R2D2-MH EU-funded project start: Increased quality of life for people with neurodevelopmental disorders

Genetics

Experts from 26 countries have laid the foundations in Paris for innovative approaches to improving the quality of life of people with neurodevelopmental disorders. The international and interdisciplinary cooperation, in which our Laboratory and the Clinic for Psychiatry, Psychosomatics and Psychotherapy of Childhood and Adolescence at Frankfurt University Hospital is also involved with three research projects, is being funded by the EU with a total of eleven million euros until 2027.

The team behind R2D2. The picture was taken during the kick-off meeting in Paris, at the Institute Pasteur, who is coordinating this effort.

Embracing developmental diversity as factor for well being

Together with 26 world-leading interdisciplinary research groups from Europe and associated countries, we are committed to improving the quality of life of individuals with neurodevelopmental disorders. The EU-funded project Risk and Resilience in Developmental Diversity and Mental Health (R2D2-MH) adopts a new approach:  We are not studying only the risk but we will consider developmental or genetic diversity, as well as a diagnosis and life experiences as factors that influence mental well-being and functioning across the lifespan.

Large proportion of the population affected - neurobiological mechanisms little researched

Mental Health defines personal well-being and 38,2% of the population in the EU population are faced with a mental disorder or challenge which cost EU economies over €600 billion per year. Neurodevelopmental disorders (NDDs) are conditions affecting growth and development in the brain and typically start early in life. These include conditions such as autism, attention deficit / hyperactivity disorder (ADHD). People with NDDs and their families experience greater discrimination and stigma which has a further negative impact on well-being. Currently, there are no highly effective, evidenced based approaches to improve medium to long-term MH outcomes in the context of NDDs. This is due partly to a limited understanding of the neurobiological mechanisms involved in the transition from MH to illness throughout the life course and the interaction with environmental factors. The distinction between diversity and disorder is exactly where R2D2-MH comes in.

Developmental model of Risk versus Resilience
R2D2-MH will investigate large-scale and deep-phenotyped cohorts to identify individuals at similar risks for MH, but with different MH outcomes. Clinical cohorts are biased for participants with poor MH outcomes. Resilient individuals - defined as exposed to high risk, but with low level of symptoms and good outcome- are detected in preterm cohorts, in the general populations, and in relatives of individuals with NDD.
R2D2 Workpackages
WP1 will collect, harmonize and augment the genetic data which will be further combined with brain imaging data from WP2 and real world and intervention data from WP4 and serve for the development of predictive models in WP5. WP3 will allow better definitions of MH outcomes to reduce the stigma for persons with or at risk of MH disease, it will be connected to WP6 Dissemination, Communication, Exploitation, Training to inform and train stakeholders and to exploit the outcomes. WP7 will provide the general support to all other WPs.

Towards a risk and resilience based personalized intervention

The Department for Child and Adolescent Psychiatry, Psychsosomatics and Psychotherapy of the University Hosptial Frankfurt will be involved in two workpacakges. The reserach group around Professor Ecker will focus on the characterization of risk and resilience markers of developmental diversity using brain imaging data in WP2 and combine them with gene expression, genetic as well as cell model data. Our laboratory will investigate in collaboration with Prof. Freitag in WP4, how treatment interventions interact with genetic markers on the outcome in neurodevelopmental disorders.

Inherent to all WPs is the co-creation with individuals that experience mental health problems in order to optimize study design and the defined outcome measures to ultimately increase the quality of life and well-being. 

 

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Press releases and Publications

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RAISE GENIC: Rational antiepileptic drug selection by combining gene network and ICT analyses

Genetics

Preliminary results: identification of differentially expressed genes after Valproate treatment in iPSC derived neurons

The RAISE-GENIC research network aims to identify models that allow predicting the drug therapy with the best chances of success for individual epilepsy patients for an individualized selection of anti-epileptic drugs. In our sub-project, we analyze RNA expression data of drug-treated cells and DNA sequencing data of affected patients and carry out the bioinformatic evaluation of the transcriptome networks and their processing for big data and machine learning analyses.

Valproate is known to activate a broad network of genes via transcriptomic regulation. We hypothesize that the transcriptomic response mediates success of valproate treatment and that thus alterations of the network properties are predictors of treatment outcome in patients with epilepsy.

We aim at developing a recommendation system for Valproate, integrating patients’ genetic information and the drug’s transcriptomic profile. For each patient in the study, we estimated how the genetic network properties are altered based on the individual’s mutational burden. We confirmed that the alteration of network properties are significant predictors of treatment outcome, although with moderate accuracy. In addition, we identified stable subgroups. The clinical association is currently under investigation.


Funding

Publications

in progress

Self-Injury Treatment, Assessment, Recovery: genetic risk factors

Genetics

The STAR project aims to identify the factors that contribute to the risk, prevention or recovery of non-suicidal self-injurious behaviour. The Molecular Genetics Laboratory is looking at genetic factors that may influence the reward system and the pain system in the brain. In particular, we are testing whether variants of the relevant genes might be related to behaviour and treatment outcome.

Funding

Publications

Yousaf, A., Waltes, R., Haslinger, D. et al. Quantitative genome-wide association study of six phenotypic subdomains identifies novel genome-wide significant variants in autism spectrum disorder. Transl Psychiatry 10, 215 (2020). https://doi.org/10.1038/s41398-020-00906-2

Genetic and epigenetic factors of female conduct disorder

Genetics

SILTRK5 methylation is associated with conduct disorder in females

Our clinic is currently conducting a Europe-wide study to research social behaviour disorders in girls. The special focus of this study is on emotion processing, neurobiology and therapy of conduct disorders (CD). This disorder can negatively affect the development and well-being of affected children and adolescents as well as their families, caregivers and teachers. However, research to date has mostly focused on investigating the causes, course and treatment options for boys with CD. Although CD is more common in boys than girls, approximately one to three percent of girls also suffer from it, and the number of girls with CD in Western societies such as the EU has increased significantly in recent years. A total of 17 research institutes from eight EU countries are participating in the large-scale study. The aim of the study is to better understand social behaviour disorders and to identify possible differences between boys and girls with CD and healthy control subjects in order to develop improved treatment options.

The molecular genetics laboratory is investigating which genetic and epigenetic factors influence the risk of conduct disorders (CD) in girls and whether these correspond to the risk factors described for boys. On the one hand, we are investigating the effect of environmental factors such as smoking during pregnancy in interaction with known genetic variants as a cause of CD. Secondly, we are searching genome-wide for patterns of differential methylation of DNA (epigenetics) in female patients and healthy girls.

Funding

Publications

Chiocchetti AG, Yousaf A, Waltes R, Bernhard A, Martinelli A, Ackermann K, et al. (2022) The methylome in females with adolescent Conduct Disorder: Neural pathomechanisms and environmental risk factors. PLoS ONE 17(1): e0261691. https://doi.org/10.1371/journal.pone.0261691
Farrow, E., Chiocchetti, A.G., Rogers, J.C. et al. SLC25A24 gene methylation and gray matter volume in females with and without conduct disorder: an exploratory epigenetic neuroimaging study. Transl Psychiatry 11, 492 (2021). https://doi.org/10.1038/s41398-021-01609-y
Farrow, E., Chiocchetti, A. G., Rogers, J. C., et al. (2021). Correction: SLC25A24 gene methylation and gray matter volume in females with and without conduct disorder: an exploratory epigenetic neuroimaging study. Translational psychiatry11(1), 553. https://doi.org/10.1038/s41398-021-01643-w
Freitag, C.M., Konrad, K., Stadler, C. et al. Conduct disorder in adolescent females: current state of research and study design of the FemNAT-CD consortium. Eur Child Adolesc Psychiatry 27, 1077–1093 (2018). https://doi.org/10.1007/s00787-018-1172-6
Bernhard A, Ackermann K, Martinelli A, Chiocchetti AG, et al. (2022) Neuroendocrine Stress Response in Female and Male Youths With Conduct Disorder and Associations With Early Adversity. J Am Acad Child Adolesc Psychiatry.  61(5):698-710. https://doi.org/10.1016/j.jaac.2021.11.023

Genome-wide association of common polymorphisms with psychiatric phenotypes: a systems biology study.

Genetics

Manhattan plots of genome wide association signals for autism associated phenotypes (SI: social interaction; JA: Joint Attention; NVC: non-verbal communication; RB: repetitive behaviour)

Common genetic variants explain a significant proportion of the genetic risk in autism or conduct disorder. However, it is unclear to what extent these variants also influence the expression of disorder associates phenotypes and which biological networks are particularly relevant. In this genome-wide study, we test common single nucleotide polymorphisms for association with clinical measures and identify the underlying genes. Bioinformatic and graph-theoretical analyses enable us to identify specific processes. Here we also draw on our cohort of families and affected individuals, which is unique in Germany. We also emphasise the many years of close collaboration with patients, relatives and clinics. The analysis and validation of the results are carried out in data from the Autism Genome Project and the SFARI Autism Initiative as well as the FemNAT/CD study.

Funding

Publications

Yousaf, A., Waltes, R., Haslinger, D. et al. Quantitative genome-wide association study of six phenotypic subdomains identifies novel genome-wide significant variants in autism spectrum disorder. Transl Psychiatry 10, 215 (2020). https://doi.org/10.1038/s41398-020-00906-2