For our network we have selected a multidisciplinary, highly complementary, international team of researchers from academia and private sector organizations with longstanding collaborations. Collaborative databases and sharing of materials have been key to the success of these collaborations and form a guarantee for achieving the objectives of this ETN. Additional private sector partners have been chosen in fast-progressing areas of the research and at bottlenecks and innovative edges in current research-to-clinic translation. Involvement of patient organisations ADHD-Europe and Autism-Europe enables a direct representation of patients’ voice in the research. The combination of the different sectors provides an optimal environment for original and innovative research.
- Work package 1 Prevalence and definition Read more
In this WP, we will study the overlap of ASD and ADHD, associated psychosocial risk factors, and underlying cognitive parameters.
Differential and overlapping clinical and cognitive endophenotypes of ASD and ADHD will be studied. Given the overlap in genetic influences, pattern of neurocognitive dysfunctions of ASD and ADHD, the work package has the following aims. Aim 1: Describe overlap of the disorders and associated psychosocial risk factors in a population-based (ESR1) as well as clinical samples (ESR2, ESR3), and investigate the role of age in those (in collaboration with WP3; ESR12). The specific aim of studying overlap in psychiatric morbidity is to elicit more homogeneous groups of neurodevelopmental disorders/traits that span the traditional diagnostic boundaries; characterised by, for example, higher clinical severity or a specific pattern of cognitive, genetic and environmental risk factors. Aim 2: Build on previous studies in ADHD and ASD, which have shown specific impairments in visual attention (ADHD), visuo-motor decision making (ASD), spatial working memory (ASD, ADHD) and reaction time variability (ADHD). Previous studies have assessed either children, adolescents or adults, not analysing the development of these neurocognitive abilities from childhood into adulthood. Moreover, the correlation of the cognitive abilities across disorders has not been studied. This is necessary to differentially elicit the underlying basic and the respective secondary cognitive impairments in ASD, ADHD and across clinical groups. In addition to the study of between and within group differences, dimensional measures of ADHD and ASD symptoms will be correlated with cognitive abilities across groups (ASD, ADHD). By studying children and adolescents (ESR2), as well as adults (ESR3), developmentally stable and age-specific impairments will be described. Our results will help to improve the differential diagnostics of ASD, ADHD and specific cognitive subgroups, and ultimately will help to develop individualized therapeutic approaches for specific patients.
This work package is lead by Prof. Philip Asherson, King's College London, UK.
- Work package 2 Genetics and epigenetics Read more
Twin and family studies document a high heritability for both ASD (>80%) and ADHD (around 75%). However, the precise definition of the molecular genetics landscape of the disorder is still far from being completed. The underlying genetic risk factors are numerous, with significant environmental interactions mediated through epigenetic programming. In this WP we will investigate the role of the genome, epigenome and environment in ASD and ADHD using state-of-the art high-throughput methodologies. Focus will be on shared and disorder-specific genetic/epigenetic variation to understand disease etiology and identify biomarkers useful in predicting outcome.
We will study the contribution of common and rare genetic variation to ADHD and ASD (ESR4, ESR5, ESR6), parent-of-origin effects as clues for epigenetic variation (ESR4, ESR5), the interplay between genome and microbiome, a relevant but still rather unexplored environmental influence in complex disease (ESR7) and also epigenetic factors such as DNA methylation and microRNA-based regulation of gene expression (ESR8). For this, we will use whole-exome and whole-genome sequence data, Exome and PsychChip data, GWAS genotypes and also CNV data, which will be analysed using bioinformatic tools, including pathway analysis. Also, expression and epigenetic studies in humans and genetically-engineered rodents will be performed. The identified genes will be followed up by ESR10 (WP3), where Drosophila is used as a model for testing candidate risk genes, and by ESR14 (WP4), which aims at seeking targets for the discovery of novel therapeutic compounds.
This work package is lead by Prof. Bru Cormand, Universitat de Barcelona, Spain.
- Work package 3 Model systems Read more
Understanding the molecular, cellular and developmental bases of ADHD and ASD remains extremely challenging due to the limited availability of suitable model systems. This work package will explore novel models for ADHD and ASD to provide insights into their pathology and facilitate translation of data to the bedside. Each WP3 ESR, along with two further ESRs from WP1 and WP2, will specialise in the use of one of five model systems (cell culture [ESR9], fruit fly [ESR10], zebrafish [ESR11], mouse [ESR8, WP2] or human neuroimaging [ESR12]) as well as learning to work with the other models by visiting partner laboratories. Specific objectives include mapping the function of ADHD- and ASD-linked genes across organisms and identifying novel drug targets for these diseases. The ESRs trained in this work package will be able to directly compare the strengths and weaknesses of each model and interpret comparative phenotypes, thereby speeding up translation of information between models and towards use in medical genomics.
Understanding the molecular neurobiology of phenotypically complex multifactorial disorders requires the development and characterization of disease models taking into account different contributory factors such as genetic variation, cellular mechanisms, gene‐environment interactions and developmental stages. This state-of-the-art WP encompasses cross-species training and the investigation and comparison of data in multiple disease models. Each model will be based upon defined intermediate phenotypes or endophenotypes rather than anthropomorphized symptoms or complex syndromes, taking advantage of the strengths of each system. Although fish and flies show only partial neuroanatomical overlap with humans, disease-linked behaviours are controlled by conserved neurotransmitters (e.g. dopamine in the regulation of activity and arousal). The ESRs will study two genes (CNTNAP2 and GRM5) across all models and additionally learn to exploit the complementary strengths of the models: studies in Drosophila permit the rapid characterization and validation of candidate genes; zebrafish’s small size make them ideal for drug screening; induced pluripotent stem cells (iPSCs) allow the functional consequences of genetic manipulations to be uncovered in human-derived tissue at the cellular level. Human imaging models allow direct in vivo consequences if common genetic variants in genes to be studied.
This work package is lead by Dr. William Norton, University of Leicester, UK.
- Work package 4 Prediction and treatmentRead more
Novel methods/findings that are improving our understanding of the underlying biology in neurodevelopmental disorders are yet to lead to innovation in treatment approaches or the identification of clinically useful biomarkers associated with disease and its outcome. WP4 will explore novel candidate biomarkers and treatment targets that hold promise for the development of innovative pharmacological and non-pharmacological treatments in ADHD and ASD, and for improving the prediction of clinical outcomes.
We will utilize several innovative approaches. Studying the human gut microbiome, we will discover microbial profiles associated with risk for ADHD and ASD, and specific genetic variants modifying the relationship between microbiome and brain (ESR7, collaboration with WP2), which can lead to biomarkers modifiable by diet and novel genetic targets for pharmacological interventions. To identify additional targets for the development of pharmacological treatment options, we will (1) explore binding partners to wild-type and mutant candidate proteins discovered in WP2 for their potential as novel compounds able to modify the biological targets; (2) test 50 novel compounds in zebrafish models of ADHD and ASD (in collaboration with WP3). To identify cognitive-neuroimaging biomarkers associated with ADHD and ASD symptoms that can predict clinical outcome and direct the development of non-pharmacological interventions, we will perform longitudinal studies of cognition and neuroimaging (ESRs 12,13, in collaboration with WP1). We will also directly examine effects of mindfulness intervention on improving self-control capacities, ADHD and co-occurring ASD in children with ADHD (ESR15).
This work package is lead by Prof. Jonna Kuntsi, King's College London, UK.
- Work package 5 TrainingRead more
The WP will provide and coordinate all training components that are essential for the personal development of each ESR.
The WP is responsible for the overall coordination of teaching activities, which includes the development and support of the novel e-learning tools, i.e. the e-biostatistics module, the internet-based discussion forum (iDF) and the webinar series. The WP will be instrumental in leading the Education and Career Development Board, which is critically involved in the selection of ESRs, approving the personal career development plans and monitoring progress of ESRs. In addition, the yearly meetings will be co-organized by this WP and the local hosts.
This work package is lead by Dr. Arjan de Brouwer, Radboudumc, Nijmegen, The Netherlands.
- Work package 6 ImpactRead more
The objectives of this WP are to enhance personal resources, skills, and knowledge of the ESRs to uncover their full potential in diverse research environments, and to coordinate the dissemination and valorisation of the research done within MiND.
This WP will foster the career development of the ESRs to fully tap their potential; it will coordinate all efforts on dissemination and outreach, with special emphasis on patients, healthcare professionals, policy makers and the public; it will manage the commercial exploitation of the research done in this ETN. Specific measures include a public relation strategy combining web-based efforts, media releases, and real live dissemination activities. Those will be carried out by the ESRs, overseen and with the help of senior researchers. In doing so, ESRs will not only receive excellent scientific training (see WP 5) but also learn how to communicate and eventually valorise their findings.
This work package is lead by Prof. Dr. Andreas Reif, Johann-Wolfgang Goethe University, Frankfurt, Germany.
