FOR 2107:  Neurobiology of Affective Disorders: A Translational Perspective on Brain Structure and Function

• Subject Area: Medicine
• Term: from 2014 to 2023
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 240413749

Genetic (G) and environmental (E) risk factors contribute to and interact with the etiology and potentially the longitudinal course of affective disorders (AD), i.e. major depressive disorder (MDD) and bipolar disorder (BD). The neurobiological correlates by which these predispositions exert their influence on brain structure and function are poorly understood. The aims of the FOR2107 are therefore:1. Establishing consequences (humans, animals), resp. neurobiological mechanisms (animals) of G and E risk factors for AD, particularly on the level of brain structure and function.2. Uncovering neurobiological determinants for the course of illness (onset, relapse, diagnostic shifts, alterations in brain structure and function over time).3. De-novo subgrouping of patients based on biological, cognitive, and psychopathological longitudinal data (novel “biotypes”).In the first funding period, a human cohort (N=2500) of AD patients, subjects at genetic and/or environmental risk, and control subjects (WP1) has been established. All participants underwent extensive deep-phenotyping (MR imaging, clinical course, neuropsychology, personality, risk/protective factors). Biomaterial, i.e. blood, stool, urine, hair, and saliva is stored in a central biobank (CP1). Subjects have been analysed for genetic and epigenetic markers (WP5, CP1). In the second funding period, re-assessment after 2 years for all MACS participants will be completed. A methodological work package (WP6) is developing methods for data reduction, quality assurance for longitudinal MRI data, bioinformatics support, and (deep) machine learning techniques.In the parallelised animal project cluster, risk factors in rats are being experimentally manipulated (WP2). Genetic risk was introduced by a rodent model (Cacna1c deficiency) and its interactions with environmental risk and protective factors are studied. Results will be linked to humans with corresponding risks. The animals have gone and will further go through deep phenotypic characterization regarding cognition, emotion, and social function, paralleling the variables assessed in humans. A set of innovative experimental projects connect and integrate data from the human and animal part, investigating the role of microRNA/ neuroplasticity (WP3), immune signatures (WP4), and (epi-)genetics/gene expression (WP5). Respective biomaterial from humans (WP1) and animals (WP2) will be analysed in parallel in WPs3-5 and integrated in WP6. The FOR2107 provides a large and unique cohort of AD patients, with novel possibilities to investigate GxE interactions on multiple (epi-)genetic and (endo-)phenotypic levels across time. It will delineate pathophysiological entities with common neurobiological underpinnings and will pave the way for an etiologic understanding of AD, potentially leading to their prevention, the prediction of individual disease courses, and novel therapies in the future.

• DFG Programme: Research Units
• International Connection: Switzerland

Projects

• Central Project 2 - Management and Administration (Applicants Dannlowski, Udo ;  Kircher, Tilo ;  Krug, Axel )
• Central project Biomaterial Bank (BMB) (Applicants Pfefferle, Petra Ina ;  Renz, Harald )
• Coordination Funds (Applicant Kircher, Tilo )
• Dissecting the neurobiology in the course of affective disorders - the Marburg/Münster affective disorders cohort study (MACS) (Applicants Dannlowski, Udo ;  Kircher, Tilo ;  Nenadic, Igor )
• Gene x environment interactions on brain and behaviour in the Cacna1c genetic rat model: Calcium signalling, microRNAs, and immune activation (Applicants Schwarting, Rainer K.W. ;  Wöhr, Markus )
• Inflammatory mechanisms in the context of gene x environment interactions in affective disorders (Applicants Alferink, Judith ;  Culmsee, Carsten ;  Garn, Holger )
• Integrative analyses of genetic, epigenetic, transcriptomic, and environmental vulnerability factors of affective disorders (Applicants Nöthen, Markus M. ;  Rietschel, Marcella ;  Witt, Stephanie )
• Multimodal Cross-Disorder Biotype Identification and Multimethod Data Analytic Support (Applicants Dempfle, Astrid ;  Hahn, Tim ;  Jansen, Andreas ;  Müller-Myhsok, Bertram )
• The contribution of environmentally induced global impairments in microRNA biogenesis to the etiology of affective disorders (Applicant Schratt, Ph.D., Gerhard Martin )

• Partner Organisation: Schweizerischer Nationalfonds (SNF)
• Spokesperson: Professor Dr. Tilo Kircher