610 Medizin und Gesundheit
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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.
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.
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.
Zusammenfassung
1) Fragestellung und zentrale Untersuchung
Unter der Hypothese, dass die Transportrate des Glukosetransporters Typ 3 (GLUT3)
abhängig von der Kopienanzahl (CNV) des für ihn kodierenden Gens SLC2A3 ist,
wurden Zelllinien mit drei Kopien (Duplikation) mit Kontroll-Zelllinien mit nur zwei Kopien
bezüglich ihrer Glukoseaufnahme miteinander verglichen (n=2; N=9). Hierzu wurde die
zelluläre Glukoseaufnahme mittels radioaktiv markierter 2-Desoxyglukose in via
Eppstein-Barr-Virus immortalisierten lymphoblastoiden Zelllinien (EBV-LCLs)
gemessen. In den initialen Untersuchungen zeigt sich, dass das Protokoll an manchen
Stellen zu viel Spielraum lässt. Die Methode wird daraufhin standardisiert und bezüglich
einiger Parameter angepasst: g-Zentrifugeneinstellung, Mischen/Aliquotieren,
Zellanzahl, Replikatanzahl, Inkubationszeit/-intervalle und Durchführungsdauer.
2) Wichtigste Ergebnisse
Die funktionelle Untersuchung zur Duplikation des SLC2A3-Gens in Patienten mit
Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) zeigt schließlich im
dynamischen Aushungerungsversuch der EBV-LCLs über vier Tage (Vergleich t2 zu t1)
statistisch für die Gruppen eine deutliche Differenz mit mittlerer Effektstärke (Lineares
Gemischtes Modell; p = 0,06; Cohens d = 0,37).
Zum zweiten Messzeitpunkt (t2) zeigt sich statistisch zwischen den Gruppen eine sehr
signifikante Differenz mit hoher Effektstärke (Lineares Gemischtes Modell; p < 0,006;
Cohens d = 0,55).
Damit konnte in dieser Arbeit nachgewiesen werden, dass die SLC2A3-Duplikation
neben dem Gendosiseffekt auf mRNA-Ebene auch hypermorph funktionelle
Veränderungen auf zellulärer Ebene nach sich zieht. Nachfolgende Untersuchungen
sollten vor diesem Hintergrund mögliche Kofaktoren investigieren und auf Alterationen
in nachgeschalteten Signalwegen abzielen.
In der dargestellten Arbeit wurden verschiedene Hypothesen im Hinblick auf die berufliche und gesundheitliche Belastung von Eltern mit Kindern, die an ADHS leiden, untersucht. So wurde zunächst der Fragestellung nachgegangen, in wieweit das von ADHS betroffene Kind in der Familie selbst zu einer erhöhten Belastung der Eltern am Arbeitsplatz und somit zu einer gesteigerten gesundheitlichen Einschränkung führt. Zudem untersuchten wir die Auswirkungen einer möglichen eigenen ADHS-Symptomatik in der Kindheit laut WURS auf die gesundheitliche Verfassung und die Leistungsfähigkeit am Arbeitsplatz. Schließlich wurde in der dritten Hypothese die Frage untersucht, in wieweit ein Effekt der Anzahl betroffener Kinder mit ADHS innerhalb einer Familie feststellbar ist.
Entsprechend wurde eine vergleichende Untersuchung mit einer klinischen Stichprobe (n=91) und einer gesunden Vergleichsstichprobe (n=198) durchgeführt. Um die verschiedenen Einflussfaktoren verifizierbar zu machen, wurden verschiedene Untersuchungsinstrumente in Form von Fragebögen sowohl an die klinische Stichprobe als auch an die Vergleichsstichprobe (Familien, deren Kinder als gesund beschrieben wurden) verteilt. Zur allgemeinen Einschätzung von Verhaltensauffälligkeiten der Kinder in den jeweiligen Familien wurde die Child-Behavior-Checklist von den Eltern ausgefüllt. Zudem schätzten die Eltern über den Fremdbeurteilungsbogen für hyperkinetische Störungen die ADHS-Symptomatik ihrer Kinder ein. Darüber hinaus beurteilten die Eltern eine mögliche eigene ADHS-Symptomatik in der Kindheit über die retrospektiv ausgelegte Wender Utah Rating Scale. Der individuelle Gesundheitszustand der Väter und Mütter wurde über den „EQ-5D“ erfragt, während die Belastung am Arbeitsplatz mittels der Work Limitation Questionnaire ermittelt wurde. Schließlich füllten alle teilnehmenden Eltern einen sozioökonomischen Fragebogen aus, in dem Alter, Geschlecht, Familienstand, Schulabschluss und das Haushaltsnettoeinkommen berücksichtigt wurden.
In zahlreichen, im Diskussionsteil bereits erwähnten Studien wurde eine Mehrbelastung der Eltern festgestellt. In der vorliegenden Arbeit wurden darüber hinaus die konkreten Auswirkungen dieser bereits festgestellten Mehrbelastung auf den Gesundheitszustand und das berufliche Umfeld untersucht. Die Untersuchung dieser Auswirkungen auf das alltägliche Leben der betroffenen Eltern geriet bislang kaum in den Fokus wissenschaftlicher Arbeiten. Um zukünftig betroffene Familien gezielter in unterschiedlichen Lebensbereichen unterstützen zu können ist es jedoch von eminenter Bedeutung, diese Auswirkungen zu kennen und besser zu verstehen.
In den Ergebnissen konnte konkret gezeigt werden, dass bezüglich der Hypothese 1 die Anwesenheit eines ADHS-Kindes innerhalb einer Familie den Gesundheitszustand der Eltern laut Selbsturteil im EQ-5D signifikant beeinflusst. Im Rahmen der beruflichen Belastung war feststellbar, dass ein ADHS-Kind sich signifikant auf die physische Konstitution laut WLQ der Eltern auswirkt. Die Untersuchung der Hypothese II ergab, dass eine mögliche eigene ADHS-Symptomatik in der Kindheit sich auf unterschiedliche Dimensionen im beruflichen Umfeld auswirkt, jedoch nicht signifikant auf den individuellen Gesundheitszustand. Väter und Mütter, die selbst in ihrer Kindheit ADHS-Symptome angaben, geben eine signifikante Beeinträchtigung bezüglich der mentalen Fähigkeiten, des Zeitmanagements und der allgemeinen Arbeitsproduktivität laut Selbsteinschätzung im WLQ an. Eine physische Einschränkung am Arbeitsplatz laut WLQ war bei den Vätern signifikant feststellbar, nicht jedoch bei den Müttern. Die Ergebnisse der Hypothese III ergaben, dass bezüglich der Arbeitsfähigkeit bereits bei einem oder mehr Kindern mit ADHS die kognitiven Fähigkeiten der Eltern am Arbeitsplatz laut WLQ beeinträchtigt sind. Gleichermaßen wird die Arbeitsproduktivität bereits bei einem oder mehr von ADHS betroffenen Kindern signifikant beeinflusst. Auf die physische Konstitution der Eltern laut Selbsteinschätzung im WLQ haben ein oder auch mehrere von ADHS betroffene Kinder jedoch keinen signifikanten Einfluss. Die zeitliche Organisation der Eltern am Arbeitsplatz laut WLQ ist folglich bei einem Kind mit ADHS noch nicht signifikant beeinträchtigt, wohl aber, wenn mehr als ein Kind betroffen ist. Ebenso ist der Gesundheitszustand der Eltern laut EQ-5D erst ab zwei betroffenen Kindern in einer Familie durch diesen Umstand beeinflusst.
Zusammenfassend lässt sich also feststellen, dass durch die Anwesenheit eines Kindes mit ADHS in einer Familie eher der Gesundheitszustand der Eltern signifikant beeinflusst wird, wohingegen die eigene ADHS-Symptomatik der Eltern in der Kindheit viel mehr zu einer signifikanten und mehrdimensionalen Beeinträchtigung am Arbeitsplatz führt. Diese Erkenntnis zeigt, dass die eigene ADHS-Symptomatik der Eltern in der Kindheit neben der Anwesenheit eines ADHS - Kindes nicht unerhebliche Auswirkungen auf die alltäglichen Aufgaben der Betroffenen hat. Die Erkenntnis dieser neuen Zusammenhänge sollte in zukünftigen Forschungsvorhaben berücksichtigt werden.
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.
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.
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.
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.
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.