Dataset Information

Comorbid problems in ADHD: degree of association, shared endophenotypes, and formation of distinct subtypes. Implications for a future DSM.

ABSTRACT: We aimed to assess which comorbid problems (oppositional defiant behaviors, anxiety, autistic traits, motor coordination problems, and reading problems) were most associated with Attention-Deficit/Hyperactivity Disorder (ADHD); to determine whether these comorbid problems shared executive and motor problems on an endophenotype level with ADHD; and to determine whether executive functioning (EF)-and motor-endophenotypes supported the hypothesis that ADHD with comorbid problems is a qualitatively different phenotype than ADHD without comorbid problems. An EF-and a motor-endophenotype were formed based on nine neuropsychological tasks administered to 816 children from ADHD-and control-families. Additional data on comorbid problems were gathered using questionnaires. Results indicated that oppositional defiant behaviors appeared the most important comorbid problems of ADHD, followed by autistic traits, and than followed by motor coordination problems, anxiety, and reading problems. Both the EF-and motor-endophenotype were correlated and cross-correlated in siblings to autistic traits, motor coordination problems and reading problems, suggesting ADHD and these comorbid problems may possibly share familial/genetic EF and motor deficits. No such results were found for oppositional defiant behaviors and anxiety. ADHD in co-occurrence with comorbid problems may not be best seen as a distinct subtype of ADHD, but further research is warranted.

SUBMITTER: Rommelse NN

PROVIDER: S-EPMC2708322 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Comorbid problems in ADHD: degree of association, shared endophenotypes, and formation of distinct subtypes. Implications for a future DSM.

Rommelse Nanda N J NN Altink Marieke E ME Fliers Ellen A EA Martin Neilson C NC Buschgens Cathelijne J M CJ Hartman Catharina A CA Buitelaar Jan K JK Faraone Stephen V SV Sergeant Joseph A JA Oosterlaan Jaap J

Journal of abnormal child psychology 20090801 6

We aimed to assess which comorbid problems (oppositional defiant behaviors, anxiety, autistic traits, motor coordination problems, and reading problems) were most associated with Attention-Deficit/Hyperactivity Disorder (ADHD); to determine whether these comorbid problems shared executive and motor problems on an endophenotype level with ADHD; and to determine whether executive functioning (EF)-and motor-endophenotypes supported the hypothesis that ADHD with comorbid problems is a qualitatively ...[more]

PMID: 19308723

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Project description:Heterogeneity in attention-deficit/hyperactivity disorder (ADHD), with complex interactive operations of genetic and environmental factors, is expressed in a variety of disorder manifestations: severity, co-morbidities of symptoms, and the effects of genes on phenotypes. Neurodevelopmental influences of genomic imprinting have set the stage for the structural-physiological variations that modulate the cognitive, affective, and pathophysiological domains of ADHD. The relative contributions of genetic and environmental factors provide rapidly proliferating insights into the developmental trajectory of the condition, both structurally and functionally. Parent-of-origin effects seem to support the notion that genetic risks for disease process debut often interact with the social environment, i.e., the parental environment in infants and young children. The notion of endophenotypes, markers of an underlying liability to the disorder, may facilitate detection of genetic risks relative to a complex clinical disorder. Simple genetic association has proven insufficient to explain the spectrum of ADHD. At a primary level of analysis, the consideration of epigenetic regulation of brain signalling mechanisms, dopamine, serotonin, and noradrenaline is examined. Neurotrophic factors that participate in the neurogenesis, survival, and functional maintenance of brain systems, are involved in neuroplasticity alterations underlying brain disorders, and are implicated in the genetic predisposition to ADHD, but not obviously, nor in a simple or straightforward fashion. In the context of intervention, genetic linkage studies of ADHD pharmacological intervention have demonstrated that associations have fitted the "drug response phenotype," rather than the disorder diagnosis. Despite conflicting evidence for the existence, or not, of genetic associations between disorder diagnosis and genes regulating the structure and function of neurotransmitters and brain-derived neurotrophic factor (BDNF), associations between symptoms-profiles endophenotypes and single nucleotide polymorphisms appear reassuring.

Project description:Exposure to cigarette smoke creates a field of injury throughout the entire respiratory tract inducing genomic alterations that lead to an “at-risk” airway where and lung cancers develop. Lung squamous cell carcinoma (SCC) arises in the epithelial layer of the bronchial airways and is often preceded by the development of premalignant lesions(PMLs). The presence of high-grade persistent or progressive PMLs is a marker of increased lung cancer risk both at the lesion site elsewhere in the lung. Effective tools to identify and treat premalignant lesions at highest risk of progression to invasive carcinoma are lacking. We profiled via RNA-Seq airway brushing and biopsies (divided into two cohorts: discovery and validation) obtained from high-risk smokers undergoing lung cancer screening via serial auto-fluorescence bronchoscopy procedures. We identified four distinct molecular subtypes (Proliferative, Inflammatory, Secretory, and Normal) in the bronchial biopsies that correspond to a spectrum of biological and morphological alterations. The Proliferative subtype was enriched with dysplastic PMLs from current smokers that exhibit up-regulation of KRT5 and KI67 as well as metabolic and cell cycle pathways, and down-regulation of cilium-associated processes and FOXJ1 expression. Molecular subtype classification in the validation cohort biopsies replicated these significant clinical and biological associations. Airway brushes from normal fluorescing areas of the large airway classified as the Proliferative subtype specifically predicts the presence of biopsies of this same subtype. Within the Proliferative subtype, genes associated with interferon signaling and antigen processing and presentation were observed to be down-regulated among dysplastic biopsies that persistent or progress in the future. Innate and adaptive immune cells were computationally predicted to be depleted in these biopsies and this was confirmed via immunofluorescence staining of adjacent biopsies. These findings provide a proof of concept that molecular biomarkers of endobronchial biopsies can enhance histopathological grading and that immunoprevention strategies are an important future direction in intercepting the progression of PMLs to lung cancer.

Project description:BACKGROUND:Compared to typically developing individuals, individuals with attention-deficit-hyperactivity disorder (ADHD) are on average more often exposed to stressful conditions (e.g., school failure, family conflicts, financial problems). We hypothesized that high exposure to stress relates to a more persistent and complex (i.e., multi-problem) form of ADHD, while low-stress exposure relates to remitting ADHD over the course of adolescence. METHOD:Longitudinal data (ages 11, 13, 16, and 19) came from the Tracking Adolescents' Individual Life Survey (TRAILS). We selected children diagnosed with ADHD (n = 244; 167 males; 77 females) from the TRAILS clinical cohort and children who screened positive (n = 365; 250 males; 115 females) and negative (gender-matched: n = 1222; 831 males; 391 females) for ADHD from the TRAILS general population sample cohort (total n = 1587). Multivariate latent class growth analysis was applied to parent- and self-ratings of stress exposure, core ADHD problems (attention problems, hyperactivity/impulsivity), effortful control, emotion dysregulation (irritability, extreme reactivity, frustration), and internalizing problems (depression, anxiety, somatic complaints). RESULTS:Seven distinct developmental courses in stress exposure and psychopathology were discerned, of which four related to ADHD. Two persistent ADHD courses of severely affected adolescents were associated with very high curvilinear stress exposure peaking in mid-adolescence: (1) Severe combined type with ongoing, severe emotional dysregulation, and (2) combined type with a high and increasing internalization of problems and elevated irritability; two partly remitting ADHD courses had low and declining stress exposure: (3) inattentive type, and (4) moderate combined type, both mostly without comorbid problems. CONCLUSIONS:High-stress exposure between childhood and young adulthood is strongly intertwined with a persistent course of ADHD and with comorbid problems taking the form of either severe and persistent emotion dysregulation (irritability, extreme reactivity, frustration) or elevated and increasing irritability, anxiety, and depression. Conversely, low and declining stress exposure is associated with remitting ADHD and decreasing internalizing and externalizing problems. Stress exposure is likely to be a facilitating and sustaining factor in these two persistent trajectories of ADHD with comorbid problems into young adulthood. Our findings suggest that a bidirectional, continuing, cycle of stressors leads to enhanced symptoms, in turn leading to more stressors, and so forth. Consideration of stressful conditions should, therefore, be an inherent part of the diagnosis and treatment of ADHD, to potentiate prevention and interruption of adverse trajectories.

Dataset Information

Comorbid problems in ADHD: degree of association, shared endophenotypes, and formation of distinct subtypes. Implications for a future DSM.

Publications

Comorbid problems in ADHD: degree of association, shared endophenotypes, and formation of distinct subtypes. Implications for a future DSM.

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