Genetic contributions to transdiagnostic symptom dimensions in patients with major depressive disorder, bipolar disorder, and schizophrenia spectrum disorders

Friederike S David; Frederike Stein; Till F M Andlauer; Fabian Streit; Stephanie H Witt; Stefan Herms; Per Hoffmann; Stefanie Heilmann-Heimbach; Nils Opel; Jonathan Repple; Andreas Jansen; Igor Nenadić; Sergi Papiol; Urs Heilbronner; Janos L Kalman; Sabrina K Schaupp; Fanny Senner; Eva C Schulte; Peter G Falkai; Thomas G Schulze; Udo Dannlowski; Tilo Kircher; Marcella Rietschel; Markus M Nöthen; Axel Krug; Andreas J Forstner

doi:10.1016/j.schres.2023.01.002

Genetic contributions to transdiagnostic symptom dimensions in patients with major depressive disorder, bipolar disorder, and schizophrenia spectrum disorders

Schizophr Res. 2023 Feb:252:161-171. doi: 10.1016/j.schres.2023.01.002. Epub 2023 Jan 16.

Authors

Friederike S David¹, Frederike Stein², Till F M Andlauer³, Fabian Streit⁴, Stephanie H Witt⁵, Stefan Herms⁶, Per Hoffmann⁶, Stefanie Heilmann-Heimbach¹, Nils Opel⁷, Jonathan Repple⁷, Andreas Jansen⁸, Igor Nenadić², Sergi Papiol⁹, Urs Heilbronner¹⁰, Janos L Kalman⁹, Sabrina K Schaupp¹⁰, Fanny Senner⁹, Eva C Schulte⁹, Peter G Falkai¹¹, Thomas G Schulze¹², Udo Dannlowski⁷, Tilo Kircher², Marcella Rietschel⁴, Markus M Nöthen¹, Axel Krug¹³, Andreas J Forstner¹⁴

Affiliations

¹ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.
² Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany; Center for Mind, Brain and Behavior, University of Marburg, Marburg, Germany.
³ Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
⁴ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
⁵ Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany; Center for Innovative Psychiatry and Psychotherapy Research, Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Mannheim, Germany.
⁶ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Biomedicine, University of Basel, Basel, Switzerland.
⁷ Institute for Translational Psychiatry, University of Münster, Münster, Germany.
⁸ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany; Center for Mind, Brain and Behavior, University of Marburg, Marburg, Germany; Core-Facility Brainimaging, Faculty of Medicine, University of Marburg, Marburg, Germany.
⁹ Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany; Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
¹⁰ Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany.
¹¹ Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.
¹² Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, Germany; Department of Psychiatry & Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
¹³ Department of Psychiatry and Psychotherapy, University of Marburg, Marburg, Germany; Department of Psychiatry und Psychotherapy, University Hospital Bonn, Bonn, Germany.
¹⁴ Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Institute of Neuroscience and Medicine (INM-1), Research Center Jülich, Jülich, Germany; Centre for Human Genetics, University of Marburg, Marburg, Germany. Electronic address: forstner@uni-bonn.de.

PMID: 36652833
DOI: 10.1016/j.schres.2023.01.002

Abstract

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorders (SZ) exhibit considerable phenotypic and genetic overlap. However, the contribution of genetic factors to their shared psychopathological symptom dimensions remains unclear. The present exploratory study investigated genetic contributions to the symptom dimensions "Depression", "Negative syndrome", "Positive formal thought disorder", "Paranoid-hallucinatory syndrome", and "Increased appetite" in a transdiagnostic subset of the German FOR2107 cohort (n = 1042 patients with MDD, BD, or SZ). As replication cohort, a subset of the German/Austrian PsyCourse study (n = 816 patients with MDD, BD, or SZ) was employed. First, the relationship between symptom dimensions and common variants associated with MDD, BD, and SZ was investigated via polygenic risk score (PRS) association analyses, with disorder-specific PRS as predictors and symptom dimensions as outcomes. In the FOR2107 study sample, PRS for BD and SZ were positively associated with "Positive formal thought disorder", the PRS for SZ was positively associated with "Paranoid-hallucinatory syndrome", and the PRS for BD was negatively associated with "Depression". The effects of PRS for SZ were replicated in PsyCourse. No significant associations were observed for the MDD PRS. Second, genome-wide association studies (GWAS) were performed for the five symptom dimensions. No genome-wide significant associations and no replicable suggestive associations (p < 1e-6 in the GWAS) were identified. In summary, our results suggest that, similar to diagnostic categories, transdiagnostic psychiatric symptom dimensions are attributable to polygenic contributions with small effect sizes. Further studies in larger thoroughly phenotyped psychiatric cohorts are required to elucidate the genetic factors that shape psychopathological symptom dimensions.

Keywords: Affective disorders; Factor model; GWAS; Polygenic risk scores; Psychosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bipolar Disorder* / psychology
Depressive Disorder, Major* / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
Hallucinations
Humans
Multifactorial Inheritance
Risk Assessment
Schizophrenia* / diagnosis