The interplay between polygenic score for tumor necrosis factor-α, brain structural connectivity, and processing speed in major depression

Kira Flinkenflügel; Marius Gruber; Susanne Meinert; Katharina Thiel; Alexandra Winter; Janik Goltermann; Paula Usemann; Katharina Brosch; Frederike Stein; Florian Thomas-Odenthal; Adrian Wroblewski; Julia-Katharina Pfarr; Friederike S David; Eva C Beins; Dominik Grotegerd; Tim Hahn; Elisabeth J Leehr; Katharina Dohm; Jochen Bauer; Andreas J Forstner; Markus M Nöthen; Hamidreza Jamalabadi; Benjamin Straube; Nina Alexander; Andreas Jansen; Stephanie H Witt; Marcella Rietschel; Igor Nenadić; Martijn P van den Heuvel; Tilo Kircher; Jonathan Repple; Udo Dannlowski

doi:10.1038/s41380-024-02577-7

The interplay between polygenic score for tumor necrosis factor-α, brain structural connectivity, and processing speed in major depression

Kira Flinkenflügel, Marius Gruber, Susanne Meinert, Katharina Thiel, Alexandra Winter, Janik Goltermann, Paula Usemann, Katharina Brosch, Frederike Stein, Florian Thomas-Odenthal, Adrian Wroblewski, Julia-Katharina Pfarr, Friederike S David, Eva C Beins, Dominik Grotegerd, Tim Hahn, Elisabeth J Leehr, Katharina Dohm, Jochen Bauer, Andreas J ForstnerMarkus M Nöthen, Hamidreza Jamalabadi, Benjamin Straube, Nina Alexander, Andreas Jansen, Stephanie H Witt, Marcella Rietschel, Igor Nenadić, Martijn P van den Heuvel, Tilo Kircher, Jonathan Repple, Udo Dannlowski

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Reduced processing speed is a core deficit in major depressive disorder (MDD) and has been linked to altered structural brain network connectivity. Ample evidence highlights the involvement of genetic-immunological processes in MDD and specific depressive symptoms. Here, we extended these findings by examining associations between polygenic scores for tumor necrosis factor-α blood levels (TNF-α PGS), structural brain connectivity, and processing speed in a large sample of MDD patients. Processing speed performance of n = 284 acutely depressed, n = 177 partially and n = 198 fully remitted patients, and n = 743 healthy controls (HC) was estimated based on five neuropsychological tests. Network-based statistic was used to identify a brain network associated with processing speed. We employed general linear models to examine the association between TNF-α PGS and processing speed. We investigated whether network connectivity mediates the association between TNF-α PGS and processing speed. We identified a structural network positively associated with processing speed in the whole sample. We observed a significant negative association between TNF-α PGS and processing speed in acutely depressed patients, whereas no association was found in remitted patients and HC. The mediation analysis revealed that brain connectivity partially mediated the association between TNF-α PGS and processing speed in acute MDD. The present study provides evidence that TNF-α PGS is associated with decreased processing speed exclusively in patients with acute depression. This association was partially mediated by structural brain connectivity. Using multimodal data, the current findings advance our understanding of cognitive dysfunction in MDD and highlight the involvement of genetic-immunological processes in its pathomechanisms.

Original language	English
Pages (from-to)	3151-3159
Number of pages	9
Journal	Molecular Psychiatry
Volume	29
Issue number	10
DOIs	https://doi.org/10.1038/s41380-024-02577-7
Publication status	Published - Oct 2024

Bibliographical note

Funding

This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; SFB-TRR58, Projects C09 and Z02 to UD), the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of M\u00FCnster (grant Dan3/012/17 to UD), IMF M\u00FCnster RE111604 to RR und RE111722 to RR, IMF M\u00FCnster RE 22 17 07 to Jonathan Repple and the Deanery of the Medical Faculty of the University of M\u00FCnster. TH was supported by the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/4). MP was supported by an ERC Consolidator grant (ERC-COG 101001062) and a NWO VIDI grant of the Dutch Research Council (Netherlands Organisation for Scientific Research Grant VIDI-452-16-015). SdL received funding from ZonMw Open Competition, project REMOVE 09120011910032. This work is part of the German multicenter consortium \u201CNeurobiology of Affective Disorders. A translational perspective on brain structure and function\u201C, funded by the German Research Foundation (Deutsche Forschungsgemeinschaft DFG; Forschungsgruppe/Research Unit FOR2107). Principal investigators (PIs) with respective areas of responsibility in the FOR2107 consortium are Work Package WP1, FOR2107/MACS cohort and brainimaging: Tilo Kircher (speaker FOR2107; DFG grant numbers KI 588/14-1, KI 588/14-2), Udo Dannlowski (co-speaker FOR2107; DA 1151/5-1, DA 1151/5-2), Axel Krug (KR 3822/5-1, KR 3822/7-2), Igor Nenadic (NE 2254/1-2), Carsten Konrad (KO 4291/3-1). WP2, animal phenotyping: Markus W\u00F6hr (WO 1732/4-1, WO 1732/4-2), Rainer Schwarting (SCHW 559/14-1, SCHW 559/14-2). WP3, miRNA: Gerhard Schratt (SCHR 1136/3-1, 1136/3-2). WP4, immunology, mitochondriae: Judith Alferink (AL 1145/5-2), Carsten Culmsee (CU 43/9-1, CU 43/9-2), Holger Garn (GA 545/5-1, GA 545/7-2). WP5, genetics: Marcella Rietschel (RI 908/11-1, RI 908/11-2), Markus N\u00F6then (NO 246/10-1, NO 246/10-2), Stephanie Witt (WI 3439/3-1, WI 3439/3-2). WP6, multi-method data analytics: Andreas Jansen (JA 1890/7-1, JA 1890/7-2), Tim Hahn (HA 7070/2-2), Bertram M\u00FCller-Myhsok (MU1315/8-2), Astrid Dempfle (DE 1614/3-1, DE 1614/3-2). CP1, biobank: Petra Pfefferle (PF 784/1-1, PF 784/1-2), Harald Renz (RE 737/20-1, 737/20-2). CP2, administration. Tilo Kircher (KI 588/15-1, KI 588/17-1), Udo Dannlowski (DA 1151/6-1), Carsten Konrad (KO 4291/4-1). Anxiety extension project Benjamin Straube (STR 1146/18-1), Tilo Kircher (KI 588/22-1), Udo Dannlowski (DA 1151/11\u20111). Martijn van den Heuvel was supported by an ALW open (ALWOP.179) and VIDI (452-16-015) grant from the Netherlands Organization for Scientific Research (NWO) and a Fellowship of MQ. Data access and responsibility: All PIs take responsibility for the integrity of the respective study data and their components. All authors and coauthors had full access to all study data. Acknowledgements and members by Work Package (WP): WP1: Henrike Br\u00F6hl, Katharina Brosch, Bruno Dietsche, Rozbeh Elahi, Jennifer Engelen, Sabine Fischer, Jessica Heinen, Svenja Klingel, Felicitas Meier, Tina Meller, Julia-Katharina Pfarr, Kai Ringwald, Torsten Sauder, Simon Schmitt, Frederike Stein, Annette Tittmar, Dilara Y\u00FCksel (Dept. of Psychiatry, Marburg University). Mechthild Wallnig, Rita Werner (Core-Facility Brainimaging, Marburg University). Carmen Schade-Brittinger, Maik Hahmann (Coordinating Centre for Clinical Trials, Marburg). Michael Putzke (Psychiatric Hospital, Friedberg). Rolf Speier, Lutz Lenhard (Psychiatric Hospital, Haina). Birgit K\u00F6hnlein (Psychiatric Practice, Marburg). Peter Wulf, J\u00FCrgen Kleebach, Achim Becker (Psychiatric Hospital Hephata, Schwalmstadt-Treysa). Ruth B\u00E4r (Care facility Bischoff, Neukirchen). Matthias M\u00FCller, Michael Franz, Siegfried Scharmann, Anja Haag, Kristina Spenner, Ulrich Ohlenschl\u00E4ger (Psychiatric Hospital Vitos, Marburg). Matthias M\u00FCller, Michael Franz, Bernd Kundermann (Psychiatric Hospital Vitos, Gie\u00DFen). Christian B\u00FCrger, Katharina Dohm, Fanni Dzvonyar, Verena Enneking, Stella Fingas, Katharina F\u00F6rster, Janik Goltermann, Dominik Grotegerd, Hannah Lemke, Susanne Meinert, Nils Opel, Ronny Redlich, Jonathan Repple, Katharina Thiel, Kordula Vorspohl, Bettina Walden, Lena Waltemate, Kira Flinkenfl\u00FCgel, Alexandra Winter, Dario Zaremba (Dept. of Psychiatry, University of M\u00FCnster). Harald Kugel, Jochen Bauer, Walter Heindel, Birgit Vahrenkamp (Dept. of Clinical Radiology, University of M\u00FCnster). Gereon Heuft, Gudrun Schneider (Dept. of Psychosomatics and Psychotherapy, University of M\u00FCnster). Thomas Reker (LWL-Hospital M\u00FCnster). Gisela Bartling (IPP M\u00FCnster). Ulrike Buhlmann (Dept. of Clinical Psychology, University of M\u00FCnster). WP2: Marco Bartz, Miriam Becker, Christine Bl\u00F6cher, Annuska Berz, Moria Braun, Ingmar Conell, Debora dalla Vecchia, Darius Dietrich, Ezgi Esen, Sophia Estel, Jens Hensen, Ruhkshona Kayumova, Theresa Kisko, Rebekka Obermeier, Anika P\u00FCtzer, Nivethini Sangarapillai, \u00D6zge Sungur, Clara Raithel, Tobias Redecker, Vanessa Sandermann, Finnja Schramm, Linda Tempel, Natalie Vermehren, Jakob V\u00F6rckel, Stephan Weingarten, Maria Willadsen, C\u00FCneyt Yildiz (Faculty of Psychology, Marburg University). WP4: Jana Freff (Dept. of Psychiatry, University of M\u00FCnster). Susanne Michels, Goutham Ganjam, Katharina Els\u00E4sser (Faculty of Pharmacy, Marburg University). Felix Ruben Picard, Nicole L\u00F6wer, Thomas Ruppersberg (Institute of Laboratory Medicine and Pathobiochemistry, Marburg University). WP5: Helene Dukal, Christine Hohmeyer, Lennard St\u00FCtz, Viola Lahr, Fabian Streit, Josef Frank, Lea Sirignano (Dept. of Genetic Epidemiology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University). Stefanie Heilmann-Heimbach, Stefan Herms, Per Hoffmann (Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn). Andreas J. Forstner (Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn; Centre for Human Genetics, Marburg University). WP6: Anastasia Benedyk, Miriam Bopp, Roman Ke\u00DFler, Maximilian L\u00FCckel, Verena Schuster, Christoph Vogelbacher (Dept. of Psychiatry, Marburg University). Jens Sommer, Olaf Steinstr\u00E4ter (Core-Facility Brainimaging, Marburg University). Thomas W.D. M\u00F6bius (Institute of Medical Informatics and Statistics, Kiel University). CP1: Julian Glandorf, Fabian Kormann, Arif Alkan, Fatana Wedi, Lea Henning, Alena Renker, Karina Schneider, Elisabeth Folwarczny, Dana Stenzel, Kai Wenk, Felix Picard, Alexandra Fischer, Sandra Blumenau, Beate Kleb, Doris Finholdt, Elisabeth Kinder, Tamara W\u00FCst, Elvira Przypadlo, Corinna Brehm (Comprehensive Biomaterial Bank Marburg, Marburg University). The data represent original work. The manuscript has been published on a non-commercial preprint server (https://osf.io/5b6ek/). TK received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, neuraxpharm. This funding is not associated with the current work. On behalf of all other authors, the corresponding author states that there is no conflict of interest and nothing to disclose.

Funders	Funder number
University of Bonn, School of Medicine & University Hospital Bonn
Tim Hahn
Universität Heidelberg
Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn
Central Institute of Mental Health
Philipps-Universität Marburg
Doris Finholdt
Janssen Pharmaceutica
Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg
Servier
Medical Faculty Mannheim
European Research Council	ERC-COG 101001062
Deutsche Forschungsgemeinschaft	DA1151/5-2, KO 4291/3-1, WO 1732/4-2, 1136/3-2, RI 908/11-1, FOR2107, NE 2254/1-2, KI 588/14-2, SFB-TRR58, KI 588/14-1, AL 1145/5-2, GA 545/7-2, SCHW 559/14-2, RI 908/11-2, FOR2107 DA1151/5-1, 452-16-015, KR 3822/7-2, DA 1151/5-1
Bertram Müller-Myhsok	KO 4291/4-1, RE 737/20-1, DE 1614/3-2, PF 784/1-1, DA 1151/11‑1, KI 588/17-1, 737/20-2, KI 588/15-1, KI 588/22-1, PF 784/1-2, MU1315/8-2, DE 1614/3-1, DA 1151/6-1
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	VIDI-452-16-015
International Myeloma Foundation	HA7070/4, RE111604, RE 22 17 07, HA7070/2-2, RE111722, HA7070/3
Medizinische Fakultät, Westfälische Wilhelms-Universität Münster	Dan3/012/17
Markus Nöthen	JA 1890/7-2, WI 3439/3-2
ZonMw Open Competition	09120011910032

Keywords

Humans
Depressive Disorder, Major/genetics
Male
Female
Adult
Tumor Necrosis Factor-alpha/metabolism
Brain/metabolism
Middle Aged
Magnetic Resonance Imaging/methods
Neuropsychological Tests
Multifactorial Inheritance/genetics
Nerve Net/metabolism
Processing Speed

Access to Document

10.1038/s41380-024-02577-7

Persistent URL (handle)

Persistent link

Cite this

Flinkenflügel, K., Gruber, M., Meinert, S., Thiel, K., Winter, A., Goltermann, J., Usemann, P., Brosch, K., Stein, F., Thomas-Odenthal, F., Wroblewski, A., Pfarr, J.-K., David, F. S., Beins, E. C., Grotegerd, D., Hahn, T., Leehr, E. J., Dohm, K., Bauer, J., ... Dannlowski, U. (2024). The interplay between polygenic score for tumor necrosis factor-α, brain structural connectivity, and processing speed in major depression. Molecular Psychiatry, 29(10), 3151-3159. https://doi.org/10.1038/s41380-024-02577-7

@article{3ca947ed95394dfcbc887e6616c75d05,

title = "The interplay between polygenic score for tumor necrosis factor-α, brain structural connectivity, and processing speed in major depression",

abstract = "Reduced processing speed is a core deficit in major depressive disorder (MDD) and has been linked to altered structural brain network connectivity. Ample evidence highlights the involvement of genetic-immunological processes in MDD and specific depressive symptoms. Here, we extended these findings by examining associations between polygenic scores for tumor necrosis factor-α blood levels (TNF-α PGS), structural brain connectivity, and processing speed in a large sample of MDD patients. Processing speed performance of n = 284 acutely depressed, n = 177 partially and n = 198 fully remitted patients, and n = 743 healthy controls (HC) was estimated based on five neuropsychological tests. Network-based statistic was used to identify a brain network associated with processing speed. We employed general linear models to examine the association between TNF-α PGS and processing speed. We investigated whether network connectivity mediates the association between TNF-α PGS and processing speed. We identified a structural network positively associated with processing speed in the whole sample. We observed a significant negative association between TNF-α PGS and processing speed in acutely depressed patients, whereas no association was found in remitted patients and HC. The mediation analysis revealed that brain connectivity partially mediated the association between TNF-α PGS and processing speed in acute MDD. The present study provides evidence that TNF-α PGS is associated with decreased processing speed exclusively in patients with acute depression. This association was partially mediated by structural brain connectivity. Using multimodal data, the current findings advance our understanding of cognitive dysfunction in MDD and highlight the involvement of genetic-immunological processes in its pathomechanisms.",

keywords = "Humans, Depressive Disorder, Major/genetics, Male, Female, Adult, Tumor Necrosis Factor-alpha/metabolism, Brain/metabolism, Middle Aged, Magnetic Resonance Imaging/methods, Neuropsychological Tests, Multifactorial Inheritance/genetics, Nerve Net/metabolism, Processing Speed",

author = "Kira Flinkenfl{\"u}gel and Marius Gruber and Susanne Meinert and Katharina Thiel and Alexandra Winter and Janik Goltermann and Paula Usemann and Katharina Brosch and Frederike Stein and Florian Thomas-Odenthal and Adrian Wroblewski and Julia-Katharina Pfarr and David, {Friederike S} and Beins, {Eva C} and Dominik Grotegerd and Tim Hahn and Leehr, {Elisabeth J} and Katharina Dohm and Jochen Bauer and Forstner, {Andreas J} and N{\"o}then, {Markus M} and Hamidreza Jamalabadi and Benjamin Straube and Nina Alexander and Andreas Jansen and Witt, {Stephanie H} and Marcella Rietschel and Igor Nenadi{\'c} and {van den Heuvel}, {Martijn P} and Tilo Kircher and Jonathan Repple and Udo Dannlowski",

note = "{\textcopyright} 2024. The Author(s).",

year = "2024",

month = oct,

doi = "10.1038/s41380-024-02577-7",

language = "English",

volume = "29",

pages = "3151--3159",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Springer Nature",

number = "10",

}

Flinkenflügel, K, Gruber, M, Meinert, S, Thiel, K, Winter, A, Goltermann, J, Usemann, P, Brosch, K, Stein, F, Thomas-Odenthal, F, Wroblewski, A, Pfarr, J-K, David, FS, Beins, EC, Grotegerd, D, Hahn, T, Leehr, EJ, Dohm, K, Bauer, J, Forstner, AJ, Nöthen, MM, Jamalabadi, H, Straube, B, Alexander, N, Jansen, A, Witt, SH, Rietschel, M, Nenadić, I, van den Heuvel, MP, Kircher, T, Repple, J & Dannlowski, U 2024, 'The interplay between polygenic score for tumor necrosis factor-α, brain structural connectivity, and processing speed in major depression', Molecular Psychiatry, vol. 29, no. 10, pp. 3151-3159. https://doi.org/10.1038/s41380-024-02577-7

TY - JOUR

T1 - The interplay between polygenic score for tumor necrosis factor-α, brain structural connectivity, and processing speed in major depression

AU - Flinkenflügel, Kira

AU - Gruber, Marius

AU - Meinert, Susanne

AU - Thiel, Katharina

AU - Winter, Alexandra

AU - Goltermann, Janik

AU - Usemann, Paula

AU - Brosch, Katharina

AU - Stein, Frederike

AU - Thomas-Odenthal, Florian

AU - Wroblewski, Adrian

AU - Pfarr, Julia-Katharina

AU - David, Friederike S

AU - Beins, Eva C

AU - Grotegerd, Dominik

AU - Hahn, Tim

AU - Leehr, Elisabeth J

AU - Dohm, Katharina

AU - Bauer, Jochen

AU - Forstner, Andreas J

AU - Nöthen, Markus M

AU - Jamalabadi, Hamidreza

AU - Straube, Benjamin

AU - Alexander, Nina

AU - Jansen, Andreas

AU - Witt, Stephanie H

AU - Rietschel, Marcella

AU - Nenadić, Igor

AU - van den Heuvel, Martijn P

AU - Kircher, Tilo

AU - Repple, Jonathan

AU - Dannlowski, Udo

PY - 2024/10

Y1 - 2024/10

N2 - Reduced processing speed is a core deficit in major depressive disorder (MDD) and has been linked to altered structural brain network connectivity. Ample evidence highlights the involvement of genetic-immunological processes in MDD and specific depressive symptoms. Here, we extended these findings by examining associations between polygenic scores for tumor necrosis factor-α blood levels (TNF-α PGS), structural brain connectivity, and processing speed in a large sample of MDD patients. Processing speed performance of n = 284 acutely depressed, n = 177 partially and n = 198 fully remitted patients, and n = 743 healthy controls (HC) was estimated based on five neuropsychological tests. Network-based statistic was used to identify a brain network associated with processing speed. We employed general linear models to examine the association between TNF-α PGS and processing speed. We investigated whether network connectivity mediates the association between TNF-α PGS and processing speed. We identified a structural network positively associated with processing speed in the whole sample. We observed a significant negative association between TNF-α PGS and processing speed in acutely depressed patients, whereas no association was found in remitted patients and HC. The mediation analysis revealed that brain connectivity partially mediated the association between TNF-α PGS and processing speed in acute MDD. The present study provides evidence that TNF-α PGS is associated with decreased processing speed exclusively in patients with acute depression. This association was partially mediated by structural brain connectivity. Using multimodal data, the current findings advance our understanding of cognitive dysfunction in MDD and highlight the involvement of genetic-immunological processes in its pathomechanisms.

AB - Reduced processing speed is a core deficit in major depressive disorder (MDD) and has been linked to altered structural brain network connectivity. Ample evidence highlights the involvement of genetic-immunological processes in MDD and specific depressive symptoms. Here, we extended these findings by examining associations between polygenic scores for tumor necrosis factor-α blood levels (TNF-α PGS), structural brain connectivity, and processing speed in a large sample of MDD patients. Processing speed performance of n = 284 acutely depressed, n = 177 partially and n = 198 fully remitted patients, and n = 743 healthy controls (HC) was estimated based on five neuropsychological tests. Network-based statistic was used to identify a brain network associated with processing speed. We employed general linear models to examine the association between TNF-α PGS and processing speed. We investigated whether network connectivity mediates the association between TNF-α PGS and processing speed. We identified a structural network positively associated with processing speed in the whole sample. We observed a significant negative association between TNF-α PGS and processing speed in acutely depressed patients, whereas no association was found in remitted patients and HC. The mediation analysis revealed that brain connectivity partially mediated the association between TNF-α PGS and processing speed in acute MDD. The present study provides evidence that TNF-α PGS is associated with decreased processing speed exclusively in patients with acute depression. This association was partially mediated by structural brain connectivity. Using multimodal data, the current findings advance our understanding of cognitive dysfunction in MDD and highlight the involvement of genetic-immunological processes in its pathomechanisms.

KW - Humans

KW - Depressive Disorder, Major/genetics

KW - Male

KW - Female

KW - Adult

KW - Tumor Necrosis Factor-alpha/metabolism

KW - Brain/metabolism

KW - Middle Aged

KW - Magnetic Resonance Imaging/methods

KW - Neuropsychological Tests

KW - Multifactorial Inheritance/genetics

KW - Nerve Net/metabolism

KW - Processing Speed

U2 - 10.1038/s41380-024-02577-7

DO - 10.1038/s41380-024-02577-7

M3 - Article

C2 - 38693319

SN - 1359-4184

VL - 29

SP - 3151

EP - 3159

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 10

ER -

The interplay between polygenic score for tumor necrosis factor-α, brain structural connectivity, and processing speed in major depression

Abstract

Bibliographical note

Funding

Keywords

Access to Document

Persistent URL (handle)

Fingerprint

Cite this