Nature meets Nurture: Elucidating the liability for mental disorders through imaging genomics, epigenetics, and gene-by-environment interactions
Donnerstag, 03.06.2021:
10:15 - 11:45

Chair der Sitzung: Philippe Jawinski, Humboldt-Universität zu Berlin
Chair der Sitzung: Miriam Schiele, Universitätsklinikum Freiburg
Ort: From (epi)genetics to cognition

Zusammenfassung der Sitzung

Over the past decade, molecular genetic research has seen rapid advances in the identification of replicable variations associated with mental disorders. Although genetic predispositions impact human behavior throughout the lifespan, the development and course of diseases also crucially relies on environmental conditions. This symposium presents four studies using state-of-the-art imaging genomic, epigenetic and gene-by-environment methods to unravel the mechanisms through which genes increase the risk for psychopathology. The first talk focuses on how genetics affect the speed of biological ageing as one of the greatest ubiquitous risk factors for disease vulnerability: Philippe Jawinski (HU Berlin) presents results from N = 42,000 participants of the UK Biobank imaging cohort, suggesting that the biological age of the brain (‘brain age’) genetically overlaps with various physical and mental health phenotypes. Following this, Lea Sirignano (ZI Mannheim) reports on a longitudinal study that examines genetic response predictors and gene expression changes after therapeutic sleep deprivation in depression. The next talk is held by Miriam Schiele (UKL Freiburg), who reports on gene-by-environment interactions in anxiety and how protective coping abilities may exert a buffering effect on the interplay of genetic disposition and environmental adversity. Finally, Martin Reuter (Uni Bonn) presents on the relation between social cognitive functioning and genetic and epigenetic serotonergic markers, which have been associated with affective processes in the normal and psychopathological range. This symposium seeks to demonstrate, discuss, and disseminate the rapidly growing opportunities to elucidate the liability for mental disorders by applying molecular genetic techniques in our field.


The ageing brain: Identification of 25 associated genomic loci and evidence for a shared genetic basis with mental and physical health

Philippe Jawinski1, Helena Braun1, Stephan Ripke2,3, Sebastian Markett1

1Department of Psychology, Humboldt-Universität zu Berlin, Berlin; 2Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin, Berlin, Germany; 3Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

From a biological perspective, humans age at different speeds. A growing body of research suggests that the biological age of the brain is linked to major cognitive and affective disorders. Here we investigated the molecular genetics of brain age gap, i.e., the difference between an individual’s brain-predicted and chronological age, and examined its genetic overlap with over 1,200 mental and physical health phenotypes. We used structural MRI data and supervised machine learning to estimate brain age in a discovery sample of 32,634 UK Biobank individuals. We show that brain age gap is under substantial genetic control, with a SNP-based heritability of about 30%. We identify 25 independent genome-wide significant variations, of which 21 showed consistent effect directions and 18 replicated at p < 0.05 in a multi-ancestry follow-up meta-analysis of 6,703 individuals. The strongest contributing locus covers the gene MAPT (discovery p = 2E-52), which encodes the tau protein associated with Alzheimer’s disease. Further, we demonstrate that brain age gap genetically correlates with various neurological, psychological and psychiatric phenotypes, and we use Mendelian Randomization to derive evidence for a putative causal role of cardiovascular and metabolic syndrome conditions on accelerated brain ageing. Due to a relatively low degree of polygenicity, we predict that the number of genomic regions discovered for brain age gap will rapidly rise with increasing sample size when compared to other complex traits. In this light, brain ageing has great potential to evolve into a genetically well-understood phenomenon with broad implications for physical and mental health.

Longitudinal assessment in therapeutic sleep deprivation to unravel the genetics of depression

Lea Sirignano1, Nina Christmann1,2,3, Carsten Sticht4, Jens Treutlein1, Josef Frank1, Fabian Streit1, Stephanie H. Witt1, Lea Zillich1, Carolina De La Torre4, Steffen Conrad von Heydendorff2, Junfang Chen2, Bertram Müller-Myhsok5,6,7, Andreas Meyer-Lindenberg2, Christian C. Witt8, Maria Gilles2, Michael Deuschle2, Marcella Rietschel1, Jerome C. Foo1

1Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; 2Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; 3Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; 4Medical Research Center, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; 5Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany; 6Munich Cluster of Systems Biology, SyNergy, Munich, Germany; 7Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; 8Department of Anaesthesiology and Operative Intensive Care, University Hospital Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

Therapeutic sleep deprivation (TSD) rapidly induces robust, transient antidepressant effects in a large proportion of major mood disorder patients suffering from a depressive episode, but underlying biological factors remain poorly understood. We conducted a naturalistic study which aimed to examine clinical and genetic factors predicting response to TSD.

The present study examined 15 healthy controls and 78 patients experiencing an episode of major depression undergoing TSD, consisting of a period of ~36 hours without sleep (6:00 to 18:00 the following day). Before and after TSD and after recovery sleep, biomaterials were collected and depressive symptoms/therapy response were assessed. We assessed polygenic risk scores (PRS) for major depressive disorder (MDD) and their association with therapy response and investigated transcriptome-wide gene expression changes caused by TSD in MDD.

The comparison across disease states showed significantly higher PRS in non-responders than in healthy controls. Descriptively, non-responders showed higher PRS than responders. Transcriptome-wide gene expression showed differential gene expression after TSD between responders and non-responders. Gene Set Enrichment Analysis showed differential expression in gene sets involved in immunological function, inflammatory response, and sleep regulation. The examination of longitudinal gene set trajectories showed that those gene sets were upregulated in responders after TSD. In non-responders, strong downregulation in the majority of gene sets was observed after TSD, with upregulation in immunological gene sets after recovery sleep.

We will discuss the results, and present the comprehensive framework for the ongoing phase 2 of the investigation, with an extended ambulatory and biomaterial assessment.

Risk or resilience? Gene-environment interactions in anxiety

Miriam Schiele

Klinik für Psychiatrie und Psychotherapie, Universitätsklinikum Freiburg, Deutschland

Genetic and environmental factors are assumed to interactively influence the pathogenesis of anxiety disorders and related phenotypes. However, protective influences such as functional coping ability may exert a buffering effect on the interplay of genetic disposition and environmental adversity in the conferral of risk or resilience to anxiety-related traits and, ultimately, the manifestation of disease.

In the present talk, coping ability will be explored as an additional dimension in an extended gene-environment-coping (G x E x C) model. Exemplarily, functional variants in select candidate genes associated with anxiety, i.e. in the serotonin transporter gene (5-HTTLPR/rs25531) and the neuropeptide receptor S gene (NPSR1 rs324981) will be highlighted regarding their interplay with environmental adversity by example of childhood trauma as well as coping characteristics that, depending on their individual constellation, can either increase or decrease disorder risk.

Taken together, these results provide novel insights for clinical practice, particularly with regard to the development, improvement, and application of preventive therapeutic interventions.

Genetic and epigenetic serotonergic markers predict theory of mind abilities

Martin Reuter1, Peter Kirsch2, Vera Zamoscik2, Andrea Felten1, Thomas Plieger1

1Universität Bonn, Deutschland; 2ZI-Mannheim, Deutschland

The serotonergic (5-HT) system is related to affective and cognitive processes and explains behavioral variability in the normal and psychopathological range. For this reason, the hypothesis was put forward that genetic and epigenetic markers related to 5-HT metabolism predict individual differences in social cognitive functioning. Social cognitions are complex mental processes necessary for perceiving, interpreting and reacting to the behaviors of others. In order to test this hypothesis one of the most prominent theory of mind tasks, the reading the mind in the eye test (RMET), was administered to N = 435 participants and measures of performance were related to the functional MAO-A VNTR polymorphism (relevant for 5-HT catabolism) and to epigenetic markers in the promoter of the TPH-2 gene (relevant for 5-HT synthesis). It was postulated that genetic and epigenetic markers of high 5-HT activity are positively related to RMET performance. Results show that the MAO-A high activity allele, together with the degree of methylation at a promoter CpG site on the TPH-2 gene explain significant proportions of variance in the RMET performance even after controlling for age and sex effects. Present findings yield evidence for the importance of 5-HT for social cognition. Based on additional findings, the role of a TRP-rich diet for theory of mind functions is discussed.