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Genetic factors influencing a neurobiological substrate for psychiatric disorders

View ORCID ProfileTill F. M. Andlauer, View ORCID ProfileThomas W. Mühleisen, View ORCID ProfileFelix Hoffstaedter, View ORCID ProfileAlexander Teumer, View ORCID ProfileKatharina Wittfeld, View ORCID ProfileAnja Teuber, View ORCID ProfileCéline S. Reinbold, Dominik Grotegerd, View ORCID ProfileRobin Bülow, View ORCID ProfileSvenja Caspers, View ORCID ProfileUdo Dannlowski, View ORCID ProfileStefan Herms, View ORCID ProfilePer Hoffmann, View ORCID ProfileTilo Kircher, View ORCID ProfileHeike Minnerup, View ORCID ProfileSusanne Moebus, View ORCID ProfileIgor Nenadić, View ORCID ProfileHenning Teismann, View ORCID ProfileUwe Völker, International FTD-Genomics Consortium (IFGC), The 23andMe Research Team, View ORCID ProfileAmit Etkin, View ORCID ProfileKlaus Berger, View ORCID ProfileHans J. Grabe, View ORCID ProfileMarkus M. Nöthen, View ORCID ProfileKatrin Amunts, View ORCID ProfileSimon B. Eickhoff, View ORCID ProfilePhilipp G. Sämann, View ORCID ProfileBertram Müller-Myhsok, View ORCID ProfileSven Cichon
doi: https://doi.org/10.1101/774463
Till F. M. Andlauer
1Max Planck Institute of Psychiatry, Munich, Germany
2Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
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  • ORCID record for Till F. M. Andlauer
Thomas W. Mühleisen
3Institute of Neuroscience and Medicine (INM-1, INM-7), Research Centre Jülich, Germany
4Cécile and Oskar Vogt Institute of Brain Research, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
5Department of Biomedicine, University of Basel, Switzerland
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Felix Hoffstaedter
3Institute of Neuroscience and Medicine (INM-1, INM-7), Research Centre Jülich, Germany
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Alexander Teumer
6Institute for Community Medicine, University Medicine Greifswald, Germany
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Katharina Wittfeld
7German Center for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Germany
8Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
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Anja Teuber
9Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
10Institut für Energie- und Umwelttechnik e.V. (IUTA, Institute of Energy and Environmental Technology), Duisburg, Germany
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Céline S. Reinbold
5Department of Biomedicine, University of Basel, Switzerland
11Center for Lifespan Changes in Brain and Cognition, Department of Psychology, University of Oslo, Oslo, Norway
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Dominik Grotegerd
12Department of Psychiatry and Psychotherapy, Westfälische Wilhelms-Universität Münster, Münster, Germany
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Robin Bülow
13Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Germany
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Svenja Caspers
3Institute of Neuroscience and Medicine (INM-1, INM-7), Research Centre Jülich, Germany
14Institute for Anatomy I, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Udo Dannlowski
12Department of Psychiatry and Psychotherapy, Westfälische Wilhelms-Universität Münster, Münster, Germany
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Stefan Herms
5Department of Biomedicine, University of Basel, Switzerland
15Department of Genomics, Life & Brain Center, University of Bonn, Germany
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Per Hoffmann
3Institute of Neuroscience and Medicine (INM-1, INM-7), Research Centre Jülich, Germany
5Department of Biomedicine, University of Basel, Switzerland
15Department of Genomics, Life & Brain Center, University of Bonn, Germany
16Institute of Human Genetics, University of Bonn, Germany
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Tilo Kircher
17Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg, Marburg, Germany
18Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Marburg, Germany
19Marburg University Hospital – UKGM, Marburg, Germany
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Heike Minnerup
9Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
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Susanne Moebus
20IMIBE, University Hospital of Essen, University Duisburg-Essen, Germany
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Igor Nenadić
17Department of Psychiatry and Psychotherapy, Philipps-Universität Marburg, Marburg, Germany
18Center for Mind, Brain and Behavior (CMBB), University of Marburg and Justus Liebig University Giessen, Marburg, Germany
19Marburg University Hospital – UKGM, Marburg, Germany
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Henning Teismann
9Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
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Uwe Völker
21Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Germany
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Amit Etkin
22Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94304, USA
23Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, 94304, USA
24Veterans Affairs Palo Alto Healthcare System, and the Sierra Pacific Mental Illness, Research, Education, and Clinical Center (MIRECC), Palo Alto, CA, 94394, USA
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Klaus Berger
9Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany
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Hans J. Grabe
25Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
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Markus M. Nöthen
15Department of Genomics, Life & Brain Center, University of Bonn, Germany
16Institute of Human Genetics, University of Bonn, Germany
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Katrin Amunts
3Institute of Neuroscience and Medicine (INM-1, INM-7), Research Centre Jülich, Germany
4Cécile and Oskar Vogt Institute of Brain Research, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
26JARA-Brain, Jülich-Aachen Research Alliance, Jülich, Germany
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Simon B. Eickhoff
3Institute of Neuroscience and Medicine (INM-1, INM-7), Research Centre Jülich, Germany
27Institute of Clinical Neuroscience and Medical Psychology, Heinrich-Heine University, Düsseldorf, Germany
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Philipp G. Sämann
1Max Planck Institute of Psychiatry, Munich, Germany
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Bertram Müller-Myhsok
1Max Planck Institute of Psychiatry, Munich, Germany
28Institute of Translational Medicine, University of Liverpool, United Kingdom
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Sven Cichon
3Institute of Neuroscience and Medicine (INM-1, INM-7), Research Centre Jülich, Germany
5Department of Biomedicine, University of Basel, Switzerland
29Institute of Medical Genetics and Pathology, University Hospital Basel, Switzerland
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  • For correspondence: s.cichon@fz-juelich.de
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Abstract

A retrospective meta-analysis of magnetic resonance imaging voxel-based morphometry studies proposed that reduced gray matter volumes in the dorsal anterior cingulate and the left and right anterior insular cortex – areas that constitute hub nodes of the salience network – represent a common substrate for major psychiatric disorders. Here, we investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease. To this end, after a data reduction step, we conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts (n=2,271), followed by meta-analysis and replication in a fifth cohort (n=865). After correction for covariates, the heritability of the common substrate was estimated at 0.50 (standard error 0.18). The top single-nucleotide polymorphism (SNP) rs17076061 was associated with the common substrate at genome-wide significance and replicated, explaining 1.2% of the common substrate variance. This SNP mapped to a locus on chromosome 5q35.2 harboring genes involved in neuronal development and regeneration. In follow-up analyses, rs17076061 was not robustly associated with psychiatric disease, and no overlap was found between the broader genetic architecture of the common substrate and genetic risk for major depressive disorder, bipolar disorder, or schizophrenia. In conclusion, our study identified that common genetic variation indeed influences the common substrate, but that these variants do not directly translate to increased disease risk. Future studies should investigate gene-by-environment interactions and employ functional imaging to understand how salience network structure translates to psychiatric disorder risk.

Competing Interest Statement

The authors have declared no competing interest.

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Genetic factors influencing a neurobiological substrate for psychiatric disorders
Till F. M. Andlauer, Thomas W. Mühleisen, Felix Hoffstaedter, Alexander Teumer, Katharina Wittfeld, Anja Teuber, Céline S. Reinbold, Dominik Grotegerd, Robin Bülow, Svenja Caspers, Udo Dannlowski, Stefan Herms, Per Hoffmann, Tilo Kircher, Heike Minnerup, Susanne Moebus, Igor Nenadić, Henning Teismann, Uwe Völker, International FTD-Genomics Consortium (IFGC), The 23andMe Research Team, Amit Etkin, Klaus Berger, Hans J. Grabe, Markus M. Nöthen, Katrin Amunts, Simon B. Eickhoff, Philipp G. Sämann, Bertram Müller-Myhsok, Sven Cichon
bioRxiv 774463; doi: https://doi.org/10.1101/774463
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Genetic factors influencing a neurobiological substrate for psychiatric disorders
Till F. M. Andlauer, Thomas W. Mühleisen, Felix Hoffstaedter, Alexander Teumer, Katharina Wittfeld, Anja Teuber, Céline S. Reinbold, Dominik Grotegerd, Robin Bülow, Svenja Caspers, Udo Dannlowski, Stefan Herms, Per Hoffmann, Tilo Kircher, Heike Minnerup, Susanne Moebus, Igor Nenadić, Henning Teismann, Uwe Völker, International FTD-Genomics Consortium (IFGC), The 23andMe Research Team, Amit Etkin, Klaus Berger, Hans J. Grabe, Markus M. Nöthen, Katrin Amunts, Simon B. Eickhoff, Philipp G. Sämann, Bertram Müller-Myhsok, Sven Cichon
bioRxiv 774463; doi: https://doi.org/10.1101/774463

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