Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral developmental disorder, affecting 3-7% of children. It is characterized by a persistent pattern of impulsiveness and inattention, with or without hyperactivity. Structural imaging studies have demonstrated regional brain changes, including (sub)cortical grey matter volume reductions in children with ADHD. Twin studies indicate that ADHD is highly heritable. However, genome-wide-association studies have failed to reliably identify genetic variants that explain even a small part of the genetic risk. Most likely, the combination of many genetic variants explains the vulnerability to ADHD. We propose a novel approach that utilizes functional genomic information to group genes into ?functional gene networks? (FGNs). We will subsequently test for the association of FGNs with ADHD symptoms and a clinical diagnosis of ADHD, in a large population-based cohort (n=3600) and a clinical cohort (N=300 cases). In addition, we will investigate how these FGNs relate to ADHD by conducting functional genetic experiments as well as brain imaging experiments. Large international replication cohorts are available. This project integrates expertise from child psychiatry, functional genomics and brain imaging. We propose to link functional gene networks to brain morphology, and directly relate any patterns observed to the morphological and clinical correlates of ADHD, aiming to formulate an integrative theory of the genetically mediated neural substrates of ADHD.

Selective serotonin transporter (5-HTT) inhibitors (SSRIs) are commonly-used antidepressants during pregnancy, leading to high serotonin levels in the foetus. While the treatment is beneficial and safe for the mother, it may be harmful for the unborn child, because serotonin plays an important role in brain development during the prenatal phase. This possibility is suggested by reports of anxiety- and depression-like symptoms during adulthood, after developmental SSRI exposure in rodents. These behavioural symptoms are also seen in 5-HTT knockout (5-HTT-/-) mice and rats, and in association with the common human 5-HTT polymorphism. From the perspective of neuronal circuits, it has been established that 5-HTT-/- rodents show altered neuronal organization of the somatosensory cortex, and that the 5-HTT polymorphism is associated with large scale functional changes in corticolimbic circuits. Yet, because of lack of methodological consistency across studies, it remains unclear how behavioural changes induced by prenatal SSRI exposure are reflected in the brain. Our proposal aims to uncover the effects of SSRI-use during pregnancy by conducting multidisciplinary studies that will encompass analyses of behaviour, neural connectivity, physiology and gene expression. To this end we will integrate behavioural, neuroimaging, electrophysiological, and molecular techniques targeting the somatosensory and corticolimbic systems. Besides prenatally SSRI-exposed rats and children, 5-HTT-/- rats will be used. We anticipate that elucidation of early serotonergic modulations will have far-reaching implications that range from improved fundamental understanding of links between gene, brain and behaviour, to an improved clinical understanding of effects of SSRI medication during pregnancy.

Erasmus University Rotterdam is the founding organisation of the Netherlands Institute for Health Sciences (NIHES). NIHES was accredited as research school by the Royal Netherlands Academy of Arts and Sciences (KNAW) in 1992, and re-accredited 1997, 2002 and 2008 (see Appendix I). In 2007, an International Review and Advisory Committee evaluated the overall quality of the NIHES research groups involved, as well as the international teaching programme as outstanding, meeting the highest international standards. NIHES mission is to further improve scientific education and research in determinants of diseases and health, the efficiency and effectiveness of health care and services, and the theory and methods of health sciences. The institute provides high quality, internationally attractive and competitive research training programmes in quantitative medicine and health sciences for Masters students and PhD students. NIHES participates in the Erasmus MC research Masters programme in Clinical Research (re-accreditation in progress) and collaborates narrowly with the research school Molecular Medicine. For Masters students NIHES offers a two-year full time research Masters programme in Health Sciences and a one-year full time or part-time Masters programme in Health Sciences, both with specializations in epidemiology, clinical epidemiology, genetic epidemiology and public health. Upon completion of the Masters programme the students receive a Master of Science degree in Health Sciences. A recent re-accreditation report by the Accreditation Organisation of the Netherlands and Flanders (NVAO) evaluated the two-year research Masters programme as excellent with respect to the learning outcomes, educational programme, lecturers involved and success rate. At an international level, the NIHES Masters programmes in Health Sciences are comparable to Masters programmes of leading schools in epidemiology and public health elsewhere in Europe (the London School of Hygiene and Tropical Medicine) and in the United States of America (Harvard School of Public Health, Johns Hopkins Bloomberg School of Public Health), regarding the quality as well as the contents of the programmes. Several NIHES lecturers hold an adjunct professorship at Harvard School of Public Health, and there is a close research collaboration between NIHES and the top institutes mentioned above. One of the key features of the NIHES education and research programme is that students choose their own research topic and field of research. After a series of rotations that introduces them to a wide range of research topics spanning molecular medicine, epidemiology, statistics and genetics, PhD students continue their research training by attending more advanced courses, to deepen and broaden their knowledge, thereby building upon the knowledge gained during the Masters phase according to the self-selected specialization. They may choose among the nearly 100 available NIHES courses, but they are also encouraged to find suitable courses elsewhere at Erasmus MC (e.g. in the research schools Molecular Medicine or Medical Genetics) or at other universities. This application focuses on a new, highly challenging graduate sub-programme, in which the emphasis is on the combination of genetic epidemiology and molecular medicine, under the heading of Clinical & Genetic Epidemiology. The main goal of this sub-programme is to enable promising students who want to pursue an academic career on the cross road of clinical and genetic epidemiology and molecular medicine to become part of the next generation of top researchers in the field of genomic research. In the graduate sub-programme Clinical & Genetic Epidemiology expertise in the programmes of genetic epidemiology is combined with that of molecular medicine. Prof. Dr. van Duijn is the coordinator of the new sub-programme. In this area, key issues are the discovery of genes related to major diseases and the efforts in the translation of gene-findings for clinical medicine, i.e. treatment or prevention. Advances in genetic epidemiology research are rapidly unravelling the role of genetic factors in the pathogeneses of common diseases such as heart disease, osteoporosis, asthma, and type 2 diabetes. One major promise is that these advances will lead to personalized medicine, where preventive and therapeutic interventions for complex diseases can be individually tailored to a persons genetic profile. Developments in high-throughput technologies are also creating a constant demand for new statistical approaches; statistical genetics now plays an important role in gene discovery and in translational studies. In the framework of the Erasmus MC Graduate School, NIHES works together with other KNAW accredited research schools (Molecular Medicine, Cardiology, Medical Genetics). For this application targeting Clinical & Genetic Epidemiology, Molecular Medicine is the main partner. Both NIHES and Molecular Medicine have a major interest and track record in etiological research but both are working on a translational studies as new subject of interest. With this application we aim to extend the collaboration in a joint training programme in which participants can specialize in experimental, etiologic, prognostic or molecular research after rotating course modules and exploring the disease specific research programmes of the groups involved.