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: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

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Abstract

BACKGROUND: Major depressive disorder (MDD) and type 2 diabetes (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 so, 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 MDD patients and 539 healthy controls.

RESULTS: Polygenic risk score for T2D across MDD patients and healthy controls 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 FA variation may mediate the association between PGS 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 MDD patients and healthy controls, 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

Funding

Funders	Funder number
ALW	452-16-015
DFG Forschungsgruppe/Research Unit
Department of Psychiatry
Doris Finholdt
Innovative Medizinische Forschung	RE 111904, RE111604, RE 22 17 07, RE111722
Innovative Medizinische Forschung M?nster
Medical Faculty of M?nster
University of M?nster
Janssen Pharmaceuticals
Philipps-Universität Marburg	737/20-2, RE 737/20-1, 07/14, PF 784/1-1, PF 784/1-2
Philipps-Universität Marburg
Deutsche Forschungsgemeinschaft	KO 4291/3-1, FOR2107, KI 588/17-1, NE 2254/1-2, KI 588/14-2, KI 588/15-1, DA1151/5–2, KI 588/14-1, SFB-TRR58, KR 3822/5–1, DA 1151/6-1, FOR2107 DA1151/5–1, KR 3822/7-2, DA 1151/5-1
Deutsche Forschungsgemeinschaft
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Westfälische Wilhelms-Universität Münster
Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg	Dan3/012/17
Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg
Servier
Aard- en Levenswetenschappen, Nederlandse Organisatie voor Wetenschappelijk Onderzoek

UN SDGs

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

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10.1016/j.bpsc.2021.02.010

Association between genetic risk for type 2 diabetes and structural brain connectivity in major depressive disorderFinal published version, 577 KBLicence: 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{a203c99c6c874dedac17c464c131eded,

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 (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 so, 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 MDD patients and 539 healthy controls.RESULTS: Polygenic risk score for T2D across MDD patients and healthy controls 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 FA variation may mediate the association between PGS 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 MDD patients and healthy controls, 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.",

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 = "Copyright {\textcopyright} 2021. Published by Elsevier Inc.",

year = "2022",

month = mar,

doi = "10.1016/j.bpsc.2021.02.010",

language = "English",

volume = "7",

pages = "333--340",

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

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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

PY - 2022/3

Y1 - 2022/3

N2 - BACKGROUND: Major depressive disorder (MDD) and type 2 diabetes (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 so, 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 MDD patients and 539 healthy controls.RESULTS: Polygenic risk score for T2D across MDD patients and healthy controls 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 FA variation may mediate the association between PGS 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 MDD patients and healthy controls, 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 (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 so, 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 MDD patients and 539 healthy controls.RESULTS: Polygenic risk score for T2D across MDD patients and healthy controls 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 FA variation may mediate the association between PGS 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 MDD patients and healthy controls, 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.

U2 - 10.1016/j.bpsc.2021.02.010

DO - 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

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