitanstieg wie ihre Cdh13+/+ und Cdh13+/- MS Geschwister auf der hell-erleuchteten Seite aufwiesen. In dem Barnes Labyrinth (einem Test für räumliches Lernen) zeigte sich, dass alle Tiere, gemessen an den Fehlern und der Zeit die sie brauchten bis sie den Ausgang fanden, zunächst ähnliche Lernerfolge hatten. Im zweiten Teil des Experiments, in dem der Ausgang auf eine neue Position gelegt wurde, begangen Cdh13-/- Mäuse ohne MS hingegen mehr Fehler als Cdh13-/- MS Mäusee. In der Kontext-Angst-Konditionierung (KAK) zeigten männliche Cdh13-/- Mäuse mehr Angst-Starre während der Extinktions-Wiederholung; ein Befund der eine reduzierte Angst-Auslöschung impliziert. Im Abstiegs-Test, einem Impulsivitätstest, blieben Cdh13-/- Mäuse länger auf einem Podest stehen. Mittels qPCR konnte außerdem gezeigt werden dass sowohl ein Cdh13-/- Defizit, als auch MS, Veränderungen von GABAergen und glutamatergen Faktoren, so wie Änderungen in dem wichtigen Signalmolekühl Glykogensynthase-Kinase 3 (Gsk3a) verursacht haben. Die Ergebnisse der RNA Sequenzierung zeigten eine Anreicherung von Veränderungen in Adhesions-, Entwicklungs- und Endoplasmatischen Reticulumgenen in Cdh13-/- defiziten Tieren im Vergleich zu Cdh13+/+ Mäusen. Im selben Versuch trug MS zu einer erhöhten Aktivierung von Anti-Apoptotischen Signalwegen im Hippocampus bei, während Zell-Adhesionsmoleküle maßgeblich von der Wechselwirkung beider Faktoren betroffen waren. Zusammenfassend waren Cdh13+/+ und Cdh13+/- Mäuse im Gegensatz zu Cdh13-/- Tieren größtenteils stressresitenter, während die RNA Sequenzierung aufzeigte, dass CDH13 Schlüsselkomponenten von Zell-Zell-Adhesions, Überlebens und Zell-Stress-Signalwegen reguiert. Dies suggeriert, dass CDH13 die Programmierung und Anpassung an Umwelteinflüsse steuert, was wiederum lang anhaltende Auswirkungen auf molekularer Ebene und auf das Verhalten der Mäuse zur Folge hat. Abschließend legen die Befunde eine Rolle von CDH13 in der Umgebungsanpassung während der Entwicklung nahe. KW - Cadherine KW - Genexpression KW - Tiermodell KW - Animales Nervensystem KW - Verhalten KW - Cdh13 KW - RNA Sequencing KW - Gene by Environment KW - Neurodevelopmental Disorder KW - ADHD KW - Hippocampus KW - Prefrontal cortex KW - Amygdala KW - Raphe KW - Adaptation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-179591 ER - TY - JOUR A1 - Jansch, Charline A1 - Günther, Katharina A1 - Waider, Jonas A1 - Ziegler, Georg C. A1 - Forero, Andrea A1 - Kollert, Sina A1 - Svirin, Evgeniy A1 - Pühringer, Dirk A1 - Kwok, Chee Keong A1 - Ullmann, Reinhard A1 - Maierhofer, Anna A1 - Flunkert, Julia A1 - Haaf, Thomas A1 - Edenhofer, Frank A1 - Lesch, Klaus-Peter T1 - Generation of a human induced pluripotent stem cell (iPSC) line from a 51-year-old female with attention-deficit/hyperactivity disorder (ADHD) carrying a duplication of SLC2A3 JF - Stem Cell Research N2 - Fibroblasts were isolated from a skin biopsy of a clinically diagnosed 51-year-old female attention-deficit/hyperactivity disorder (ADHD) patient carrying a duplication of SLC2A3, a gene encoding neuronal glucose transporter-3 (GLUT3). Patient fibroblasts were infected with Sendai virus, a single-stranded RNA virus, to generate transgene-free human induced pluripotent stem cells (iPSCs). SLC2A3-D2-iPSCs showed expression of pluripotency-associated markers, were able to differentiate into cells of the three germ layers in vitro and had a normal female karyotype. This in vitro cellular model can be used to study the role of risk genes in the pathogenesis of ADHD, in a patient-specific manner. KW - ADHD KW - SLC2A3 KW - induced pluripotent stem cells Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176654 VL - 28 ER - TY - JOUR A1 - Geissler, Julia A1 - Jans, Thomas A1 - Banaschewski, Tobias A1 - Becker, Katja A1 - Renner, Tobias A1 - Brandeis, Daniel A1 - Döpfner, Manfred A1 - Dose, Christina A1 - Hautmann, Christopher A1 - Holtmann, Martin A1 - Jenkner, Carolin A1 - Millenet, Sabina A1 - Romanos, Marcel T1 - Individualised short-term therapy for adolescents impaired by attention-deficit/hyperactivity disorder despite previous routine care treatment (ESCAadol)-Study protocol of a randomised controlled trial within the consortium ESCAlife JF - Trials N2 - Background: Despite the high persistence rate of attention-deficit/hyperactivity disorder (ADHD) throughout the lifespan, there is a considerable gap in knowledge regarding effective treatment strategies for adolescents with ADHD. This group in particular often shows substantial psychosocial impairment, low compliance and insufficient response to psychopharmacological interventions. Effective and feasible treatments should further consider the developmental shift in ADHD symptoms, comorbidity and psychosocial adversity as well as family dysfunction. Thus, individualised interventions for adolescent ADHD should comprise a multimodal treatment strategy. The randomised controlled ESCAadol study addresses the needs of this patient group and compares the outcome of short-term cognitive behavioural therapy with parent-based telephone-assisted self-help. Methods/design: In step 1, 160 adolescents aged 12 to 17 years with a diagnosis of ADHD will undergo a treatment as usual (TAU) observation phase of 1 month. In step 2, those still severely affected are randomised to the intervention group with an Individualised Modular Treatment Programme (IMTP) or a telephone-assisted self-help programme for parents (TASH) as an active control condition. The IMTP was specifically designed for the needs of adolescent ADHD. It comprises 10 sessions of individual cognitive behavioural therapy with the adolescents and/or the parents, for which participants choose three out of 10 available focus modules (e.g. organisational skills and planning, emotion regulation, problem solving and stress management, dysfunctional family communication). TASH combines a bibliotherapeutic component with 10 counselling sessions for the parents via telephone. Primary outcome is the change in ADHD symptoms in a clinician-rated diagnostic interview. Outcomes are assessed at inclusion into the study, after the TAU phase, after the intervention phase and after a further 12-week follow-up period. The primary statistical analysis will be by intention-to-treat, using linear regression models. Additionally, we will analyse psychometric and biological predictors and moderators of treatment response. Discussion: ESCAadol compares two short-term non-pharmacological interventions as cost-efficient and feasible treatment options for adolescent ADHD, addressing the specific needs and obstacles to treatment success in this group. We aim to contribute to personalised medicine for adolescent ADHD intended to be implemented in routine clinical care. KW - ADHD KW - adolescents KW - attention-deficit/hyperactivity disorder KW - behaviour therapy KW - RCT KW - individualised modular treatment programme KW - telephone-assisted self-help Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176061 VL - 19 IS - 254 ER - TY - JOUR A1 - Emser, Theresa S. A1 - Johnston, Blair A. A1 - Steele, J. Douglas A1 - Kooij, Sandra A1 - Thorell, Lisa A1 - Christiansen, Hanna T1 - Assessing ADHD symptoms in children and adults: evaluating the role of objective measures JF - Behavioral and Brain Functions N2 - Background: Diagnostic guidelines recommend using a variety of methods to assess and diagnose ADHD. Applying subjective measures always incorporates risks such as informant biases or large differences between ratings obtained from diverse sources. Furthermore, it has been demonstrated that ratings and tests seem to assess somewhat different constructs. The use of objective measures might thus yield valuable information for diagnosing ADHD. This study aims at evaluating the role of objective measures when trying to distinguish between individuals with ADHD and controls. Our sample consisted of children (n = 60) and adults (n = 76) diagnosed with ADHD and matched controls who completed self- and observer ratings as well as objective tasks. Diagnosis was primarily based on clinical interviews. A popular pattern recognition approach, support vector machines, was used to predict the diagnosis. Results: We observed relatively high accuracy of 79% (adults) and 78% (children) applying solely objective measures. Predicting an ADHD diagnosis using both subjective and objective measures exceeded the accuracy of objective measures for both adults (89.5%) and children (86.7%), with the subjective variables proving to be the most relevant. Conclusions: We argue that objective measures are more robust against rater bias and errors inherent in subjective measures and may be more replicable. Considering the high accuracy of objective measures only, we found in our study, we think that they should be incorporated in diagnostic procedures for assessing ADHD. KW - ADHD KW - support vector machines KW - classification KW - objective assessment KW - children/adults Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175717 VL - 14 IS - 11 ER - TY - JOUR A1 - Schäfer, Nadine A1 - Friedrich, Maximilian A1 - Jørgensen, Morten Egevang A1 - Kollert, Sina A1 - Koepsell, Hermann A1 - Wischmeyer, Erhard A1 - Lesch, Klaus-Peter A1 - Geiger, Dietmar A1 - Döring, Frank T1 - Functional analysis of a triplet deletion in the gene encoding the sodium glucose transporter 3, a potential risk factor for ADHD JF - PLoS ONE N2 - Sodium-glucose transporters (SGLT) belong to the solute carrier 5 family, which is characterized by sodium dependent transport of sugars and other solutes. In contrast, the human SGLT3 (hSGLT3) isoform, encoded by SLC5A4, acts as a glucose sensor that does not transport sugar but induces membrane depolarization by Na\(^{+}\) currents upon ligand binding. Whole-exome sequencing (WES) of several extended pedigrees with high density of attention-deficit/hyperactivity disorder (ADHD) identified a triplet ATG deletion in SLC5A4 leading to a single amino acid loss (ΔM500) in the hSGLT3 protein imperfectly co-segregating with the clinical phenotype of ADHD. Since mutations in homologous domains of hSGLT1 and hSGLT2 were found to affect intestinal and renal function, respectively, we analyzed the functional properties of hSGLT3[wt] and [ΔM500] by voltage clamp and current clamp recordings from cRNA-injected Xenopus laevis oocytes. The cation conductance of hSGLT3[wt] was activated by application of glucose or the specific agonist 1-desoxynojirimycin (DNJ) as revealed by inward currents in the voltage clamp configuration and cell depolarization in the current clamp mode. Almost no currents and changes in membrane potential were observed when glucose or DNJ were applied to hSGLT3[ΔM500]-injected oocytes, demonstrating a loss of function by this amino acid deletion in hSGLT3. To monitor membrane targeting of wt and mutant hSGLT3, fusion constructs with YFP were generated, heterologously expressed in Xenopus laevis oocytes and analyzed for membrane fluorescence by confocal microscopy. In comparison to hSGLT3[wt] the fluorescent signal of mutant [ΔM500] was reduced by 43% indicating that the mutant phenotype might mainly result from inaccurate membrane targeting. As revealed by homology modeling, residue M500 is located in TM11 suggesting that in addition to the core structure (TM1-TM10) of the transporter, the surrounding TMs are equally crucial for transport/sensor function. In conclusion, our findings indicate that the deletion [ΔM500] in hSGLT3 inhibits membrane targeting and thus largely disrupts glucose-induced sodium conductance, which may, in interaction with other ADHD risk-related gene variants, influence the risk for ADHD in deletion carriers. KW - Xenopus laevis oocytes KW - ADHD KW - glucose KW - cell membranes KW - membrane proteins KW - membrane potential KW - crystal structure KW - amino acid analysis Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176495 VL - 13 IS - 10 ER - TY - JOUR A1 - Brevik, Erlend J A1 - van Donkelaar, Marjolein M. J. A1 - Weber, Heike A1 - Sánchez-Mora, Cristina A1 - Jacob, Christian A1 - Rivero, Olga A1 - Kittel-Schneider, Sarah A1 - Garcia-martinez, Iris A1 - Aebi, Marcel A1 - van Hulzen, Kimm A1 - Cormand, Bru A1 - Ramos-Quiroga, Josep A A1 - Lesch, Klaus-Peter A1 - Reif, Andreas A1 - Ribases, Marta A1 - Franke, Barbara A1 - Posserud, Maj-Britt A1 - Johansson, Stefan A1 - Lundervold, Astri J. A1 - Haavik, Jan A1 - Zayats, Tetyana T1 - Genome-wide analyses of aggressiveness in attention-deficit hyperactivity disorder JF - American Journal of Medical Genetics Part B-Neuropsychiatric Genetics N2 - Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P<5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders. KW - Large multicenter ADHD KW - Antisocial behavior KW - Diagnostic approach KW - Rating scale KW - Gene KW - Deficit/hyperactivity disorder KW - Susceptibility loci KW - Conduct disorder KW - Association KW - Adult KW - ADHD KW - Aggression KW - GWAS Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188116 VL - 171B IS - 5 ER - TY - JOUR A1 - Zayats, T A1 - Jacobsen, KK A1 - Kleppe, R A1 - Jacob, CP A1 - Kittel-Schneider, S A1 - Ribasés, M A1 - Ramos-Quiroga, JA A1 - Richarte, V A1 - Casas, M A1 - Mota, NR A1 - Grevet, EH A1 - Klein, M A1 - Corominas, J A1 - Bralten, J A1 - Galesloot, T A1 - Vasquez, AA A1 - Herms, S A1 - Forstner, AJ A1 - Larsson, H A1 - Breen, G A1 - Asherson, P A1 - Gross-Lesch, S A1 - Lesch, KP A1 - Cichon, S A1 - Gabrielsen, MB A1 - Holmen, OL A1 - Bau, CHD A1 - Buitelaar, J A1 - Kiemeney, L A1 - Faraone, SV A1 - Cormand, B A1 - Franke, B A1 - Reif, A A1 - Haavik, J A1 - Johansson, S T1 - Exome chip analyses in adult attention deficit hyperactivity disorder JF - Translational Psychiatry N2 - Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable childhood-onset neuropsychiatric condition, often persisting into adulthood. The genetic architecture of ADHD, particularly in adults, is largely unknown. We performed an exome-wide scan of adult ADHD using the Illumina Human Exome Bead Chip, which interrogates over 250 000 common and rare variants. Participants were recruited by the International Multicenter persistent ADHD CollaboraTion (IMpACT). Statistical analyses were divided into 3 steps: (1) gene-level analysis of rare variants (minor allele frequency (MAF)<1%); (2) single marker association tests of common variants (MAF⩾1%), with replication of the top signals; and (3) pathway analyses. In total, 9365 individuals (1846 cases and 7519 controls) were examined. Replication of the most associated common variants was attempted in 9847 individuals (2077 cases and 7770 controls) using fixed-effects inverse variance meta-analysis. With a Bonferroni-corrected significance level of 1.82E−06, our analyses of rare coding variants revealed four study-wide significant loci: 6q22.1 locus (P=4.46E−08), where NT5DC1 and COL10A1 reside; the SEC23IP locus (P=6.47E−07); the PSD locus (P=7.58E−08) and ZCCHC4 locus (P=1.79E−06). No genome-wide significant association was observed among the common variants. The strongest signal was noted at rs9325032 in PPP2R2B (odds ratio=0.81, P=1.61E−05). Taken together, our data add to the growing evidence of general signal transduction molecules (NT5DC1, PSD, SEC23IP and ZCCHC4) having an important role in the etiology of ADHD. Although the biological implications of these findings need to be further explored, they highlight the possible role of cellular communication as a potential core component in the development of both adult and childhood forms of ADHD. KW - chip analyses KW - ADHD KW - adulthood KW - Illumina Human Exome Bead Chip Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168297 VL - 6 IS - e923 ER - TY - JOUR A1 - Jarick, I. A1 - Volckmar, A. L. A1 - Pütter, C. A1 - Pechlivanis, S. A1 - Nguyen, T. T. A1 - Dauvermann, M. R. A1 - Beck, S. A1 - Albayrak, Ö. A1 - Scherag, S. A1 - Gilsbach, S. A1 - Cichon, S. A1 - Hoffmann, P. A1 - Degenhardt, F. A1 - Nöthen, M. M. A1 - Schreiber, S. A1 - Wichmann, H. E. A1 - Jöckel, K. H. A1 - Heinrich, J. A1 - Tiesler, C. M. T. A1 - Faraone, S. V. A1 - Walitza, S. A1 - Sinzig, J. A1 - Freitag, C. A1 - Meyer, J. A1 - Herpertz-Dahlmann, B. A1 - Lehmkuhl, G. A1 - Renner, T. J. A1 - Warnke, A. A1 - Romanos, M. A1 - Lesch, K. P. A1 - Reif, A. A1 - Schimmelmann, B. G. A1 - Hebebrand, J. A1 - Scherag, A. A1 - Hinney, A. T1 - Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder JF - Molecular Psychiatry N2 - Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls \((P=2.8 × 10^{-4})\) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients \((P=1.2 × 10^{-3})\) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control \((P=4.3 × 10^{-2})\). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease. KW - children KW - ADHD KW - CNVs KW - GWAS KW - PARK2 Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121131 VL - 19 IS - 19 ER - TY - JOUR A1 - Brem, Silvia A1 - Grünblatt, Edna A1 - Drechsler, Renate A1 - Riederer, Peter A1 - Walitza, Susanne T1 - The neurobiological link between OCD and ADHD JF - Attention Deficit and Hyperactivity Disorders N2 - Obsessive compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) are two of the most common neuropsychiatric diseases in paediatric populations. The high comorbidity of ADHD and OCD with each other, especially of ADHD in paediatric OCD, is well described. OCD and ADHD often follow a chronic course with persistent rates of at least 40–50 %. Family studies showed high heritability in ADHD and OCD, and some genetic findings showed similar variants for both disorders of the same pathogenetic mechanisms, whereas other genetic findings may differentiate between ADHD and OCD. Neuropsychological and neuroimaging studies suggest that partly similar executive functions are affected in both disorders. The deficits in the corresponding brain networks may be responsible for the perseverative, compulsive symptoms in OCD but also for the disinhibited and impulsive symptoms characterizing ADHD. This article reviews the current literature of neuroimaging, neurochemical circuitry, neuropsychological and genetic findings considering similarities as well as differences between OCD and ADHD. KW - OCD KW - ADHD KW - neuroimaging KW - genetics KW - neuropsychology KW - fMRI KW - MRI KW - EEG KW - neurobiology Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121312 VL - 6 IS - 3 ER - TY - THES A1 - Merker, Sören T1 - Genome-wide screenings in attention-deficit/hyperactivity disorder (ADHD): investigation of novel candidate genes SLC2A3 and LPHN3 T1 - Genomweite Untersuchungen des Aufmerksamkeitsdefizit/ Hyperaktivitätssyndroms (ADHS): Analyse der neuen Kandidatengene SLC2A3 und LPHN3 N2 - Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent childhood-onset neurodevelopmental disorder that involves a substantial risk of persisting into adolescence and adulthood. A number of genome-wide screening studies in ADHD have been conducted in recent years, giving rise to the discovery of several variants at distinct chromosomal loci, thus emphasising the genetically complex and polygenic nature of this disorder. Accordingly, promising novel candidate genes have emerged, such as the gene encoding the glucose transporter isoform 3 (SLC2A3) and the gene encoding the latrophilin isoform 3 (LPHN3). In this thesis, both genes were investigated in form of two separated projects. The first focused on SLC2A3 polymorphisms associated with ADHD and their potential physiological impact. For this purpose, gene expression analyses in peripheral cell models were performed as well as functional EEG measurements in humans. The second project concerned the murine gene Lphn3 including the goal of developing a mouse line containing a genetically modified Lphn3 with conditional knockout potential. In this respect, a specific DNA vector was applied to target the Lphn3 gene locus in murine embryonic stem (ES) cells as a prerequisite for the generation of appropriate chimeric mice. The results of the first project showed that SLC2A3 duplication carriers displayed increased SLC2A3 mRNA expression in peripheral blood cells and significantly altered event-related potentials (ERPs) during tests of cognitive response control and working memory, possibly involving changes in prefrontal brain activity and memory processing. Interestingly, ADHD patients with the rs12842 T-allele, located within and tagging the SLC2A3 gene, also exhibited remarkable effects during these EEG measurements. However, such effects reflected a reversed pattern to the aforementioned SLC2A3 duplication carriers with ADHD, thus indicative of an opposed molecular mechanism. Besides, it emerged that the impact of the aforementioned SLC2A3 variants on different EEG parameters was generally much more pronounced in the group of ADHD patients than the healthy control group, implying a considerable interaction effect. Concerning the second project, preliminary results were gathered including the successful targeting of Lphn3 in murine ES cells as well as the production of highly chimeric, phenotypically unremarkable and mostly fertile mouse chimeras. While germline transmission of the modified Lphn3 allele has not yet occurred, there are still several newborn chimeric mice that will be tested in the near future. In conclusion, the findings suggest that SLC2A3 variants associated with ADHD are accompanied by transcriptional and functional changes in humans. Future research will help to elucidate the molecular network and neurobiological basis involved in these effects and apparently contributing to the complex clinical picture of ADHD. Moreover, given the increasing number of publications concerning latrophilins in recent years and the multitude of research opportunities provided by a conditional knockout of Lphn3 in mice, the establishment of a respective mouse line, which currently is in progress, constitutes a promising approach for the investigation of this gene and its role in ADHD. N2 - Das Aufmerksamkeitsdefizit/Hyperaktivitätssyndrom (ADHS) ist eine hoch prävalente und bereits in der Kindheit beginnende Neuroentwicklungsstörung, die eine erhebliche Persistenz ins Jugend- und Erwachsenenalter aufweist. In den vergangenen Jahren wurde eine Vielzahl von genomweiten Studien zu ADHS durchgeführt, welche zur Identifizierung zahlreicher genetischer Varianten an unterschiedlichen chromosomalen Loci geführt und somit die genetisch komplexe polygene Natur dieser Störung zur Geltung gebracht haben. Auf diese Weise traten auch neue Kandidatengene zutage, wie zum Beispiel das Gen für die Glukosetransporter-Isoform-3 (SLC2A3) und das Gen, welches Latrophilin-3 kodiert (LPHN3). Innerhalb dieser Thesis wurden beide Gene in Form von zwei voneinander getrennten Projekten untersucht. Das erste Projekt beschäftigte sich mit humanen ADHS-assoziierten SLC2A3-Polymorphismen und ihrer potentiellen physiologischen Bedeutung. Für diesen Zweck wurden Genexpressionsanalysen in peripheren Zellmodellen sowie funktionelle EEG-Messungen im Menschen durchgeführt. Im zweiten Projekt ging es um das murine Gen Lphn3 mit dem Ziel, eine Mauslinie zu entwickeln, die ein genetisch verändertes Lphn3 mit konditionalem Knockout-Potenzial aufweist. In diesem Zusammenhang wurde ein spezifischer DNA-Vektor verwendet, der auf den Lphn3-Genlocus in murinen embryonalen Stammzellen (ES-Zellen) abzielte, was eine Voraussetzung für die Erzeugung von geeigneten chimären Mäusen darstellt. Die Ergebnisse des ersten Projektes legten nahe, dass SLC2A3-Duplikationsträger erhöhte SLC2A3-mRNA-Expression in peripheren Blutzellen aufweisen sowie signifikant veränderte ereigniskorrelierte Potentiale während eines Tests kognitiver Reaktionskontrolle sowie eines Arbeitsgedächtnis-Tests, was möglicherweise von veränderter präfrontaler Hirnaktiviät bzw. Gedächtnis-Prozessierung begleitet wird. Interessanterweise zeigten ADHS-Patienten mit T-Allel des im SLC2A3-Gen liegenden SNPs rs12842 ebenfalls deutliche Effekte während dieser EEG-Messungen, allerdings in entgegengesetzter Form zu den zuvor genannten SLC2A3-Duplikationsträgern mit ADHS, was auf einen gegensätzlichen molekularen Mechanismus hindeutet. Zudem stellte sich heraus, dass der Einfluss der zuvor genannten SLC2A3-Varianten auf verschiedene EEG-Parameter innerhalb der ADHS-Gruppe generell deutlich stärker ausgeprägt war als in der gesunden Kontrollgruppe, also einen beachtlichen Interaktionseffekt impliziert. Bezüglich des zweiten Projektes konnten bisher Zwischenergebnisse erzielt werden: das erfolgreiche Targeting des Lphn3-Gens in murinen ES-Zellen sowie die Produktion hochchimärer, phänotypisch unauffälliger und größtenteils fertiler Maus-Chimären. Obgleich die Keimbahntransmission des modifizierten Lphn3-Allels bislang noch nicht eingetreten ist, gibt es noch eine Reihe an neugeborenen chimären Mäusen, die in nächster Zeit erst noch getestet werden müssen. Zusammenfassend deuten die Ergebnisse darauf hin, dass Variationen des SLC2A3-Gens, die mit ADHS assoziiert sind, mit transkriptionellen und funktionellen Veränderungen im Menschen einhergehen. Zukünftige Forschungsarbeiten werden dabei helfen, die molekularen Netzwerke und neurobiologischen Grundlagen zu verdeutlichen, die an diesen Effekten beteiligt sind und offenbar zu dem komplexen klinischen Bild von ADHS beitragen. Angesichts der steigenden Zahl an Publikationen über Latrophiline in den letzten Jahren und der unzähligen Forschungsmöglichkeiten, die ein konditionaler Knockout von Lphn3 in Mäusen bietet, stellt die derzeit laufende Etablierung einer entsprechenden Mauslinie einen vielversprechenden Ansatz dar, dieses Gen und seine Rolle für ADHS zu untersuchen. KW - Genexpression KW - Glucosetransportproteine KW - Aufmerksamkeits-Defizit-Syndrom KW - Latrophilin receptor KW - Knockout-Maus KW - ADHD KW - Genetics KW - Glucosetransporter Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-100129 ER - TY - JOUR A1 - Biehl, Stefanie C. A1 - Ehlis, Ann-Christine A1 - Müller, Laura D. A1 - Niklaus, Andrea A1 - Pauli, Paul A1 - Herrmann, Martin J. T1 - The impact of task relevance and degree of distraction on stimulus processing JF - BMC Neuroscience N2 - Background The impact of task relevance on event-related potential amplitudes of early visual processing was previously demonstrated. Study designs, however, differ greatly, not allowing simultaneous investigation of how both degree of distraction and task relevance influence processing variations. In our study, we combined different features of previous tasks. We used a modified 1-back task in which task relevant and task irrelevant stimuli were alternately presented. The task irrelevant stimuli could be from the same or from a different category as the task relevant stimuli, thereby producing high and low distracting task irrelevant stimuli. In addition, the paradigm comprised a passive viewing condition. Thus, our paradigm enabled us to compare the processing of task relevant stimuli, task irrelevant stimuli with differing degrees of distraction, and passively viewed stimuli. EEG data from twenty participants was collected and mean P100 and N170 amplitudes were analyzed. Furthermore, a potential connection of stimulus processing and symptoms of attention deficit hyperactivity disorder (ADHD) was investigated. Results Our results show a modulation of peak N170 amplitudes by task relevance. N170 amplitudes to task relevant stimuli were significantly higher than to high distracting task irrelevant or passively viewed stimuli. In addition, amplitudes to low distracting task irrelevant stimuli were significantly higher than to high distracting stimuli. N170 amplitudes to passively viewed stimuli were not significantly different from either kind of task irrelevant stimuli. Participants with more symptoms of hyperactivity and impulsivity showed decreased N170 amplitudes across all task conditions. On a behavioral level, lower N170 enhancement efficiency was significantly correlated with false alarm responses. Conclusions Our results point to a processing enhancement of task relevant stimuli. Unlike P100 amplitudes, N170 amplitudes were strongly influenced by enhancement and enhancement efficiency seemed to have direct behavioral consequences. These findings have potential implications for models of clinical disorders affecting selective attention, especially ADHD. KW - Selective attention KW - Working memory KW - Cognitive control KW - P100 KW - N170 KW - ADHD Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97271 UR - http://www.biomedcentral.com/1471-2202/14/107 ER - TY - THES A1 - Geissler, Julia Maria T1 - Neuropsychological Endophenotypes of Attention-Deficit/Hyperactivity Disorder T1 - Neuropsychologische Endophänotypen des Aufmerksamkeitsdefizit-/Hyperaktivitätssyndroms N2 - Attention-Deficit/Hyperactivity Disorder (ADHD) endophenotypes as a link between phenotype and genotype were the focus of the present work. Candidate endophenotypes were investigated via neuropsychological tasks during the simultaneous recording of a 21-channel electroencephalogram. Since endophenotypes are assumed to more closely reflect genetic variation, the influence of ADHD-associated genes Catechol-O-methyl transferase (COMT), the dopamine transporter (DAT, SLC6A3) and Latrophilin-3 (LPHN3) was analysed. Response inhibition was assessed with a cued Continuous Performance Test, for working memory we used an n-back task, sensory gating was measured via the paired clicks paradigm and response time variability (RTV) was quantified by the standard deviation of reaction times. The sample comprised medicated (N=36) and unmedicated (N=42) ADHD patients and matched control children and adolescents (N=41). The electrophysiological correlate of response inhibition was the centroid location during response execution and inhibition, and the degree of anteriorization (NGA). Sensory gating reflects the attenuation of the P50 response to the second of two auditory stimuli presented in short succession. Working memory was examined during target and non-target trials, reflecting specific information processing stages: early sensory processing (P100 and N100), selection of material (P150), memory retrieval (N300), event categorization (P300) and updating of working memory content (P450). Performance was quantified in terms of omission errors reflecting inattention and false alarms reflecting impulsivity, as well as speed and variability of reactions. Unmedicated ADHD patients had more omission errors and more variable reaction times, pointing to difficulties with attention and state regulation. NGA did not prove an optimal endophenotype candidate, since it was not yet developed in approximately half of the examined children and adolescents. It was independent of diagnosis; however ADHD risk alleles for DAT conferred lower NGA as well as more variable reaction times across groups. DAT genotype interacted with diagnosis on the level of centroid location, however, it did not manifest in performance deficits. In the case of sensory gating, homozygosity for the DAT allele associated with ADHD (10R) conferred impairment. ADHD was only relevant in participants without genetic risk, where patients without medication struggled most with suppression. In the working memory task, DAT modulated the timing of material selection in interaction with cognitive load and diagnosis: under high load unmedicated patients showed delayed responses, while under low load risk carriers on medication had faster responses than controls. Early processing and event-categorization were stronger in unmedicated ADHD with risk genotype, but dampened without risk. An interesting trend emerged for LPHN3, where carrying all risk variants was associated with higher NGA in ADHD patients irrespective of medication. This warrants further study, as the haplotype also exerts a positive influence on sensory gating specifically in patients. At the same time within the genetic risk group, unmedicated patients had the weakest NGA. However, the LPHN3 risk haplotype effected more posterior Go centroids, putatively facilitating response execution, which is supported by a higher number of false alarms. When inhibition was required, the risk variants led to more posterior centroids in unmedicated compared to medicated patients as well as controls, speaking to differences in inhibition-related brain activation. While as expected the risk haplotype led to compromised gating in unmedicated ADHD, this was reversed in healthy controls where the haplotype was acting in a protective manner with enhanced filtering. During working memory operations, the risk haplotype showed stronger N300 responses suggesting investment of more resources. While COMT did not exert an influence on NGA directly, carriers of the risk allele (met) had more posterior centroids both during response execution and inhibition, and displayed more variable responses in addition to being more prone to false alarms. Unmedicated patients produced smaller P300 during successful execution of responses than controls in absence of the risk allele, while with risk they had shorter latencies and presumably tend towards premature reactions. Additionally, it brought out impairments in sensory gating, thus making unmedicated patients less able to filter out irrelevant information, while they were able to compensate with the protective genotype. The influence of COMT on sensory gating seems to be specific for ADHD, as this gene was of no consequence in healthy controls. In the working memory task, met was beneficial for updating as reflected by P450 amplitude. In ADHD irrespective of medication COMT did not change P450 strength, but for controls this effect was observed. N2 - Endophänotypen als Bindeglied zwischen Phänotyp und Genotyp des Aufmerksamkeitsdefizit-/Hyperaktivitätssyndroms (ADHS) besitzen großes Potential als diagnostische Marker. Im Fokus der vorliegenden Arbeit standen Antworthemmung, Arbeitsgedächtnis, Reaktionszeitvariabilität (RTV) und sensorisches Gating als Kandidaten-Endophänotypen, sowie die Untersuchung des Einflusses genetischer Varianten in den ADHS-assoziierten Genen COMT, DAT und LPHN3. Die Stichprobe im Kindes- und Jugendalter bestehend aus medizierten (N=36) und unmedizierten (N=42) ADHS-Patienten sowie gesunden Kontrollen (N=41) wurde neuropsychologisch untersucht bei simultaner Ableitung eines 21-Kanal-EEGs. Die NoGo-Anteriorisierung (NGA) als elektrophysiologisches Korrelat der Antworthemmung basiert auf der Lage der Feldschwerpunkte (Zentroide) der P300 in Antwortausführungs- (Go) und Inhibitionstrials (NoGo). Sensorisches Gating beschreibt die Unterbindung der Reizweiterleitung bei schneller Reizfolge zur Prävention kortikaler Überstimulation, was sich in einer gedämpften P50-Amplitude zeigt. Um sowohl frühe als auch späte Aspekte des arbeitsgedächtnisbezogenen Informationsverarbeitungsprozesses zu erfassen, wurden ereigniskorrelierte Komponenten korrespondieren mit früher sensorischer Verarbeitung (P100 und N100), Materialselektion (P150), Abruf von Gedächtnisinhalten (N300), Ereigniskategorisierung (P300) und Aktualisierung der Arbeitsgedächtnisinhalten (P450) analysiert. Auslassungsfehler dienten als Indikator für Aufmerksamkeitdefizite, Falschalarme als Indikator für Impulsivität. Unmedizierte ADHD-Patienten zeigten neben variableren Reaktionszeiten mehr Auslassungsfehler, was Hinweise auf Defizite in Aufmerksamkeit und Zustandsregulation gibt. Die NGA erwies sich als beschränkt geeigneter Endophänotyp, da viele Probanden im eingeschlossenen Altersspektrum keine NGA aufwiesen. Die NGA war bei Trägern der DAT-Risikovariante (10R) schwächer ausgeprägt. Nur in Anwesenheit eines protektiven 9R-Allels korrespondierte Stimulanzienmedikation mit einer Anteriorisierung beider Zentroide. Während homozygote 10R-Träger Beeinträchtigungen im sensorischen Gating zeigten, kam ohne genetisches Risiko die Diagnose zum Tragen, da hier die Gruppe mit unmedizierten ADHS die größten Defizite aufwies. Während der Arbeitsgedächtnisaufgabe modulierte DAT die Materialauswahl in Interaktion mit kognitivem Load: unter hohem Load zeigten Patienten ohne Medikation genotypunabhängig verzögerte Reaktionen, während bei niedrigem Load medizierte Patienten mit Risikogenotyp die kürzesten Latenzen aufwiesen. Während bei unmediziertem ADHD der DAT-Risikogenotyp mit höheren P150-Amplituden und somit verstärkter Ressourcenallokation zur Materialselektion korrespondierte, zeigte diese Gruppe bei Vorhandensein eines 9R-Allels gedämpfte P100-Amplituden im Vergleich zu medizierten Patienten und Kontrollen, was auf abnorme frühe sensorischen Verarbeitung hinweist. Zuletzt bedeutete der DAT-Risikogenotyp für unmediziertes ADHS höhere P300-Amplituden, während diese Gruppe mit dem protektiven Genotyp die schwächsten P300-Reaktionen (Ereigniskategorisierung) zeigten. Ein interessanter Trend zeigte sich für den LPHN3-Risikohaplotyp, der bei ADHS medikationsunabhängig mit besserer NGA assoziiert war. Auf Zentroidebene zeigten Risikohaplotypträger mehr posterior gelegene Go-Zentroide, was die Reaktionsausführung begünstigt und sich in einer höheren Anzahl an Falschalarmen niederschlägt. Bei erforderlicher Inhibition ging der Risikohaplotyp bei unmedizierten Patienten mit mehr posterioren Zentroiden als in den Vergleichsgruppen einher, was für Unterschiede in inhibitionsspezifischer Gehirnaktivität spricht. In Bezug auf sensorisches Gating erzeugte der LPHN3-Haplotyp gegenläufige Effekte in Patienten und Kontrollen. Während der Risikohaplotyp in der unmedizierten ADHS-Gruppe erwartungsgemäß mit schwächerem Gating assoziiert war, wirkte er in Kontrollen und medizierten Patienten protektiv in Form überlegener Filterfähigkeiten. Der Risikohaplotyp zeigte bei Arbeitsgedächtnisaufgaben höhere N300-Amplituden als Indiz für Ressourceninvestition beim Abruf von Gedächtnisinhalten. Während sich die NGA als unabhängig vom COMT-Genotyp erwies, lagen die Zentroide bei Probanden mit Met-Allel weiter posterior, sie zeigten darüber hinaus eine variablere Leistung mit mehr Falschalarmen. Generell bedeutete die mit ADHS assoziierte COMT-Variante eine erhöhte RTV sowie schlechtere Gatingleistung in unmediziertem ADHD, während sie durch das protektive Val-Allele in die Lage versetzte, dieses Defizit ohne Medikation zu kompensieren. Dieser Einfluss von COMT auf sensorisches Gating war spezifisch für ADHS. In Aufgaben, welche das Arbeitsgedächtnis beanspruchen, war die Met-Variante von Vorteil für Aktualisierungsvorgänge (P450), was im Gegensatz zu den Gating-Effekten nur in Kontrollen auftrat. KW - Aufmerksamkeits-Defizit-Syndrom KW - Elektroencephalographie KW - Arbeitsgedächtnis KW - Endophänotyp KW - Antworthemmung KW - Latrophilin-3 KW - Dopamintransporter KW - Catechol-O-Methyltransferase KW - ADHD KW - Endophenotype KW - Latrophilin-3 KW - Response Inhibition KW - Sensory Gating Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-79221 ER - TY - JOUR A1 - Jain, M. A1 - Vélez, J. I. A1 - Acosta, M. T. A1 - Palacio, L. G. A1 - Balog, J. A1 - Roessler, E. A1 - Pineda, D. A1 - Londoño, A. C. A1 - Palacio, J. D. A1 - Arbelaez, A. A1 - Lopera, F. A1 - Elia, J. A1 - Hakonarson, H. A1 - Seitz, C. A1 - Freitag, C. M. A1 - Palmason, H. A1 - Meyer, J. A1 - Romanos, M. A1 - Walitza, S. A1 - Hemminger, U. A1 - Warnke, A. A1 - Romanos, J. A1 - Renner, T. A1 - Jacob, C. A1 - Lesch, K.-P. A1 - Swanson, J. A1 - Castellanos, F. X. A1 - Bailey-Wilson, J. E. A1 - Arcos-Burgos, M. A1 - Muenke, M. T1 - A cooperative interaction between LPHN3 and 11q doubles the risk for ADHD JF - Molecular Psychiatry N2 - In previous studies of a genetic isolate, we identified significant linkage of attention deficit hyperactivity disorder (ADHD) to 4q, 5q, 8q, 11q and 17p. The existence of unique large size families linked to multiple regions, and the fact that these families came from an isolated population, we hypothesized that two-locus interaction contributions to ADHD were plausible. Several analytical models converged to show significant interaction between 4q and 11q (P<1 × 10−8) and 11q and 17p (P<1 × 10−6). As we have identified that common variants of the LPHN3 gene were responsible for the 4q linkage signal, we focused on 4q–11q interaction to determine that single-nucleotide polymorphisms (SNPs) harbored in the LPHN3 gene interact with SNPs spanning the 11q region that contains DRD2 and NCAM1 genes, to double the risk of developing ADHD. This interaction not only explains genetic effects much better than taking each of these loci effects by separated but also differences in brain metabolism as depicted by proton magnetic resonance spectroscopy data and pharmacogenetic response to stimulant medication. These findings not only add information about how high order genetic interactions might be implicated in conferring susceptibility to develop ADHD but also show that future studies of the effects of genetic interactions on ADHD clinical information will help to shape predictive models of individual outcome. KW - ADHD KW - genetic interaction KW - LPHN3 KW - NCAM1 KW - DRD2 Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125128 VL - 17 ER - TY - JOUR A1 - Bender, Stephan A1 - Resch, Franz A1 - Klein, Christoph A1 - Renner, Tobias A1 - Fallgatter, Andreas J. A1 - Weisbrod, Matthias A1 - Romanos, Marcel T1 - Influence of Stimulant Medication and Response Speed on Lateralization of Movement-Related Potentials in Attention-Deficit/Hyperactivity Disorder JF - PLoS One N2 - Background: Hyperactivity is one of the core symptoms in attention deficit hyperactivity disorder (ADHD). However, it remains unclear in which way the motor system itself and its development are affected by the disorder. Movement-related potentials (MRP) can separate different stages of movement execution, from the programming of a movement to motor post-processing and memory traces. Pre-movement MRP are absent or positive during early childhood and display a developmental increase of negativity. Methods: We examined the influences of response-speed, an indicator of the level of attention, and stimulant medication on lateralized MRP in 16 children with combined type ADHD compared to 20 matched healthy controls. Results: We detected a significantly diminished lateralisation of MRP over the pre-motor and primary motor cortex during movement execution (initial motor potential peak, iMP) in patients with ADHD. Fast reactions (indicating increased visuo-motor attention) led to increased lateralized negativity during movement execution only in healthy controls, while in children with ADHD faster reaction times were associated with more positive amplitudes. Even though stimulant medication had some effect on attenuating group differences in lateralized MRP, this effect was insufficient to normalize lateralized iMP amplitudes. Conclusions: A reduced focal (lateralized) motor cortex activation during the command to muscle contraction points towards an immature motor system and a maturation delay of the (pre-) motor cortex in children with ADHD. A delayed maturation of the neuronal circuitry, which involves primary motor cortex, may contribute to ADHD pathophysiology. KW - deficit-hyperactivity disorder KW - anticipatory mechanisms KW - motor preparation KW - TIC disorder KW - children KW - ADHD KW - methylphenidate KW - contingent negative-variation KW - continuous performance-test KW - slow cortical potentials Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135262 VL - 7 IS - 6 ER - TY - THES A1 - Weißflog, Lena T1 - Molecular Genetics of Emotional Dysregulation in Attention-Deficit/Hyperactivity Disorder T1 - Molekulargenetik emotionaler Dysregulation bei Aufmerksamkeitsdefizit-/Hyperaktivitätssyndrom N2 - Attention-deficit/hyperactivity disorder (ADHD) is a genetically complex childhood onset neurodevelopmental disorder which is highly persistent into adulthood. Several chromo-somal regions associated with this disorder were identified previously in genome-wide linkage scans, association (GWA) and copy number variation (CNV) studies. In this work the results of case-control and family-based association studies using a can-didate gene approach are presented. For this purpose, possible candidate genes for ADHD have been finemapped using mass array-based SNP genotyping. The genes KCNIP4, CDH13 and DIRAS2 have been found to be associated with ADHD and, in addition, with cluster B and cluster C personality disorders (PD) which are known to be related to ADHD. Most of the associations found in this work would not withstand correction for multiple testing. However, a replication in several independent populations has been achieved and in conjunction with previous evidence from linkage, GWA and CNV studies, it is assumed that there are true associations between those genes and ADHD. Further investigation of DIRAS2 by quantitative real-time PCR (qPCR) revealed expression in the hippocampus, cerebral cortex and cerebellum of the human brain and a significant increase in Diras2 expression in the mouse brain during early development. In situ hybrid-izations on murine brain slices confirmed the results gained by qPCR in the human brain. Moreover, Diras2 is expressed in the basolateral amygdala, structures of the olfactory system and several other brain regions which have been implicated in the psychopatholo-gy of ADHD. In conclusion, the results of this work provide further support to the existence of a strong genetic component in the pathophysiology of ADHD and related disorders. KCNIP4, CDH13 and DIRAS2 are promising candidates and need to be further examined to get more knowledge about the neurobiological basis of this common disease. This knowledge is essential for understanding the molecular mechanisms underlying the emergence of this disorder and for the development of new treatment strategies. N2 - Bei Aufmerksamkeitsdefizit-/Hyperaktivitätssyndrom (ADHS) handelt es sich um eine ge-netisch komplexe neuronale Entwicklungsstörung, die im Kindesalter einsetzt und eine hohe Persistenz ins Erwachsenenalter aufweist. Mehrere chromosomale Regionen zeigten eine Assoziation mit dieser Erkrankung in genomweiten Kopplungsanalysen, Assoziations- (GWA) und Copie Number Variation (CNV) Studien. In dieser Arbeit werden die Ergebnisse von Fall-Kontroll- und Familien-basierten Assozia-tionsstudien, basierend auf der Annahme bestimmter Kandidatengene, vorgestellt. Die möglichen Kandidatengene wurden mit Hilfe eines massenspektrometrischen Verfahrens für SNP Genotypisierungen untersucht. Für die Gene KCNIP4, CDH13 und DIRAS2 konnte eine Assoziation mit ADHS und zudem mit Persönlichkeitsstörungen gefunden werden. Die meisten der in dieser Arbeit berichteten Assoziationen würden einer Korrektur für multiples Testen nicht standhalten. Dennoch kann von einer tatsächlichen Assoziation dieser Gene mit ADHS ausgegangen werden da eine Replikation in verschiedenen unab-hängigen Stichproben stattgefunden hat und zudem vorangegangene Kopplungsanalysen, GWA und CNV Studien auf eine Assoziation hindeuten. Die weitere Untersuchung des DIRAS2 Gens mit Hilfe von quantitativer real-time PCR (qPCR) ergab eine Expression des Gens im Hippocampus, dem zerebralen Kortex und dem Kleinhirn des Menschen. Zudem wurde ein signifikanter Anstieg der Diras2 Expression im murinen Gehirn während der frühen Entwicklungsstadien beobachtet. In situ Hybridisie-rungen auf Maushirnschnitten bestätigten die Ergebnisse der qPCR im menschlichen Ge-hirn. Außerdem wird Diras2 in der basolateralen Amygdala, in Komponenten des olfakto-rischen Systems und in mehreren anderen Hirnarealen, die vermutlich an der Pathologie von ADHS beteiligt sind, exprimiert. Zusammenfassend untermauern die Ergebnisse dieser Arbeit die Tatsache dass eine star-ke genetische Komponente an der Entstehung von ADHS beteiligt ist. KCNIP4, CDH13 und DIRAS2 sind vielversprechende Kandidatengene und sollten weiter untersucht werden um nähere Einblicke in die Neurobiologie dieser häufigen Erkrankung zu erhalten. Das dadurch erlangte Wissen ist notwendig um die molekularen Mechanismen die ADHS zu-grunde liegen zu verstehen und um neue Behandlungsstrategien entwickeln zu können. KW - Aufmerksamkeits-Defizit-Syndrom KW - Molekulargenetik KW - Assoziation KW - ADHD KW - genetics KW - association studies Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-69345 ER - TY - JOUR A1 - Biehl, Stefanie C. A1 - Dresler, Thomas A1 - Reif, Andreas A1 - Scheuerpflug, Peter A1 - Deckert, Jürgen A1 - Herrmann, Martin J. T1 - Dopamine Transporter (DAT1) and Dopamine Receptor D4 (DRD4) Genotypes Differentially Impact on Electrophysiological Correlates of Error Processing JF - PLoS One N2 - Recent studies as well as theoretical models of error processing assign fundamental importance to the brain's dopaminergic system. Research about how the electrophysiological correlates of error processing—the error-related negativity (ERN) and the error positivity (Pe)—are influenced by variations of common dopaminergic genes, however, is still relatively scarce. In the present study, we therefore investigated whether polymorphisms in the DAT1 gene and in the DRD4 gene, respectively, lead to interindividual differences in these error processing correlates. One hundred sixty participants completed a version of the Eriksen Flanker Task while a 26-channel EEG was recorded. The task was slightly modified in order to increase error rates. During data analysis, participants were split into two groups depending on their DAT1 and their DRD4 genotypes, respectively. ERN and Pe amplitudes after correct responses and after errors as well as difference amplitudes between errors and correct responses were analyzed. We found a differential effect of DAT1 genotype on the Pe difference amplitude but not on the ERN difference amplitude, while the reverse was true for DRD4 genotype. These findings are in line with predictions from theoretical models of dopaminergic transmission in the brain. They furthermore tie results from clinical investigations of disorders impacting on the dopamine system to genetic variations known to be at-risk genotypes. KW - haplotypes KW - electroencephalography KW - basal ganglia KW - reaction time KW - dopaminergics KW - dopamine KW - ADHD KW - research errors Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137930 VL - 6 IS - 12 ER - TY - THES A1 - Weiland, Romy T1 - Facial reactions in response to gustatory and olfactory stimuli in healthy adults, patients with eating disorders, and patients with attention-deficit hyperactivity disorder T1 - Mimische Reaktionen auf Geschmacks- und Geruchsreize bei gesunden Erwachsenen, Patientinnen mit Essstörungen und Patientinnen mit Aufmerksamkeitsdefizit/Hyperaktivitätsstörung N2 - The aim of this project was to investigate whether reflex-like innate facial reactions to tastes and odors are altered in patients with eating disorders. Qualitatively different tastes and odors have been found to elicit specific facial expressions in newborns. This specificity in newborns is characterized by positive facial reactions in response to pleasant stimuli and by negative facial reactions in response to unpleasant stimuli. It is, however, unclear, whether these specific facial displays remain stable during ontogeny (1). Despite the fact that several studies had shown that taste-and odor-elicited facial reactions remain quite stable across a human’s life-span, the specificity of research questions, as well as different research methods, allow only limited comparisons between studies. Moreover, the gustofacial response patterns might be altered in pathological eating behavior (2). To date, however, the question of whether dysfunctional eating behavior might alter facial activity in response to tastes and odors has not been addressed. Furthermore, changes in facial activity might be linked to deficient inhibitory facial control (3). To investigate these three research questions, facial reactions in response to tastes and odors were assessed. Facial reactions were analyzed using the Facial Action Coding System (FACS, Ekman & Friesen, 1978; Ekman, Friesen, & Hager, 2002) and electromyography. N2 - Ziel dieses Projektes war es zu untersuchen, ob spezifische, mimische Reaktionen auf Geschmacks- und Geruchsreize bei Patientinnen mit Essstörungen verändert sind. Bei Neugeborenen rufen qualitativ verschiedene Geschmacksreize und Geruchsreize spezifische mimische Reaktionsmuster hervor. Diese Spezifität zeichnet sich infolge angenehmer Reize durch positive mimische Reaktionen und infolge unangenemher Reize durch negative mimische Reaktionen aus. Es ist jedoch unklar, ob diese spezifischen Reaktionsmuster während der ontogentischen Entwicklung stabil bleibe (1). Trotz der Befunde, dass geschmacks- und geruchsinduzierte mimische Reaktionen bei Erwachsenen relativ stabil bleiben, erlauben spezifische Forschungsfragen und verschiedene Methoden nur einen begrenzten Vergleich zwischen den Studien. Darüber hinaus könnten die gustofazialen Reaktionsmuster bei Patientinnen mit Essstörungen verändert sein (2). Diese Frage wurde jedoch bisher nicht untersucht. Weiterhin könnten Veränderungen in den mimischen Reaktionen bei essgestörten Patientinnen durch eine defizitäre Hemmungskontrolle bedingt sein (3). Zur Klärung dieser drei Fragestellungen wurden mimische Reaktionen auf Geschmacks- und Geruchsreize erfasst. Die Mimikanalyse erfolgte mit Hilfe des Facial Action Coding Systems (FACS, Ekman & Friesen, 1978; Ekman, Friesen, & Hager, 2002) und des Elektromyogramms. KW - Mimik KW - Geschmack KW - Geruch KW - Essstörung KW - Aufmerksamkeits-Defizit-Syndrom KW - facial expressions KW - gustation KW - olfaction KW - eating disorders KW - ADHD Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-51759 ER -