Association Between Genetic Risk for Type 2 Diabetes and Structural Brain Connectivity in Major Depressive Disorder

Jonathan Repple; Amelie König; Siemon C. de Lange; Nils Opel; Ronny Redlich; Susanne Meinert; Dominik Grotegerd; Marco Mauritz; Tim Hahn; Tiana Borgers; Elisabeth J. Leehr; Nils Winter; Janik Goltermann; Verena Enneking; Stella M. Fingas; Hannah Lemke; Lena Waltemate; Katharina Dohm; Maike Richter; David M. A. Mehler; Vincent Holstein; Marius Gruber; Igor Nenadic; Axel Krug; Katharina Brosch; Simon Schmitt; Frederike Stein; Tina Meller; Andreas Jansen; Olaf Steinsträter; Azmeraw T. Amare; Tilo Kircher; Bernhard T. Baune; Martijn P. van den Heuvel; Udo Dannlowski

doi:https://doi.org/10.1016/j.bpsc.2021.02.010

Association Between Genetic Risk for Type 2 Diabetes and Structural Brain Connectivity in Major Depressive Disorder

Jonathan Repple, Amelie König, Siemon C. de Lange, Nils Opel, Ronny Redlich, Susanne Meinert, Dominik Grotegerd, Marco Mauritz, Tim Hahn, Tiana Borgers, Elisabeth J. Leehr, Nils Winter, Janik Goltermann, Verena Enneking, Stella M. Fingas, Hannah Lemke, Lena Waltemate, Katharina Dohm, Maike Richter, David M. A. MehlerVincent Holstein, Marius Gruber, Igor Nenadic, Axel Krug, Katharina Brosch, Simon Schmitt, Frederike Stein, Tina Meller, Andreas Jansen, Olaf Steinsträter, Azmeraw T. Amare, Tilo Kircher, Bernhard T. Baune, Martijn P. van den Heuvel, Udo Dannlowski

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

7 Citations (Scopus)

Abstract

Background: Major depressive disorder (MDD) and type 2 diabetes mellitus (T2D) are known to share clinical comorbidity and to have genetic overlap. Besides their shared genetics, both diseases seem to be associated with alterations in brain structural connectivity and impaired cognitive performance, but little is known about the mechanisms by which genetic risk of T2D might affect brain structure and function and if they do, how these effects could contribute to the disease course of MDD. Methods: This study explores the association of polygenic risk for T2D with structural brain connectome topology and cognitive performance in 434 nondiabetic patients with MDD and 539 healthy control subjects. Results: Polygenic risk score for T2D across MDD patients and healthy control subjects was found to be associated with reduced global fractional anisotropy, a marker of white matter microstructure, an effect found to be predominantly present in MDD-related fronto-temporo-parietal connections. A mediation analysis further suggests that this fractional anisotropy variation may mediate the association between polygenic risk score and cognitive performance. Conclusions: Our findings provide preliminary evidence of a polygenic risk for T2D to be linked to brain structural connectivity and cognition in patients with MDD and healthy control subjects, even in the absence of a direct T2D diagnosis. This suggests an effect of T2D genetic risk on white matter integrity, which may mediate an association of genetic risk for diabetes and cognitive impairments.

Original language	English
Pages (from-to)	333-340
Number of pages	8
Journal	Biological Psychiatry: Cognitive Neuroscience and Neuroimaging
Volume	7
Issue number	3
Early online date	5 Mar 2021
DOIs	https://doi.org/10.1016/j.bpsc.2021.02.010
Publication status	Published - Mar 2022

Keywords

Cognition
Cognitive performance
Connectome
Fractional anisotropy
Major depressive disorder
Polygenic risk score

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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https://doi.org/10.1016/j.bpsc.2021.02.010

https://research.vu.nl/ws/files/153895297/Association_between_genetic_risk_for_type_2_diabetes_and_structural_brain_connectivity_in_major_depressive_disorder.pdfLicence: Article 25fa Dutch Copyright Act

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Repple, J., König, A., de Lange, S. C., Opel, N., Redlich, R., Meinert, S., Grotegerd, D., Mauritz, M., Hahn, T., Borgers, T., Leehr, E. J., Winter, N., Goltermann, J., Enneking, V., Fingas, S. M., Lemke, H., Waltemate, L., Dohm, K., Richter, M., ... Dannlowski, U. (2022). Association Between Genetic Risk for Type 2 Diabetes and Structural Brain Connectivity in Major Depressive Disorder. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 7(3), 333-340. https://doi.org/10.1016/j.bpsc.2021.02.010

@article{2df32ba2ec3e47019defaee380f807fb,

title = "Association Between Genetic Risk for Type 2 Diabetes and Structural Brain Connectivity in Major Depressive Disorder",

abstract = "Background: Major depressive disorder (MDD) and type 2 diabetes mellitus (T2D) are known to share clinical comorbidity and to have genetic overlap. Besides their shared genetics, both diseases seem to be associated with alterations in brain structural connectivity and impaired cognitive performance, but little is known about the mechanisms by which genetic risk of T2D might affect brain structure and function and if they do, how these effects could contribute to the disease course of MDD. Methods: This study explores the association of polygenic risk for T2D with structural brain connectome topology and cognitive performance in 434 nondiabetic patients with MDD and 539 healthy control subjects. Results: Polygenic risk score for T2D across MDD patients and healthy control subjects was found to be associated with reduced global fractional anisotropy, a marker of white matter microstructure, an effect found to be predominantly present in MDD-related fronto-temporo-parietal connections. A mediation analysis further suggests that this fractional anisotropy variation may mediate the association between polygenic risk score and cognitive performance. Conclusions: Our findings provide preliminary evidence of a polygenic risk for T2D to be linked to brain structural connectivity and cognition in patients with MDD and healthy control subjects, even in the absence of a direct T2D diagnosis. This suggests an effect of T2D genetic risk on white matter integrity, which may mediate an association of genetic risk for diabetes and cognitive impairments.",

keywords = "Cognition, Cognitive performance, Connectome, Fractional anisotropy, Major depressive disorder, Polygenic risk score",

author = "Jonathan Repple and Amelie K{\"o}nig and {de Lange}, {Siemon C.} and Nils Opel and Ronny Redlich and Susanne Meinert and Dominik Grotegerd and Marco Mauritz and Tim Hahn and Tiana Borgers and Leehr, {Elisabeth J.} and Nils Winter and Janik Goltermann and Verena Enneking and Fingas, {Stella M.} and Hannah Lemke and Lena Waltemate and Katharina Dohm and Maike Richter and Mehler, {David M. A.} and Vincent Holstein and Marius Gruber and Igor Nenadic and Axel Krug and Katharina Brosch and Simon Schmitt and Frederike Stein and Tina Meller and Andreas Jansen and Olaf Steinstr{\"a}ter and Amare, {Azmeraw T.} and Tilo Kircher and Baune, {Bernhard T.} and {van den Heuvel}, {Martijn P.} and Udo Dannlowski",

note = "Funding Information: This work is part of the German multicenter consortium “Neurobiology of Affective Disorders: A Translational Perspective on Brain Structure and Function” funded by the DFG Forschungsgruppe/Research Unit FOR2107. The FOR2107 cohort project (WP1) was approved by the Ethics Committees of the Medical Faculties, University of Marburg (AZ: 07/14) and University of M{\"u}nster (AZ: 2014-422-b-S). Funding Information: TK received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, and Neuraxpharm. This cooperation has no relevance to the work that is covered in the manuscript. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]) (Grant Nos. FOR2107 DA1151/5–1 , DA1151/5–2 , SFB-TRR58 , and Projects C09 and Z02 [to UD]), the Interdisciplinary Center for Clinical Research (IZKF) of the Medical Faculty of M{\"u}nster (Grant No. Dan3/012/17 [to UD]), Innovative Medizinische Forschung M{\"u}nster (Grant Nos. RE111604 and RE111722 [to RR] and Grant Nos. RE 22 17 07 and RE 111904 [to JR]), and the Deanery of the Medical Faculty of the University of M{\"u}nster (to NO). Funding Information: Respective areas of responsibility, DFG grant information, and principal investigators for the FOR2107 consortium are as follows: Work Package WP1, FOR2107/MACS cohort, and brain imaging (Grant Nos. KI 588/14-1 and KI 588/14-2 [to TK, speaker FOR2107], Grant Nos. DA 1151/5-1 and DA 1151/5-2 [to UD, cospeaker FOR2107], Grant Nos. KR 3822/5–1 and KR 3822/7-2 [to AK], Grant No. NE 2254/1-2 [to IN], and Grant No. KO 4291/3-1 [principal investigator, Carsten Konrad,]). CP1, biobank (Grant Nos. PF 784/1-1 and PF 784/1-2 [to PP] and Grant Nos. RE 737/20-1 and 737/20-2 [principal investigator, Harald Renz]). CP2, administration (Grant Nos. KI 588/15-1 and KI 588/17-1 [to TK], Grant No. DA 1151/6-1 [to UD], Grant No. KO 4291/4–1 [principal investigator, Carsten Konrad]). The Netherlands Organization for Scientific Research (NWO) supported the work through a Division of Earth and Life Sciences (ALW) Open grant (Grant No. ALWOP.179 [to MPvdH]) and a Vidi grant (Grant No. 452-16-015 [to MPvdH]). MQ provided support via fellowship (to MPvdH). Funding Information: This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]) (Grant Nos. FOR2107 DA1151/5?1, DA1151/5?2, SFB-TRR58, and Projects C09 and Z02 [to UD]), the Interdisciplinary Center for Clinical Research (IZKF) of the Medical Faculty of M?nster (Grant No. Dan3/012/17 [to UD]), Innovative Medizinische Forschung M?nster (Grant Nos. RE111604 and RE111722 [to RR] and Grant Nos. RE 22 17 07 and RE 111904 [to JR]), and the Deanery of the Medical Faculty of the University of M?nster (to NO). This work is part of the German multicenter consortium ?Neurobiology of Affective Disorders: A Translational Perspective on Brain Structure and Function? funded by the DFG Forschungsgruppe/Research Unit FOR2107. The FOR2107 cohort project (WP1) was approved by the Ethics Committees of the Medical Faculties, University of Marburg (AZ: 07/14) and University of M?nster (AZ: 2014-422-b-S). Respective areas of responsibility, DFG grant information, and principal investigators for the FOR2107 consortium are as follows: Work Package WP1, FOR2107/MACS cohort, and brain imaging (Grant Nos. KI 588/14-1 and KI 588/14-2 [to TK, speaker FOR2107], Grant Nos. DA 1151/5-1 and DA 1151/5-2 [to UD, cospeaker FOR2107], Grant Nos. KR 3822/5?1 and KR 3822/7-2 [to AK], Grant No. NE 2254/1-2 [to IN], and Grant No. KO 4291/3-1 [principal investigator, Carsten Konrad,]). CP1, biobank (Grant Nos. PF 784/1-1 and PF 784/1-2 [to PP] and Grant Nos. RE 737/20-1 and 737/20-2 [principal investigator, Harald Renz]). CP2, administration (Grant Nos. KI 588/15-1 and KI 588/17-1 [to TK], Grant No. DA 1151/6-1 [to UD], Grant No. KO 4291/4?1 [principal investigator, Carsten Konrad]). The Netherlands Organization for Scientific Research (NWO) supported the work through a Division of Earth and Life Sciences (ALW) Open grant (Grant No. ALWOP.179 [to MPvdH]) and a Vidi grant (Grant No. 452-16-015 [to MPvdH]). MQ provided support via fellowship (to MPvdH). Data access and responsibility: All principal investigators take responsibility for the integrity of the respective study data and their components. All authors and coauthors had full access to all study data. Acknowledgments and members by work package: WP1: Henrike Br?hl, Katharina Brosch, Bruno Dietsche, Rozbeh Elahi, Jennifer Engelen, Sabine Fischer, Jessica Heinen, Svenja Klingel, Felicitas Meier, Tina Meller, Torsten Sauder, Simon Schmitt, Frederike Stein, Annette Tittmar, Dilara Y?ksel (Department 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?hnlein (Psychiatric Practice, Marburg). Peter Wulf, J?rgen Kleebach, Achim Becker (Psychiatric Hospital Hephata, Schwalmstadt-Treysa). Ruth B?r (Care facility Bischoff, Neunkirchen). Matthias M?ller, Michael Franz, Siegfried Scharmann, Anja Haag, Kristina Spenner, Ulrich Ohlenschl?ger (Psychiatric Hospital Vitos, Marburg). Matthias M?ller, Michael Franz, Bernd Kundermann (Psychiatric Hospital Vitos, Gie?en). Christian B?rger, Katharina Dohm, Fanni Dzvonyar, Verena Enneking, Stella Fingas, Katharina F?rster, Janik Goltermann, Dominik Grotegerd, Hannah Lemke, Susanne Meinert, Nils Opel, Ronny Redlich, Jonathan Repple, Kordula Vorspohl, Bettina Walden, Dario Zaremba (Department of Psychiatry, University of M?nster). Harald Kugel, Jochen Bauer, Walter Heindel, Birgit Vahrenkamp (Departmen tof Clinical Radiology, University of M?nster). Gereon Heuft, Gudrun Schneider (Department of Psychosomatics and Psychotherapy, University of M?nster). Thomas Reker (LWL-Hospital M?nster). Gisela Bartling (IPP M?nster). Ulrike Buhlmann (Department of Clinical Psychology, University of M?nster). 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?st, Elvira Przypadlo, Corinna Brehm (Comprehensive Biomaterial Bank Marburg, Marburg University). TK received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, and Neuraxpharm. This cooperation has no relevance to the work that is covered in the manuscript. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: {\textcopyright} 2021 Society of Biological Psychiatry",

year = "2022",

month = mar,

doi = "https://doi.org/10.1016/j.bpsc.2021.02.010",

language = "English",

volume = "7",

pages = "333--340",

journal = "Biological Psychiatry: Cognitive Neuroscience and Neuroimaging",

issn = "2451-9022",

publisher = "Elsevier Inc.",

number = "3",

}

Repple, J, König, A, de Lange, SC, Opel, N, Redlich, R, Meinert, S, Grotegerd, D, Mauritz, M, Hahn, T, Borgers, T, Leehr, EJ, Winter, N, Goltermann, J, Enneking, V, Fingas, SM, Lemke, H, Waltemate, L, Dohm, K, Richter, M, Mehler, DMA, Holstein, V, Gruber, M, Nenadic, I, Krug, A, Brosch, K, Schmitt, S, Stein, F, Meller, T, Jansen, A, Steinsträter, O, Amare, AT, Kircher, T, Baune, BT, van den Heuvel, MP & Dannlowski, U 2022, 'Association Between Genetic Risk for Type 2 Diabetes and Structural Brain Connectivity in Major Depressive Disorder', Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, vol. 7, no. 3, pp. 333-340. https://doi.org/10.1016/j.bpsc.2021.02.010

TY - JOUR

T1 - Association Between Genetic Risk for Type 2 Diabetes and Structural Brain Connectivity in Major Depressive Disorder

AU - Repple, Jonathan

AU - König, Amelie

AU - de Lange, Siemon C.

AU - Opel, Nils

AU - Redlich, Ronny

AU - Meinert, Susanne

AU - Grotegerd, Dominik

AU - Mauritz, Marco

AU - Hahn, Tim

AU - Borgers, Tiana

AU - Leehr, Elisabeth J.

AU - Winter, Nils

AU - Goltermann, Janik

AU - Enneking, Verena

AU - Fingas, Stella M.

AU - Lemke, Hannah

AU - Waltemate, Lena

AU - Dohm, Katharina

AU - Richter, Maike

AU - Mehler, David M. A.

AU - Holstein, Vincent

AU - Gruber, Marius

AU - Nenadic, Igor

AU - Krug, Axel

AU - Brosch, Katharina

AU - Schmitt, Simon

AU - Stein, Frederike

AU - Meller, Tina

AU - Jansen, Andreas

AU - Steinsträter, Olaf

AU - Amare, Azmeraw T.

AU - Kircher, Tilo

AU - Baune, Bernhard T.

AU - van den Heuvel, Martijn P.

AU - Dannlowski, Udo

N1 - Funding Information: This work is part of the German multicenter consortium “Neurobiology of Affective Disorders: A Translational Perspective on Brain Structure and Function” funded by the DFG Forschungsgruppe/Research Unit FOR2107. The FOR2107 cohort project (WP1) was approved by the Ethics Committees of the Medical Faculties, University of Marburg (AZ: 07/14) and University of Münster (AZ: 2014-422-b-S). Funding Information: TK received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, and Neuraxpharm. This cooperation has no relevance to the work that is covered in the manuscript. All other authors report no biomedical financial interests or potential conflicts of interest. Funding Information: This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]) (Grant Nos. FOR2107 DA1151/5–1 , DA1151/5–2 , SFB-TRR58 , and Projects C09 and Z02 [to UD]), the Interdisciplinary Center for Clinical Research (IZKF) of the Medical Faculty of Münster (Grant No. Dan3/012/17 [to UD]), Innovative Medizinische Forschung Münster (Grant Nos. RE111604 and RE111722 [to RR] and Grant Nos. RE 22 17 07 and RE 111904 [to JR]), and the Deanery of the Medical Faculty of the University of Münster (to NO). Funding Information: Respective areas of responsibility, DFG grant information, and principal investigators for the FOR2107 consortium are as follows: Work Package WP1, FOR2107/MACS cohort, and brain imaging (Grant Nos. KI 588/14-1 and KI 588/14-2 [to TK, speaker FOR2107], Grant Nos. DA 1151/5-1 and DA 1151/5-2 [to UD, cospeaker FOR2107], Grant Nos. KR 3822/5–1 and KR 3822/7-2 [to AK], Grant No. NE 2254/1-2 [to IN], and Grant No. KO 4291/3-1 [principal investigator, Carsten Konrad,]). CP1, biobank (Grant Nos. PF 784/1-1 and PF 784/1-2 [to PP] and Grant Nos. RE 737/20-1 and 737/20-2 [principal investigator, Harald Renz]). CP2, administration (Grant Nos. KI 588/15-1 and KI 588/17-1 [to TK], Grant No. DA 1151/6-1 [to UD], Grant No. KO 4291/4–1 [principal investigator, Carsten Konrad]). The Netherlands Organization for Scientific Research (NWO) supported the work through a Division of Earth and Life Sciences (ALW) Open grant (Grant No. ALWOP.179 [to MPvdH]) and a Vidi grant (Grant No. 452-16-015 [to MPvdH]). MQ provided support via fellowship (to MPvdH). Funding Information: This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft [DFG]) (Grant Nos. FOR2107 DA1151/5?1, DA1151/5?2, SFB-TRR58, and Projects C09 and Z02 [to UD]), the Interdisciplinary Center for Clinical Research (IZKF) of the Medical Faculty of M?nster (Grant No. Dan3/012/17 [to UD]), Innovative Medizinische Forschung M?nster (Grant Nos. RE111604 and RE111722 [to RR] and Grant Nos. RE 22 17 07 and RE 111904 [to JR]), and the Deanery of the Medical Faculty of the University of M?nster (to NO). This work is part of the German multicenter consortium ?Neurobiology of Affective Disorders: A Translational Perspective on Brain Structure and Function? funded by the DFG Forschungsgruppe/Research Unit FOR2107. The FOR2107 cohort project (WP1) was approved by the Ethics Committees of the Medical Faculties, University of Marburg (AZ: 07/14) and University of M?nster (AZ: 2014-422-b-S). Respective areas of responsibility, DFG grant information, and principal investigators for the FOR2107 consortium are as follows: Work Package WP1, FOR2107/MACS cohort, and brain imaging (Grant Nos. KI 588/14-1 and KI 588/14-2 [to TK, speaker FOR2107], Grant Nos. DA 1151/5-1 and DA 1151/5-2 [to UD, cospeaker FOR2107], Grant Nos. KR 3822/5?1 and KR 3822/7-2 [to AK], Grant No. NE 2254/1-2 [to IN], and Grant No. KO 4291/3-1 [principal investigator, Carsten Konrad,]). CP1, biobank (Grant Nos. PF 784/1-1 and PF 784/1-2 [to PP] and Grant Nos. RE 737/20-1 and 737/20-2 [principal investigator, Harald Renz]). CP2, administration (Grant Nos. KI 588/15-1 and KI 588/17-1 [to TK], Grant No. DA 1151/6-1 [to UD], Grant No. KO 4291/4?1 [principal investigator, Carsten Konrad]). The Netherlands Organization for Scientific Research (NWO) supported the work through a Division of Earth and Life Sciences (ALW) Open grant (Grant No. ALWOP.179 [to MPvdH]) and a Vidi grant (Grant No. 452-16-015 [to MPvdH]). MQ provided support via fellowship (to MPvdH). Data access and responsibility: All principal investigators take responsibility for the integrity of the respective study data and their components. All authors and coauthors had full access to all study data. Acknowledgments and members by work package: WP1: Henrike Br?hl, Katharina Brosch, Bruno Dietsche, Rozbeh Elahi, Jennifer Engelen, Sabine Fischer, Jessica Heinen, Svenja Klingel, Felicitas Meier, Tina Meller, Torsten Sauder, Simon Schmitt, Frederike Stein, Annette Tittmar, Dilara Y?ksel (Department 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?hnlein (Psychiatric Practice, Marburg). Peter Wulf, J?rgen Kleebach, Achim Becker (Psychiatric Hospital Hephata, Schwalmstadt-Treysa). Ruth B?r (Care facility Bischoff, Neunkirchen). Matthias M?ller, Michael Franz, Siegfried Scharmann, Anja Haag, Kristina Spenner, Ulrich Ohlenschl?ger (Psychiatric Hospital Vitos, Marburg). Matthias M?ller, Michael Franz, Bernd Kundermann (Psychiatric Hospital Vitos, Gie?en). Christian B?rger, Katharina Dohm, Fanni Dzvonyar, Verena Enneking, Stella Fingas, Katharina F?rster, Janik Goltermann, Dominik Grotegerd, Hannah Lemke, Susanne Meinert, Nils Opel, Ronny Redlich, Jonathan Repple, Kordula Vorspohl, Bettina Walden, Dario Zaremba (Department of Psychiatry, University of M?nster). Harald Kugel, Jochen Bauer, Walter Heindel, Birgit Vahrenkamp (Departmen tof Clinical Radiology, University of M?nster). Gereon Heuft, Gudrun Schneider (Department of Psychosomatics and Psychotherapy, University of M?nster). Thomas Reker (LWL-Hospital M?nster). Gisela Bartling (IPP M?nster). Ulrike Buhlmann (Department of Clinical Psychology, University of M?nster). 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?st, Elvira Przypadlo, Corinna Brehm (Comprehensive Biomaterial Bank Marburg, Marburg University). TK received unrestricted educational grants from Servier, Janssen, Recordati, Aristo, Otsuka, and Neuraxpharm. This cooperation has no relevance to the work that is covered in the manuscript. All other authors report no biomedical financial interests or potential conflicts of interest. Publisher Copyright: © 2021 Society of Biological Psychiatry

PY - 2022/3

Y1 - 2022/3

N2 - Background: Major depressive disorder (MDD) and type 2 diabetes mellitus (T2D) are known to share clinical comorbidity and to have genetic overlap. Besides their shared genetics, both diseases seem to be associated with alterations in brain structural connectivity and impaired cognitive performance, but little is known about the mechanisms by which genetic risk of T2D might affect brain structure and function and if they do, how these effects could contribute to the disease course of MDD. Methods: This study explores the association of polygenic risk for T2D with structural brain connectome topology and cognitive performance in 434 nondiabetic patients with MDD and 539 healthy control subjects. Results: Polygenic risk score for T2D across MDD patients and healthy control subjects was found to be associated with reduced global fractional anisotropy, a marker of white matter microstructure, an effect found to be predominantly present in MDD-related fronto-temporo-parietal connections. A mediation analysis further suggests that this fractional anisotropy variation may mediate the association between polygenic risk score and cognitive performance. Conclusions: Our findings provide preliminary evidence of a polygenic risk for T2D to be linked to brain structural connectivity and cognition in patients with MDD and healthy control subjects, even in the absence of a direct T2D diagnosis. This suggests an effect of T2D genetic risk on white matter integrity, which may mediate an association of genetic risk for diabetes and cognitive impairments.

AB - Background: Major depressive disorder (MDD) and type 2 diabetes mellitus (T2D) are known to share clinical comorbidity and to have genetic overlap. Besides their shared genetics, both diseases seem to be associated with alterations in brain structural connectivity and impaired cognitive performance, but little is known about the mechanisms by which genetic risk of T2D might affect brain structure and function and if they do, how these effects could contribute to the disease course of MDD. Methods: This study explores the association of polygenic risk for T2D with structural brain connectome topology and cognitive performance in 434 nondiabetic patients with MDD and 539 healthy control subjects. Results: Polygenic risk score for T2D across MDD patients and healthy control subjects was found to be associated with reduced global fractional anisotropy, a marker of white matter microstructure, an effect found to be predominantly present in MDD-related fronto-temporo-parietal connections. A mediation analysis further suggests that this fractional anisotropy variation may mediate the association between polygenic risk score and cognitive performance. Conclusions: Our findings provide preliminary evidence of a polygenic risk for T2D to be linked to brain structural connectivity and cognition in patients with MDD and healthy control subjects, even in the absence of a direct T2D diagnosis. This suggests an effect of T2D genetic risk on white matter integrity, which may mediate an association of genetic risk for diabetes and cognitive impairments.

KW - Cognition

KW - Cognitive performance

KW - Connectome

KW - Fractional anisotropy

KW - Major depressive disorder

KW - Polygenic risk score

UR - http://www.scopus.com/inward/record.url?scp=85107277371&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.bpsc.2021.02.010

DO - https://doi.org/10.1016/j.bpsc.2021.02.010

M3 - Article

C2 - 33684623

SN - 2451-9022

VL - 7

SP - 333

EP - 340

JO - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

JF - Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

IS - 3

ER -

Association Between Genetic Risk for Type 2 Diabetes and Structural Brain Connectivity in Major Depressive Disorder

Abstract

Keywords

UN SDGs

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