Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders: Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group

Nils Opel; Anbupalam Thalamuthu; Yuri Milaneschi; Dominik Grotegerd; Claas Flint; Ramona Leenings; Janik Goltermann; Maike Richter; Tim Hahn; Georg Woditsch; Klaus Berger; Marco Hermesdorf; Andrew McIntosh; Heather C. Whalley; Mathew A. Harris; Frank P. MacMaster; Henrik Walter; Ilya M. Veer; Thomas Frodl; Angela Carballedo; Axel Krug; Igor Nenadic; Tilo Kircher; Andre Aleman; Nynke A. Groenewold; Dan J. Stein; Jair C. Soares; Giovana B. Zunta-Soares; Benson Mwangi; Mon Ju Wu; Martin Walter; Meng Li; Ben J. Harrison; Christopher G. Davey; Kathryn R. Cullen; Bonnie Klimes-Dougan; Bryon A. Mueller; Philipp G. Sämann; Brenda Penninx; Laura Nawijn; Dick J. Veltman; Lyubomir Aftanas; Ivan V. Brak; Elena A. Filimonova; Evgeniy A. Osipov; Liesbeth Reneman; Anouk Schrantee; Hans J. Grabe; Sandra Van der Auwera; Katharina Wittfeld; Norbert Hosten; Henry Völzke; Kang Sim; Ian H. Gotlib; Matthew D. Sacchet; Jim Lagopoulos; Sean N. Hatton; Ian Hickie; Elena Pozzi; Paul M. Thompson; Neda Jahanshad; Lianne Schmaal; Bernhard T. Baune; Udo Dannlowski

doi:10.1038/s41380-020-0774-9

Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders: Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group

Nils Opel, Anbupalam Thalamuthu, Yuri Milaneschi, Dominik Grotegerd, Claas Flint, Ramona Leenings, Janik Goltermann, Maike Richter, Tim Hahn, Georg Woditsch, Klaus Berger, Marco Hermesdorf, Andrew McIntosh, Heather C. Whalley, Mathew A. Harris, Frank P. MacMaster, Henrik Walter, Ilya M. Veer, Thomas Frodl, Angela CarballedoAxel Krug, Igor Nenadic, Tilo Kircher, Andre Aleman, Nynke A. Groenewold, Dan J. Stein, Jair C. Soares, Giovana B. Zunta-Soares, Benson Mwangi, Mon Ju Wu, Martin Walter, Meng Li, Ben J. Harrison, Christopher G. Davey, Kathryn R. Cullen, Bonnie Klimes-Dougan, Bryon A. Mueller, Philipp G. Sämann, Brenda Penninx, Laura Nawijn, Dick J. Veltman, Lyubomir Aftanas, Ivan V. Brak, Elena A. Filimonova, Evgeniy A. Osipov, Liesbeth Reneman, Anouk Schrantee, Hans J. Grabe, Sandra Van der Auwera, Katharina Wittfeld, Norbert Hosten, Henry Völzke, Kang Sim, Ian H. Gotlib, Matthew D. Sacchet, Jim Lagopoulos, Sean N. Hatton, Ian Hickie, Elena Pozzi, Paul M. Thompson, Neda Jahanshad, Lianne Schmaal, Bernhard T. Baune, Udo Dannlowski

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

36 Scopus citations

Abstract

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

Original language	English (US)
Pages (from-to)	4839-4852
Number of pages	14
Journal	Molecular psychiatry
Volume	26
Issue number	9
Early online date	May 28 2020
DOIs	https://doi.org/10.1038/s41380-020-0774-9
State	Published - Sep 2021

Bibliographical note

Funding Information:
Acknowledgements The ENIGMA-Major Depressive Disorder working group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to PT). LS is supported by a NHMRC Career Development Fellowship (1140764). PT is supported by grant R01MH116147. NJ is supported by grant R01MH117601. Muenster Cohort: The Muenster Neuroimaging Cohort was supported by grants of the German Research Foundation (DFG, grant FOR2107 DA1151/5–1 and DA1151/5–2 to UD; SFB-TRR58, Projects C09 and Z02 to UD;) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD and SEED 11/18 to NO) and the Deanery of the Medical Faculty of the University of Münster. These funders had no role in designing the study; collection, management, analysis, and interpretation of data; writing of the report; nor the decision to submit the report for publication. FOR2107: The FOR2107 consortium is supported by the German Research Foundation (Deutsche For-schungsgemeinschaft, DFG, Grant nos. KI 588/14–1, KI 588/14–2, KR 3822/7–1, KR 3822/7–2, NE 2254/1–2, DA1151/5–1, DA1151/ 5–2, SCHW 559/14–1, 545/7–2, RI 908/11–2, WI 3439/3–2, NO 246/ 10–2, DE 1614/3–2, HA 7070/2–2, JA 1890/7–1, JA 1890/7–2, MU 1315/8–2, RE 737/20–2, KI 588/17–1). TH was supported by the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/4) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (MzH3/020/20). BiDirect: The BiDirect-Study is funded by the German Federal Ministry of Education and Research (grants 01ER0816, 01ER1506 and 01ER1205). NESDA: Funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10–000–1002); the Center for Medical Systems Biology (CSMB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University’s Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, R01D0042157–01A, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health.Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. LS is supported by a NHMRC Career Development Fellowship (1140764) and grant R01MH117601. Bipolar Family Study: The Bipolar Family Study received funding from the European Union’s Seventh Framework Programme for research under grant agreement n° 602450. This study is also supported by Wellcome Trust award 104036/Z/14/Z. CODE: The CODE cohort was collected from studies funded by Lundbeck and the German Research Foundation (WA 1539/ 4-1, SCHN 1204/3-1). MPIP: The MPIP Munich Morphometry Sample comprises patients included in Munich Antidepressant Response Signature study and the Recurrent Unipolar Depression (RUD) Case-Control study, and control subjects acquired at the Ludwig-Maximilians-University, Munich, Department of Psychiatry. We wish to acknowledge Rosa Schirmer, Elke Schreiter, Reinhold Borschke, and Ines Eidner for MR image acquisition and data preparation, and Benno Pütz, and Bertram Müller-Myhsok for distributed computing support and the MARS and RUD Study teams for clinical phenotyping. We thank Dorothee P. Auer for initiation of the RUD study. The MARS study is supported by a grant of the Exzellenz-Stiftung of the Max Planck Society. This work has also been funded by the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN), FKZ 01GS0481. SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. This study was further supported by the EU-JPND Funding for BRIDGET (FKZ:01ED1615). Stanford: NIMH Grant R37-101495 to IG, and the National Science Foundation Integrative Graduate Education and Research Traineeship (NSF IGERT) Recipient Award 0801700 and National Science Foundation Graduate Research Fellowship Program (NSF GRFP) DGE-1147470 to MS. Melbourne: The study was funded by National Health and Medical Research Council of Australia (NHMRC) Project Grants 1064643 (PI BH) and 1024570 (PI CD). Houston: Supported in part by NIMH grant R01 085667, The Dunn Foundation, and the Pat Rutherford, Jr. Endowed Chair in Psychiatry to JCS. Imaging genetics Dublin and Clinical Depression Dublin: The study was supported by a Science Foundation Ireland (SFI) Stokes Professorship Grant to Thomas Frodl. Novosibirsk: Russian Science Foundation grant #16-15-00128 to Lyubomir Aftanas. Sydney: This study was supported by the following National Health & Medical Research Council funding sources: Program Grant (No. 566529), Centres of Clinical Research Excellence Grant (No. 264611), Australia Fellowship (No. 464914) and Clinical Research Fellowship (No. 402864). Calgary: The study was supported by Branch Out Neurological Foundation, Alberta Children’s Hospital Foundation. Magdeburg: The study was funded through the SFB779. Minnesota: The study was supported by K23MH090421, P41RR008079, National Alliance for Research on Schizophrenia and Affective Disorders, University of Minnesota Graduate School, Minnesota Medical Foundation, Deborah E. Powell Center for Women’s Health Seed Grant. Singapore: The study was supported by grant NHG SIG/15012.

Funding Information:
Conflict of interest HW and MH have previously received funding from The Sackler Trust. AM has previously received funding from Eli Lilly, Pfizer and The Sackler Trust. HG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. PT is MPI of a research related grant from Biogen, Inc for work unrelated to this manuscript. NJ is MPI of a research related grant from Biogen, Inc for work unrelated to this manuscript. PGS has previously received funding by the German Research Foundation (DFG, SA 1358/2-1) unrelated to this study. These affiliations have no relevance to the work covered in the manuscript. The remaining authors declare no conflict of interest.

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© 2020, The Author(s).

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Opel, N., Thalamuthu, A., Milaneschi, Y., Grotegerd, D., Flint, C., Leenings, R., Goltermann, J., Richter, M., Hahn, T., Woditsch, G., Berger, K., Hermesdorf, M., McIntosh, A., Whalley, H. C., Harris, M. A., MacMaster, F. P., Walter, H., Veer, I. M., Frodl, T., ... Dannlowski, U. (2021). Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders: Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group. Molecular psychiatry, 26(9), 4839-4852. https://doi.org/10.1038/s41380-020-0774-9

Brain structural abnormalities in obesity : relation to age, genetic risk, and common psychiatric disorders: Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group. / Opel, Nils; Thalamuthu, Anbupalam; Milaneschi, Yuri et al.

In: Molecular psychiatry, Vol. 26, No. 9, 09.2021, p. 4839-4852.

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

Opel, N, Thalamuthu, A, Milaneschi, Y, Grotegerd, D, Flint, C, Leenings, R, Goltermann, J, Richter, M, Hahn, T, Woditsch, G, Berger, K, Hermesdorf, M, McIntosh, A, Whalley, HC, Harris, MA, MacMaster, FP, Walter, H, Veer, IM, Frodl, T, Carballedo, A, Krug, A, Nenadic, I, Kircher, T, Aleman, A, Groenewold, NA, Stein, DJ, Soares, JC, Zunta-Soares, GB, Mwangi, B, Wu, MJ, Walter, M, Li, M, Harrison, BJ, Davey, CG, Cullen, KR , Klimes-Dougan, B , Mueller, BA, Sämann, PG, Penninx, B, Nawijn, L, Veltman, DJ, Aftanas, L, Brak, IV, Filimonova, EA, Osipov, EA, Reneman, L, Schrantee, A, Grabe, HJ, Van der Auwera, S, Wittfeld, K, Hosten, N, Völzke, H, Sim, K, Gotlib, IH, Sacchet, MD, Lagopoulos, J, Hatton, SN, Hickie, I, Pozzi, E, Thompson, PM, Jahanshad, N, Schmaal, L, Baune, BT & Dannlowski, U 2021, 'Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders: Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group', Molecular psychiatry, vol. 26, no. 9, pp. 4839-4852. https://doi.org/10.1038/s41380-020-0774-9

Opel N, Thalamuthu A, Milaneschi Y, Grotegerd D, Flint C, Leenings R et al. Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders: Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group. Molecular psychiatry. 2021 Sep;26(9):4839-4852. Epub 2020 May 28. doi: 10.1038/s41380-020-0774-9

@article{60ded6efc23f4085a6e3bb77ffe851ea,

title = "Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders: Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group",

abstract = "Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.",

author = "Nils Opel and Anbupalam Thalamuthu and Yuri Milaneschi and Dominik Grotegerd and Claas Flint and Ramona Leenings and Janik Goltermann and Maike Richter and Tim Hahn and Georg Woditsch and Klaus Berger and Marco Hermesdorf and Andrew McIntosh and Whalley, {Heather C.} and Harris, {Mathew A.} and MacMaster, {Frank P.} and Henrik Walter and Veer, {Ilya M.} and Thomas Frodl and Angela Carballedo and Axel Krug and Igor Nenadic and Tilo Kircher and Andre Aleman and Groenewold, {Nynke A.} and Stein, {Dan J.} and Soares, {Jair C.} and Zunta-Soares, {Giovana B.} and Benson Mwangi and Wu, {Mon Ju} and Martin Walter and Meng Li and Harrison, {Ben J.} and Davey, {Christopher G.} and Cullen, {Kathryn R.} and Bonnie Klimes-Dougan and Mueller, {Bryon A.} and S{\"a}mann, {Philipp G.} and Brenda Penninx and Laura Nawijn and Veltman, {Dick J.} and Lyubomir Aftanas and Brak, {Ivan V.} and Filimonova, {Elena A.} and Osipov, {Evgeniy A.} and Liesbeth Reneman and Anouk Schrantee and Grabe, {Hans J.} and {Van der Auwera}, Sandra and Katharina Wittfeld and Norbert Hosten and Henry V{\"o}lzke and Kang Sim and Gotlib, {Ian H.} and Sacchet, {Matthew D.} and Jim Lagopoulos and Hatton, {Sean N.} and Ian Hickie and Elena Pozzi and Thompson, {Paul M.} and Neda Jahanshad and Lianne Schmaal and Baune, {Bernhard T.} and Udo Dannlowski",

note = "Funding Information: Acknowledgements The ENIGMA-Major Depressive Disorder working group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to PT). LS is supported by a NHMRC Career Development Fellowship (1140764). PT is supported by grant R01MH116147. NJ is supported by grant R01MH117601. Muenster Cohort: The Muenster Neuroimaging Cohort was supported by grants of the German Research Foundation (DFG, grant FOR2107 DA1151/5–1 and DA1151/5–2 to UD; SFB-TRR58, Projects C09 and Z02 to UD;) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of M{\"u}nster (grant Dan3/012/17 to UD and SEED 11/18 to NO) and the Deanery of the Medical Faculty of the University of M{\"u}nster. These funders had no role in designing the study; collection, management, analysis, and interpretation of data; writing of the report; nor the decision to submit the report for publication. FOR2107: The FOR2107 consortium is supported by the German Research Foundation (Deutsche For-schungsgemeinschaft, DFG, Grant nos. KI 588/14–1, KI 588/14–2, KR 3822/7–1, KR 3822/7–2, NE 2254/1–2, DA1151/5–1, DA1151/ 5–2, SCHW 559/14–1, 545/7–2, RI 908/11–2, WI 3439/3–2, NO 246/ 10–2, DE 1614/3–2, HA 7070/2–2, JA 1890/7–1, JA 1890/7–2, MU 1315/8–2, RE 737/20–2, KI 588/17–1). TH was supported by the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/4) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of M{\"u}nster (MzH3/020/20). BiDirect: The BiDirect-Study is funded by the German Federal Ministry of Education and Research (grants 01ER0816, 01ER1506 and 01ER1205). NESDA: Funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10–000–1002); the Center for Medical Systems Biology (CSMB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University{\textquoteright}s Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, R01D0042157–01A, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health.Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. LS is supported by a NHMRC Career Development Fellowship (1140764) and grant R01MH117601. Bipolar Family Study: The Bipolar Family Study received funding from the European Union{\textquoteright}s Seventh Framework Programme for research under grant agreement n° 602450. This study is also supported by Wellcome Trust award 104036/Z/14/Z. CODE: The CODE cohort was collected from studies funded by Lundbeck and the German Research Foundation (WA 1539/ 4-1, SCHN 1204/3-1). MPIP: The MPIP Munich Morphometry Sample comprises patients included in Munich Antidepressant Response Signature study and the Recurrent Unipolar Depression (RUD) Case-Control study, and control subjects acquired at the Ludwig-Maximilians-University, Munich, Department of Psychiatry. We wish to acknowledge Rosa Schirmer, Elke Schreiter, Reinhold Borschke, and Ines Eidner for MR image acquisition and data preparation, and Benno P{\"u}tz, and Bertram M{\"u}ller-Myhsok for distributed computing support and the MARS and RUD Study teams for clinical phenotyping. We thank Dorothee P. Auer for initiation of the RUD study. The MARS study is supported by a grant of the Exzellenz-Stiftung of the Max Planck Society. This work has also been funded by the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN), FKZ 01GS0481. SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. This study was further supported by the EU-JPND Funding for BRIDGET (FKZ:01ED1615). Stanford: NIMH Grant R37-101495 to IG, and the National Science Foundation Integrative Graduate Education and Research Traineeship (NSF IGERT) Recipient Award 0801700 and National Science Foundation Graduate Research Fellowship Program (NSF GRFP) DGE-1147470 to MS. Melbourne: The study was funded by National Health and Medical Research Council of Australia (NHMRC) Project Grants 1064643 (PI BH) and 1024570 (PI CD). Houston: Supported in part by NIMH grant R01 085667, The Dunn Foundation, and the Pat Rutherford, Jr. Endowed Chair in Psychiatry to JCS. Imaging genetics Dublin and Clinical Depression Dublin: The study was supported by a Science Foundation Ireland (SFI) Stokes Professorship Grant to Thomas Frodl. Novosibirsk: Russian Science Foundation grant #16-15-00128 to Lyubomir Aftanas. Sydney: This study was supported by the following National Health & Medical Research Council funding sources: Program Grant (No. 566529), Centres of Clinical Research Excellence Grant (No. 264611), Australia Fellowship (No. 464914) and Clinical Research Fellowship (No. 402864). Calgary: The study was supported by Branch Out Neurological Foundation, Alberta Children{\textquoteright}s Hospital Foundation. Magdeburg: The study was funded through the SFB779. Minnesota: The study was supported by K23MH090421, P41RR008079, National Alliance for Research on Schizophrenia and Affective Disorders, University of Minnesota Graduate School, Minnesota Medical Foundation, Deborah E. Powell Center for Women{\textquoteright}s Health Seed Grant. Singapore: The study was supported by grant NHG SIG/15012. Funding Information: Conflict of interest HW and MH have previously received funding from The Sackler Trust. AM has previously received funding from Eli Lilly, Pfizer and The Sackler Trust. HG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. PT is MPI of a research related grant from Biogen, Inc for work unrelated to this manuscript. NJ is MPI of a research related grant from Biogen, Inc for work unrelated to this manuscript. PGS has previously received funding by the German Research Foundation (DFG, SA 1358/2-1) unrelated to this study. These affiliations have no relevance to the work covered in the manuscript. The remaining authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2021",

month = sep,

doi = "10.1038/s41380-020-0774-9",

language = "English (US)",

volume = "26",

pages = "4839--4852",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "9",

}

TY - JOUR

T1 - Brain structural abnormalities in obesity

T2 - relation to age, genetic risk, and common psychiatric disorders: Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group

AU - Opel, Nils

AU - Thalamuthu, Anbupalam

AU - Milaneschi, Yuri

AU - Grotegerd, Dominik

AU - Flint, Claas

AU - Leenings, Ramona

AU - Goltermann, Janik

AU - Richter, Maike

AU - Hahn, Tim

AU - Woditsch, Georg

AU - Berger, Klaus

AU - Hermesdorf, Marco

AU - McIntosh, Andrew

AU - Whalley, Heather C.

AU - Harris, Mathew A.

AU - MacMaster, Frank P.

AU - Walter, Henrik

AU - Veer, Ilya M.

AU - Frodl, Thomas

AU - Carballedo, Angela

AU - Krug, Axel

AU - Nenadic, Igor

AU - Kircher, Tilo

AU - Aleman, Andre

AU - Groenewold, Nynke A.

AU - Stein, Dan J.

AU - Soares, Jair C.

AU - Zunta-Soares, Giovana B.

AU - Mwangi, Benson

AU - Wu, Mon Ju

AU - Walter, Martin

AU - Li, Meng

AU - Harrison, Ben J.

AU - Davey, Christopher G.

AU - Cullen, Kathryn R.

AU - Klimes-Dougan, Bonnie

AU - Mueller, Bryon A.

AU - Sämann, Philipp G.

AU - Penninx, Brenda

AU - Nawijn, Laura

AU - Veltman, Dick J.

AU - Aftanas, Lyubomir

AU - Brak, Ivan V.

AU - Filimonova, Elena A.

AU - Osipov, Evgeniy A.

AU - Reneman, Liesbeth

AU - Schrantee, Anouk

AU - Grabe, Hans J.

AU - Van der Auwera, Sandra

AU - Wittfeld, Katharina

AU - Hosten, Norbert

AU - Völzke, Henry

AU - Sim, Kang

AU - Gotlib, Ian H.

AU - Sacchet, Matthew D.

AU - Lagopoulos, Jim

AU - Hatton, Sean N.

AU - Hickie, Ian

AU - Pozzi, Elena

AU - Thompson, Paul M.

AU - Jahanshad, Neda

AU - Schmaal, Lianne

AU - Baune, Bernhard T.

AU - Dannlowski, Udo

N1 - Funding Information: Acknowledgements The ENIGMA-Major Depressive Disorder working group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to PT). LS is supported by a NHMRC Career Development Fellowship (1140764). PT is supported by grant R01MH116147. NJ is supported by grant R01MH117601. Muenster Cohort: The Muenster Neuroimaging Cohort was supported by grants of the German Research Foundation (DFG, grant FOR2107 DA1151/5–1 and DA1151/5–2 to UD; SFB-TRR58, Projects C09 and Z02 to UD;) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD and SEED 11/18 to NO) and the Deanery of the Medical Faculty of the University of Münster. These funders had no role in designing the study; collection, management, analysis, and interpretation of data; writing of the report; nor the decision to submit the report for publication. FOR2107: The FOR2107 consortium is supported by the German Research Foundation (Deutsche For-schungsgemeinschaft, DFG, Grant nos. KI 588/14–1, KI 588/14–2, KR 3822/7–1, KR 3822/7–2, NE 2254/1–2, DA1151/5–1, DA1151/ 5–2, SCHW 559/14–1, 545/7–2, RI 908/11–2, WI 3439/3–2, NO 246/ 10–2, DE 1614/3–2, HA 7070/2–2, JA 1890/7–1, JA 1890/7–2, MU 1315/8–2, RE 737/20–2, KI 588/17–1). TH was supported by the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/4) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (MzH3/020/20). BiDirect: The BiDirect-Study is funded by the German Federal Ministry of Education and Research (grants 01ER0816, 01ER1506 and 01ER1205). NESDA: Funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10–000–1002); the Center for Medical Systems Biology (CSMB, NWO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University’s Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, R01D0042157–01A, MH081802, Grand Opportunity grants 1RC2 MH089951 and 1RC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health.Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. LS is supported by a NHMRC Career Development Fellowship (1140764) and grant R01MH117601. Bipolar Family Study: The Bipolar Family Study received funding from the European Union’s Seventh Framework Programme for research under grant agreement n° 602450. This study is also supported by Wellcome Trust award 104036/Z/14/Z. CODE: The CODE cohort was collected from studies funded by Lundbeck and the German Research Foundation (WA 1539/ 4-1, SCHN 1204/3-1). MPIP: The MPIP Munich Morphometry Sample comprises patients included in Munich Antidepressant Response Signature study and the Recurrent Unipolar Depression (RUD) Case-Control study, and control subjects acquired at the Ludwig-Maximilians-University, Munich, Department of Psychiatry. We wish to acknowledge Rosa Schirmer, Elke Schreiter, Reinhold Borschke, and Ines Eidner for MR image acquisition and data preparation, and Benno Pütz, and Bertram Müller-Myhsok for distributed computing support and the MARS and RUD Study teams for clinical phenotyping. We thank Dorothee P. Auer for initiation of the RUD study. The MARS study is supported by a grant of the Exzellenz-Stiftung of the Max Planck Society. This work has also been funded by the Federal Ministry of Education and Research (BMBF) in the framework of the National Genome Research Network (NGFN), FKZ 01GS0481. SHIP: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. This study was further supported by the EU-JPND Funding for BRIDGET (FKZ:01ED1615). Stanford: NIMH Grant R37-101495 to IG, and the National Science Foundation Integrative Graduate Education and Research Traineeship (NSF IGERT) Recipient Award 0801700 and National Science Foundation Graduate Research Fellowship Program (NSF GRFP) DGE-1147470 to MS. Melbourne: The study was funded by National Health and Medical Research Council of Australia (NHMRC) Project Grants 1064643 (PI BH) and 1024570 (PI CD). Houston: Supported in part by NIMH grant R01 085667, The Dunn Foundation, and the Pat Rutherford, Jr. Endowed Chair in Psychiatry to JCS. Imaging genetics Dublin and Clinical Depression Dublin: The study was supported by a Science Foundation Ireland (SFI) Stokes Professorship Grant to Thomas Frodl. Novosibirsk: Russian Science Foundation grant #16-15-00128 to Lyubomir Aftanas. Sydney: This study was supported by the following National Health & Medical Research Council funding sources: Program Grant (No. 566529), Centres of Clinical Research Excellence Grant (No. 264611), Australia Fellowship (No. 464914) and Clinical Research Fellowship (No. 402864). Calgary: The study was supported by Branch Out Neurological Foundation, Alberta Children’s Hospital Foundation. Magdeburg: The study was funded through the SFB779. Minnesota: The study was supported by K23MH090421, P41RR008079, National Alliance for Research on Schizophrenia and Affective Disorders, University of Minnesota Graduate School, Minnesota Medical Foundation, Deborah E. Powell Center for Women’s Health Seed Grant. Singapore: The study was supported by grant NHG SIG/15012. Funding Information: Conflict of interest HW and MH have previously received funding from The Sackler Trust. AM has previously received funding from Eli Lilly, Pfizer and The Sackler Trust. HG has received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care. PT is MPI of a research related grant from Biogen, Inc for work unrelated to this manuscript. NJ is MPI of a research related grant from Biogen, Inc for work unrelated to this manuscript. PGS has previously received funding by the German Research Foundation (DFG, SA 1358/2-1) unrelated to this study. These affiliations have no relevance to the work covered in the manuscript. The remaining authors declare no conflict of interest. Publisher Copyright: © 2020, The Author(s).

PY - 2021/9

Y1 - 2021/9

N2 - Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

AB - Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

UR - http://www.scopus.com/inward/record.url?scp=85083229293&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85083229293&partnerID=8YFLogxK

U2 - 10.1038/s41380-020-0774-9

DO - 10.1038/s41380-020-0774-9

M3 - Article

C2 - 32467648

AN - SCOPUS:85083229293

SN - 1359-4184

VL - 26

SP - 4839

EP - 4852

JO - Molecular Psychiatry

JF - Molecular Psychiatry

IS - 9

ER -

Brain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders: Evidence through univariate and multivariate mega-analysis including 6420 participants from the ENIGMA MDD working group

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