Contact person
Prof. Dr. B.W.J.H. Penninx
Professor of Psychiatric Epidemiology
Department of Psychiatry
VU University Medical Center
AJ Ernststraat 887
1081 HL
Amsterdam, The Netherlands
b.penninx@vumc.nl

Genome Wide Analysis and Gene-Environment studies for depression
Project leaders VUMC: Prof. Dr. D.I. Boomsma and Prof. Dr. B.W.J.H. Penninx

Positional cloning of genetic risk factors for depression
PrProject leader VUMC: Prof. Dr. P. Heutink

Whole blood gene expression profiling studies for depression, Huntington's disease & migraine
Project leader LUMC: Dr. W.M.C. van Roon
Project leader VUMC: Prof. Dr. A.B. Smit

Functional Genomics of Depression: Cellomics & Cellular assays
Project leaders VUMC: Prof. Dr. A.B. Smit and Prof. Dr. P. Heutink

Transgenesis and Viral vector based intervention
Project leaders VUMC: Prof. Dr. M. Verhage and Prof. Dr. A.B. Smit

Stress hormones, depression and anxiety disorders
Project leader LUMC/UL: Prof. Dr. E.R. de Kloet

With lifetime prevalences of around 16%, depressive disorder and anxiety disorder are the most common of all psychiatric disorders. Depression is characterized by marked and persistent downcast moods without any apparent reason. A variety of physical and cognitive signs and symptoms is associated with depression, such as sleep problems, weight loss, poor concentration, loss of appetite, excessive feelings of guilt and worthlessness and recurring thoughts of death or suicide. Anxiety covers a range of disorders including panic disorder, social phobia and generalized anxiety disorder. Both depressive and anxiety disorders frequently run a chronic course; relapses occur in 40 - 60% of the patients. Their impact is often underestimated. They prevent the patient from functioning within the family circle, at work and during leisure. This has a considerable impact on the patient's personal and professional life. According to the WHO, depression will be the second most important medical disorder worldwide by the year 2020.

The main problem with depressive and anxiety disorders are that the origins of the disease are still unclear. Studies in twins have shown that genetic predisposition plays a major role; the contribution of hereditary factors is estimated at 40%. Environmental factors appear to trigger depression and anxiety, but these are specific for individual patients. Some people are confronted with serious setbacks and grievances, but do not suffer from depression or anxiety, whereas as others may experience milder problems and become depressed or anxious. Depression and anxiety disorders are complex disorders as they arise from the interplay between individual environmental factors and genetic vulnerability. More insight into the genetic factors is needed, to better understand the biological origins of these disorders, but also to enable more targeted research into the contribution of environmental factors. So far, genetic research has suggested many candidate genes, but significant gene effects have not yet been demonstrated in large-scale studies.

Within CMSB, there is a strong collaboration among several groups in the area of depression research. The NESDA/NTR consortium of investigators was selected for genome-wide association (GWA) genotyping as one of the six Genetic Association Information Network (GAIN) studies ("Stage 1 GWA in Population-Based Samples"). GWA genotyping of 1860 cases with MDD and 1860 population-based controls as part of the GAIN initiative will be conducted by Perlegen Sciences (completed in October). For 1000 participants of the Erasmus Rucphen Family (ERF) study, who have been screened for depression and anxiety, GWA data will available in September 2007. This will allow for both cross validation of findings across cohorts as well as joint analysis. Within CMSB whole blood gene expression profiles of depressed patients, controls and twins will be generated providing new biomarkers and pathways for in depth analysis. In addition, we have the expertise for follow-up studies focusing on the contribution of polymorphisms, using cellular screening in vitro, animal models in vivo and in human (patient) groups with specific endophenotypes. The integration of the various technological platforms therefore combines the various approaches towards our systems biology approach.

CMSB aims to generate more insight into the origins of depression and anxiety disorders. Why do some individuals develop these disorders while others, given the same environmental conditions do not become depressed or anxious? Our first goal is to identify genomic regions and gene variants that mediate vulnerability to MDD as main effects and as gene-environment interactions in our own samples and through participation in large scale GWAS consortia. Second, we aim to follow up the most promising replicated regions in humans by subsequent analysis of candidate genes for cellular screens and in animal studies. Third, we aim for generation of animal models expressing phenotypes based on newly identified gene defects. Last, through longitudinal biobank studies we aim to study age-related and developmental trajectories in gene and protein expression profiles and methylation status of risk genes. This way, we hope to identify the pathways that lead to mood disorders. The identification of genetic factors will allow us to improve cellular and animal readout systems for validation purposes in drug discovery. For depression, these systems are still in their infancy. The identification of environmental factors will allow a better counselling of at-risk persons for preventive and counteractive lifestyle measures. Complemented with better and more targeted medication, this will greatly improve quality of life.

1. PSullivan P, de Geus EJC, Willemsen G, James MR, Smit JH, Zandbelt T, Arolt V, Baune BT, Blackwood D, Cichon S, Coventry WL, Domschke K, Dumenil T, Farmer A, Fava M, Gordon SD, Heutink P, Holsboer F, Hoogendijk WJ, Hottenga JJ, Kohli M, Lin D, Lucae S, MacIntyre DJ, Maier W, McGhee KA, McGuffin P, Montgomery G, Muir WJ, Nolen W, Nöthen MM, Perlis R, Pirlo K, Posthuma D, Rietschel M, Schosser A, Smoller JW, AB Smit, Tzeng JY, van Dyck R, Zitman FG, Verhage M, Martin NG, Wray NR, Boomsma DI, Penninx BW. Genome-wide association for Major Depressive Disorder: a possible role for the protein PCLO. Mol Psychiatry 2008; Dec. 9, Epub ahead of print.
2. Penninx BW, Beekman AT, Smit JH, Zitman FG, Nolen WA, Spinhoven P, Cuijpers P, de Jong PJ, van Marwijk HWJ, Assendelft WJJ, van der Meer K, Verhaak P, Wensing M, de Graaf R, Hoogendijk WJ, Ormel J, van Dyck R: The Netherlands Study of Depression and Anxiety (NESDA): Rationale, objectives and methods Int J Meth Psychiatr Res 2008; 17: 121-140.
3. Boomsma DI, Willemsen G, Sullivan PF, Heutink P, Meijer P, Sondervan D, Kluft C, Smit G, Nolen WA, Zitman FG, Smit JH, Hoogendijk WJ, van Dyck R, de Geus EJ, Penninx BW: Genome-wide association for Major Depression: Description of samples for the GAIN Major Depressive Disorder Study: NTR and NESDA biobank projects. Eur J Hum Genet 2008; 16: 335-342.
4. Boomsma DI, Beem AL, Berg M van den, Dolan CV, Koopmans JR, Vink JM, Geus EJC de, Slagboom PE: Netherlands twin family study of anxious depression (NETSAD). Twin Research 2000, 3, 323-334.

Netherlands Twin Registry
The Netherlands Twin Registry (NTR) was founded in 1987 at the Vrije Universiteit in Amsterdam in order to perform scientific research into the contribution of genetic factors to personality and mood disorders, growth and development, brain function and cognition, and risk factors for cardiovascular disease. Currently, the NTR encompasses approximately 5,000 twin pairs aged 15 - 70 and their relatives (parents, siblings, spouses). In total, around 20,000 people have participated at least once in the longitudinal survey studies of the NTR.

Netherlands Study of Depression and Anxiety (NESDA)
NESDA has recruited a large cohort of 2981 persons with and without depressive and anxiety disorders between 2004 and 2007. Longitudinal follow-up assessments - which allow examining the course of depressive and anxiety disorders – are currently ongoing and will cover 8 years of follow-up. Extended (endo) phenotyping will include (functional) imaging, biomarkers, neuropsychological traits, endocrine and autonomic nervous system functioning. In addition, depression is studied in elderly subjects, who also have extensive phenotypic data with respect to depression and DNA.

Center for Neurogenomics and Cognitive Research
The Center for Neurogenomics and Cognitive Research (CNCR) was founded jointly by the VU University Amsterdam and the VU University Medical Center. The founding directors were Prof. Dr. D.I. Boomsma (FPP), Prof. Dr. W.P.M. Geraerts (FALW) and Prof. Dr. M.P. Witter (VUMC). At the the center, neurobiologists, clinical and preclinical neuroscientists and psychologists collaborate to contribute to the development of a new integrative neural science, rooted in molecular biology and genetics and extending all the way to behavior and cognition in health and disease. The center generates integrated research programs from gene to behavior, each combining mouse and human studies.

Genetic Association Information Network studies (GAIN)

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