Association between body mass index and subcortical brain volumes in bipolar disorders–ENIGMA study in 2735 individuals

Sean R. McWhinney, Christoph Abé, for the ENIGMA Bipolar Disorders Working Group, Martin Alda, Francesco Benedetti, Erlend Bøen, Caterina del Mar Bonnin, Tiana Borgers, Katharina Brosch, Erick J. Canales-Rodríguez, Dara M. Cannon, Udo Dannlowski, Ana M. Díaz-Zuluaga, Torbjørn Elvsåshagen, Lisa T. Eyler, Janice M. Fullerton, Jose M. Goikolea, Janik Goltermann, Dominik Grotegerd, Bartholomeus C.M. HaarmanTim Hahn, Fleur M. Howells, Martin Ingvar, Tilo T.J. Kircher, Axel Krug, Rayus T. Kuplicki, Mikael Landén, Hannah Lemke, Benny Liberg, Carlos Lopez-Jaramillo, Ulrik F. Malt, Fiona M. Martyn, Elena Mazza, Colm McDonald, Genevieve McPhilemy, Sandra Meier, Susanne Meinert, Tina Meller, Elisa M.T. Melloni, Philip B. Mitchell, Leila Nabulsi, Igor Nenadic, Nils Opel, Roel A. Ophoff, Bronwyn J. Overs, Julia Katharina Pfarr, Julian A. Pineda-Zapata, Edith Pomarol-Clotet, Joaquim Raduà, Neeltje E.M. van Haren, Annabel Vreeker, Paul M Thompson, Tomas Hajek

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Abstract

Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent research sites within the ENIGMA-BD Working Group. We jointly modeled the effects of BD and BMI on subcortical volumes using mixed-effects modeling and tested for mediation of group differences by obesity using nonparametric bootstrapping. All models controlled for age, sex, hemisphere, total intracranial volume, and data collection site. Relative to controls, individuals with BD had significantly higher BMI, larger lateral ventricular volume, and smaller volumes of amygdala, hippocampus, pallidum, caudate, and thalamus. BMI was positively associated with ventricular and amygdala and negatively with pallidal volumes. When analyzed jointly, both BD and BMI remained associated with volumes of lateral ventricles and amygdala. Adjusting for BMI decreased the BD vs control differences in ventricular volume. Specifically, 18.41% of the association between BD and ventricular volume was mediated by BMI (Z = 2.73, p = 0.006). BMI was associated with similar regional brain volumes as BD, including lateral ventricles, amygdala, and pallidum. Higher BMI may in part account for larger ventricles, one of the most replicated findings in BD. Comorbidity with obesity could explain why neurostructural alterations are more pronounced in some individuals with BD. Future prospective brain imaging studies should investigate whether obesity could be a modifiable risk factor for neuroprogression.

Original languageEnglish
Pages (from-to)6806-6819
Number of pages14
JournalMolecular Psychiatry
Volume26
Issue number11
Early online date16 Apr 2021
DOIs
Publication statusPublished - 2021

Bibliographical note

Funding Information:
Conflict of interest PMT & CRKC received a grant from Biogen, Inc., for research unrelated to this manuscript. DJS has received research grants and/or consultancy honoraria from Lundbeck and Sun. LNY has received speaking/consulting fees and/or research grants from Abbvie, Alkermes, Allergan, AstraZeneca, CANMAT, CIHR, Dainippon Sumitomo Pharma, Janssen, Lundbeck, Otsuka, Sunovion, and Teva. TE received speaker’s honoraria from Lundbeck and Janssen Cilag. EV has received grants and served as consultant, advisor or CME speaker for the following entities (unrelated to the present work): AB-Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, Janssen, Lundbeck, Otsuka, Sage, Sanofi-Aventis, and Takeda.

Funding Information:
Acknowledgements We gratefully acknowledge the following contributions and research funding sources that made this study possible: PT & CRKC of the Marina del Rey studies were supported by NIH grant U54 EB020403 from the Big Data to Knowledge (BD2K) Program; CRKC also acknowledges, NIA T32AG058507, and partial research support from Biogen, Inc. (Boston, USA) for work unrelated to the topic of this manuscript. The St. Göran study was supported by grants from the Swedish Research Council (2018-02653), the Swedish foundation for Strategic Research (KF10-0039), the Swedish Brain foundation, and the Swedish Federal Government under the LUA/ALF agreement (ALF 20170019, ALFGBG-716801). This work is also part of the German multicenter consortium “Neurobiology of Affective Disorders. A translational perspective on brain structure and function”, funded by the German Research Foundation (Deutsche For-schungsgemeinschaft DFG; Forschungsgruppe/Research Unit FOR2107). Principal investigators (PIs) with respective areas of responsibility in the FOR2107 consortium are as follows: Work Package WP1, FOR2107cohort and brain imaging: TK (speaker FOR2107; DFG grant numbers KI 588/14-1, KI 588/14-2), UD (co-speaker FOR2107; DA 1151/5-1, DA 1151/5-2), AK (KR 3822/5-1, KR 3822/7-2), IN (NE 2254/1-1 and NE 2254/2-1), CK (KO 4291/3-1). Further support from the German sites was provided by MNC and FOR2107-Muenster: This work was funded by the German Research Foundation (SFB-TRR58, Project C09 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD and grant SEED11/18 to NO); FOR2107-Muenster: This work was supported by grants from the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant MzH 3/020/20 to TH) and the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, HA7070/ 4 to TH. The NUIG sample was supported by the Health Research Board (HRA_POR/2011/100). The Medellin studies (GIPSI) were supported by the PRISMA UNION TEMPORAL (UNIVERSIDAD DE ANTIOQUIA/HOSPITAL SAN VICENTE FUNDACIÓN), Colciencias-INVITACIÓN 990 de 3 de agosto de 2017, Codigo 99059634. The San Raffaele site was supported by the Italian Ministry of Health RF-2011-02350980 project. This research was also supported by the Irish Research Council (IRC) Postgraduate Scholarship, Ireland awarded to LN and to GM, and by the Health Research Board (HRA-POR-324) awarded to DMC. We thank the participants and the support of the Welcome-Trust HRB Clinical Research Facility and the Centre for Advanced Medical Imaging, St. James Hospital, Dublin, Ireland. The NUIG sample was supported by the Health Research Board (HRA_POR/2011/100). JS and RTK received support from the William K. Warren Foundation National Institute of Mental Health (R21MH113871); JS also acknowledges the National Institute of General Medical Sciences (P20GM121312). This study was also funded by EU-FP7-HEALTH-222963 ‘MOODIN-FLAME’ and EU-FP7-PEOPLE-286334 ‘PSYCHAID’. The Barcelona group would like to thank CIBERSAM (EPC) and the Instituto de Salud Carlos III (PI18/00877, and PI19/00394) for their support. This work was supported by the Singapore Bioimaging Consortium (RP C009/2006) research grant awarded to KS The CIAM group (FMH - PI) was supported by the University Research Committee, University of Cape Town and South African funding bodies National Research Foundation and Medical Research Council; DJS from CIAM was supported by the SAMRC. The Sydney studies were supported by the Australian National Health and Medical Research Council (NHMRC) Program Grant 1037196, Project Grants 1063960 and 1066177, the Lansdowne Foundation, Good Talk and Keith Pettigrew Family; as well as the Janette Mary O’Neil Research Fellowship to JMF. The study was also supported by NIMH grant number: R01 MH090553(to RAO). Funding for the Oslo-Malt cohort was provided by the South Eastern Norway Regional Health Authority (2015-078), the Ebbe Frøland foundation, and a research grant from Mrs. Throne-Holst. Lastly, this study was supported by the Canadian Institutes of Health Research (103703, 106469 and 142255), Nova Scotia Health Research Foundation, Dalhousie Clinical Research Scholarship to TH, Brain & Behavior Research Foundation (formerly NARSAD); 2007 Young Investigator and 2015 Independent Investigator Awards to TH. Lastly, EV acknowledges the support of the Spanish Ministry of Science and Innovation (PI15/00283, PI18/00805) integrated into the Plan Nacio-nal de I + D + I and co-financed by the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER); the Instituto de Salud Carlos III; the CIBER of Mental Health (CIBERSAM); the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2017 SGR 1365), the CERCA Programme, and the Departament de Salut de la Generalitat de Catalunya for the PERIS grant SLT006/17/00357.

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