The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder

Sonja M. C. de Zwarte; Rachel M. Brouwer; Ingrid Agartz; Martin Alda; Andre Aleman; Kathryn I. Alpert; Carrie E. Bearden; Alessandro Bertolino; Catherine Bois; Aurora Bonvino; Elvira Bramon; Elizabeth E. L. Buimer; Wiepke Cahn; Dara M. Cannon; Tyrone D. Cannon; Xavier Caseras; Josefina Castro-Fornieles; Qiang Chen; Yoonho Chung; Elena De la Serna; Annabella Di Giorgio; Gaelle E. Doucet; Mehmet Cagdas Eker; Susanne Erk; Scott C. Fears; Sonya F. Foley; Sophia Frangou; Andrew Frankland; Janice M. Fullerton; David C. Glahn; Vina M. Goghari; Aaron L. Goldman; Ali Saffet Gonul; Oliver Gruber; Lieuwe de Haan; Tomas Hajek; Emma L. Hawkins; Andreas Heinz; Manon H. J. Hillegers; Hilleke E. Hulshoff Pol; Christina M. Hultman; Martin Ingvar; Viktoria Johansson; Erik G. Jonsson; Fergus Kane; Matthew J. Kempton; Marinka M. G. Koenis; Miloslav Kopecek; Lydia Krabbendam; Bernd Kraemer; Stephen M. Lawrie; Rhoshel K. Lenroot; Machteld Marcelis; Jan-Bernard C. Marsman; Venkata S. Mattay; Colm McDonald; Andreas Meyer-Lindenberg; Stijn Michielse; Philip B. Mitchell; Dolores Moreno; Robin M. Murray; Benson Mwangi; Pablo Najt; Emma Neilson; Jason Newport; Jim van Os; Bronwyn Overs; Aysegul Ozerdem; Marco M. Picchioni; Anja Richter; Gloria Roberts; Aybala Saricicek Aydogan; Peter R. Schofield; Fatma Simsek; Jair C. Soares; Gisela Sugranyes; Timothea Toulopoulou; Giulia Tronchin; Henrik Walter; Lei Wang; Daniel R. Weinberger; Heather C. Whalley; Nefize Yalin; Ole A. Andreassen; Christopher R. K. Ching; Theo G. M. van Erp; Jessica A. Turner; Neda Jahanshad; Paul M. Thompson; Rene S. Kahn; Neeltje E. M. van Haren

doi:10.1016/j.biopsych.2019.03.985

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder

Sonja M. C. de Zwarte^*, Rachel M. Brouwer, Ingrid Agartz, Martin Alda, Andre Aleman, Kathryn I. Alpert, Carrie E. Bearden, Alessandro Bertolino, Catherine Bois, Aurora Bonvino, Elvira Bramon, Elizabeth E. L. Buimer, Wiepke Cahn, Dara M. Cannon, Tyrone D. Cannon, Xavier Caseras, Josefina Castro-Fornieles, Qiang Chen, Yoonho Chung, Elena De la SernaAnnabella Di Giorgio, Gaelle E. Doucet, Mehmet Cagdas Eker, Susanne Erk, Scott C. Fears, Sonya F. Foley, Sophia Frangou, Andrew Frankland, Janice M. Fullerton, David C. Glahn, Vina M. Goghari, Aaron L. Goldman, Ali Saffet Gonul, Oliver Gruber, Lieuwe de Haan, Tomas Hajek, Emma L. Hawkins, Andreas Heinz, Manon H. J. Hillegers, Hilleke E. Hulshoff Pol, Christina M. Hultman, Martin Ingvar, Viktoria Johansson, Erik G. Jonsson, Fergus Kane, Matthew J. Kempton, Marinka M. G. Koenis, Miloslav Kopecek, Lydia Krabbendam, Bernd Kraemer, Stephen M. Lawrie, Rhoshel K. Lenroot, Machteld Marcelis, Jan-Bernard C. Marsman, Venkata S. Mattay, Colm McDonald, Andreas Meyer-Lindenberg, Stijn Michielse, Philip B. Mitchell, Dolores Moreno, Robin M. Murray, Benson Mwangi, Pablo Najt, Emma Neilson, Jason Newport, Jim van Os, Bronwyn Overs, Aysegul Ozerdem, Marco M. Picchioni, Anja Richter, Gloria Roberts, Aybala Saricicek Aydogan, Peter R. Schofield, Fatma Simsek, Jair C. Soares, Gisela Sugranyes, Timothea Toulopoulou, Giulia Tronchin, Henrik Walter, Lei Wang, Daniel R. Weinberger, Heather C. Whalley, Nefize Yalin, Ole A. Andreassen, Christopher R. K. Ching, Theo G. M. van Erp, Jessica A. Turner, Neda Jahanshad, Paul M. Thompson, Rene S. Kahn, Neeltje E. M. van Haren

^*Corresponding author for this work

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

Abstract

BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.

METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.

RESULTS: FDRs-BD had significantly larger ICV (d = +10.16, q <.05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q <.05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d <-0.09, q <.05 corrected); and third ventricle was larger (d = +0.15, q <.05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.

CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

Original language	English
Pages (from-to)	545-556
Number of pages	12
Journal	Biological Psychiatry
Volume	86
Issue number	7
DOIs	https://doi.org/10.1016/j.biopsych.2019.03.985
Publication status	Published - 1 Oct 2019

Keywords

Bipolar disorder
Familial risk
Imaging
Meta-analysis
Neurodevelopment
Schizophrenia
GRAY-MATTER VOLUME
VOXEL-BASED MORPHOMETRY
HIGH GENETIC RISK
SOCIOECONOMIC-STATUS
SCHOOL PERFORMANCE
TWINS DISCORDANT
PREMORBID IQ
METAANALYSIS
CHILDHOOD
PREDISPOSITION

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de Zwarte, S. M. C., Brouwer, R. M., Agartz, I., Alda, M., Aleman, A., Alpert, K. I., Bearden, C. E., Bertolino, A., Bois, C., Bonvino, A., Bramon, E., Buimer, E. E. L., Cahn, W., Cannon, D. M., Cannon, T. D., Caseras, X., Castro-Fornieles, J., Chen, Q., Chung, Y., ... van Haren, N. E. M. (2019). The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder. Biological Psychiatry, 86(7), 545-556. https://doi.org/10.1016/j.biopsych.2019.03.985

@article{a6f16ecc5fe54aa8befc928fcaf8245a,

title = "The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder",

abstract = "BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.RESULTS: FDRs-BD had significantly larger ICV (d = +10.16, q <.05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q <.05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d <-0.09, q <.05 corrected); and third ventricle was larger (d = +0.15, q <.05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.",

keywords = "Bipolar disorder, Familial risk, Imaging, Meta-analysis, Neurodevelopment, Schizophrenia, GRAY-MATTER VOLUME, VOXEL-BASED MORPHOMETRY, HIGH GENETIC RISK, SOCIOECONOMIC-STATUS, SCHOOL PERFORMANCE, TWINS DISCORDANT, PREMORBID IQ, METAANALYSIS, CHILDHOOD, PREDISPOSITION",

author = "{de Zwarte}, {Sonja M. C.} and Brouwer, {Rachel M.} and Ingrid Agartz and Martin Alda and Andre Aleman and Alpert, {Kathryn I.} and Bearden, {Carrie E.} and Alessandro Bertolino and Catherine Bois and Aurora Bonvino and Elvira Bramon and Buimer, {Elizabeth E. L.} and Wiepke Cahn and Cannon, {Dara M.} and Cannon, {Tyrone D.} and Xavier Caseras and Josefina Castro-Fornieles and Qiang Chen and Yoonho Chung and {De la Serna}, Elena and {Di Giorgio}, Annabella and Doucet, {Gaelle E.} and Eker, {Mehmet Cagdas} and Susanne Erk and Fears, {Scott C.} and Foley, {Sonya F.} and Sophia Frangou and Andrew Frankland and Fullerton, {Janice M.} and Glahn, {David C.} and Goghari, {Vina M.} and Goldman, {Aaron L.} and Gonul, {Ali Saffet} and Oliver Gruber and {de Haan}, Lieuwe and Tomas Hajek and Hawkins, {Emma L.} and Andreas Heinz and Hillegers, {Manon H. J.} and Pol, {Hilleke E. Hulshoff} and Hultman, {Christina M.} and Martin Ingvar and Viktoria Johansson and Jonsson, {Erik G.} and Fergus Kane and Kempton, {Matthew J.} and Koenis, {Marinka M. G.} and Miloslav Kopecek and Lydia Krabbendam and Bernd Kraemer and Lawrie, {Stephen M.} and Lenroot, {Rhoshel K.} and Machteld Marcelis and Marsman, {Jan-Bernard C.} and Mattay, {Venkata S.} and Colm McDonald and Andreas Meyer-Lindenberg and Stijn Michielse and Mitchell, {Philip B.} and Dolores Moreno and Murray, {Robin M.} and Benson Mwangi and Pablo Najt and Emma Neilson and Jason Newport and {van Os}, Jim and Bronwyn Overs and Aysegul Ozerdem and Picchioni, {Marco M.} and Anja Richter and Gloria Roberts and Aydogan, {Aybala Saricicek} and Schofield, {Peter R.} and Fatma Simsek and Soares, {Jair C.} and Gisela Sugranyes and Timothea Toulopoulou and Giulia Tronchin and Henrik Walter and Lei Wang and Weinberger, {Daniel R.} and Whalley, {Heather C.} and Nefize Yalin and Andreassen, {Ole A.} and Ching, {Christopher R. K.} and {van Erp}, {Theo G. M.} and Turner, {Jessica A.} and Neda Jahanshad and Thompson, {Paul M.} and Kahn, {Rene S.} and {van Haren}, {Neeltje E. M.}",

note = "Funding Information: MSSM: This work was supported by NIMH (Grant Nos. R01 MH116147 and R01 MH113619 ). Funding Information: MFS: The Maudsley Family Study cohort collection was supported by the Wellcome Trust (Grant Nos. 085475/B/08/Z and 085475/Z/08/Z ), NIHR Biomedical Research Centre at University College London Hospital, Medical Research Council (Grant No. G0901310 ), and British Medical Association Margaret Temple Fellowship 2016. Funding Information: The researchers and studies included in this article were supported by the Research Council of Norway (Grant No. 223273), National Institutes of Health (NIH) (Grant No. R01 MH117601 [to NJ], Grant Nos. R01 MH116147, R01 MH111671, and P41 EB015922 [to PMT], Grant Nos. 5T32MH073526 and U54EB020403 [to CRKC], and Grant No. R03 MH105808 [to CEB and SCF]) and National Institute on Aging (NIA) (Grant No. T32AG058507 [to CRKC]). C-SFS: This work was supported by Canadian Institutes of Health Research. Cardiff: This work was supported by the National Centre for Mental Health, Bipolar Disorder Research Network, 2010 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (Grant No. 17319). DEU: This work was supported by Dokuz Eylul University Department of Scientific Research Projects Funding (Grant No. 2012.KB.SAG.062). This report represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or Department of Health. EGEU: This work was supported by the Ege University School of Medicine Research Foundation (Grant No. 2009-D-00017). EHRS: The Edinburgh High Risk Study was supported by the Medical Research Council. GROUP: The infrastructure for the GROUP study was supported by the Geestkracht program of the Netherlands Organisation for Health Research and Development (Grant No. 10-000-1002). ENBD_UT/BPO_FLB: This work was supported by the National Institute of Mental Health (Grant No. R01 MH 085667). HHR/PHHR: This work was supported by the Canadian Institutes of Health Research (Grant Nos. 103703, 106469, and 341717), Nova Scotia Health Research Foundation, Dalhousie Clinical Research Scholarship (to TH), 2007 Brain and Behavior Research Foundation Young Investigator Award (to TH), and Ministry of Health of the Czech Republic (Grant Nos. NR8786 and NT13891). HUBIN: This work was supported by the Swedish Research Council (Grant Nos. K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3), regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, Knut and Alice Wallenberg Foundation, and HUBIN project. IDIBAPS: This work was supported by the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI070066, PI1100683, and PI1500467) and Fundacio Marato TV3 (Grant No. 091630), co-financed by ERDF Funds from the European Commission (?A Way of Making Europe?), Brain and Behaviour Research Foundation (NARSAD Young Investigator Award), and Alicia Koplowitz Foundation. IoP-BD: The Maudsley Bipolar Twin Study was supported by the Stanley Medical Research Institute and NARSAD. IoP-SZ: This work was supported by a Wellcome Trust Research Training Fellowship (Grant No. 064971 to MMP), NARSAD Young Investigator Award (to TT), and European Community's Sixth Framework Programme through a Marie Curie Training Network called the European Twin Study Network on Schizophrenia. Lieber Institute for Brain Development (LIBD): This work was supported by the NIMH Intramural Research Program (to DRW's laboratory). LIBD is a nonprofit research institute located in Baltimore, MD. The work performed at LIBD was performed in accordance with an NIMH material transfer agreement with LIBD. MFS: The Maudsley Family Study cohort collection was supported by the Wellcome Trust (Grant Nos. 085475/B/08/Z and 085475/Z/08/Z), NIHR Biomedical Research Centre at University College London Hospital, Medical Research Council (Grant No. G0901310), and British Medical Association Margaret Temple Fellowship 2016. MooDS: This work was supported by the German Federal Ministry for Education and Research grants NGFNplus MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) and Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med program (Grant Nos. O1ZX1314B and O1ZX1314G) and Deutsche Forschungsgemeinschaft (Grant No. 1617 [to AH]). MSSM: This work was supported by NIMH (Grant Nos. R01 MH116147 and R01 MH113619). NU: This work was supported by NIH (Grant Nos. U01 MH097435, R01 MH084803, and R01 EB020062) and National Science Foundation (Grant Nos. 1636893 and 1734853). OLIN: This work was supported by NIH (Grant No. R01 MH080912). STAR: This work was supported by NIH (Grant No. R01 MH052857). SydneyBipolarGroup: The Australian cohort collection was supported by the Australian National Health and Medical Research Council Program Grants (Grant No. 510135 [to PBM] and Grant No. 1037196 [to PBM and PRS]) and Project Grants (Grant No. 1063960 [to JMF and PRS] and Grant No. 1066177 [to JMF]). UMCU: This work was supported by NARSAD (Grant No. 20244 [to MHJH]), ZonMw (Grant No. 908-02-123 [to HEHP]), VIDI (Grant No. 452-11-014 [to NEMvH] and Grant No. 917-46-370 [to HEHP]), and Stanley Medical Research Institute. CliNG: We thank Anna Fanelli, Kathrin Jakob, and Maria Keil for help with data acquisition. All authors have contributed to and approved the contents of this manuscript. GS has received research and travel support from Janssen Pharmaceutica and Otsuka Pharmaceutical and honoraria from Adamed Pharma. NY has been an investigator in clinical studies conducted together with Janssen-Cilag, Corcept Therapeutics, and COMPASS Pathways in the last 3 years. AM-L has received consultant fees from Boehringer Ingelheim, BrainsWay, Elsevier, Lundbeck International Neuroscience Foundation, and Science Advances. CRKC has received partial research support from Biogen, Inc. (Boston, MA) for work unrelated to the topic of this manuscript. The remaining authors report no biomedical financial interests or potential conflicts of interest. Funding Information: MooDS: This work was supported by the German Federal Ministry for Education and Research grants NGFNplus MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) and Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med program (Grant Nos. O1ZX1314B and O1ZX1314G ) and Deutsche Forschungsgemeinschaft (Grant No. 1617 [to AH]). Funding Information: GS has received research and travel support from Janssen Pharmaceutica and Otsuka Pharmaceutical and honoraria from Adamed Pharma. NY has been an investigator in clinical studies conducted together with Janssen-Cilag, Corcept Therapeutics, and COMPASS Pathways in the last 3 years. AM-L has received consultant fees from Boehringer Ingelheim , BrainsWay , Elsevier , Lundbeck International Neuroscience Foundation, and Science Advances. CRKC has received partial research support from Biogen, Inc. (Boston, MA) for work unrelated to the topic of this manuscript. The remaining authors report no biomedical financial interests or potential conflicts of interest. Funding Information: Cardiff: This work was supported by the National Centre for Mental Health , Bipolar Disorder Research Network , 2010 National Alliance for Research on Schizophrenia and Depression ( NARSAD ) Young Investigator Award (Grant No. 17319 ). Funding Information: HHR/PHHR: This work was supported by the Canadian Institutes of Health Research (Grant Nos. 103703 , 106469 , and 341717 ), Nova Scotia Health Research Foundation , Dalhousie Clinical Research Scholarship (to TH), 2007 Brain and Behavior Research Foundation Young Investigator Award (to TH), and Ministry of Health of the Czech Republic (Grant Nos. NR8786 and NT13891 ). Funding Information: OLIN: This work was supported by NIH (Grant No. R01 MH080912 ). Funding Information: GROUP: The infrastructure for the GROUP study was supported by the Geestkracht program of the Netherlands Organisation for Health Research and Development (Grant No. 10-000-1002 ). Funding Information: HUBIN: This work was supported by the Swedish Research Council (Grant Nos. K2007-62X-15077-04-1 , K2008-62P-20597-01-3 , K2010-62X-15078-07-2 , K2012-61X-15078-09-3 ), regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, Knut and Alice Wallenberg Foundation, and HUBIN project. Funding Information: ENBD_UT/BPO_FLB: This work was supported by the National Institute of Mental Health (Grant No. R01 MH 085667 ). Funding Information: STAR: This work was supported by NIH (Grant No. R01 MH052857 ). Funding Information: NU: This work was supported by NIH (Grant Nos. U01 MH097435 , R01 MH084803 , and R01 EB020062 ) and National Science Foundation (Grant Nos. 1636893 and 1734853 ). Funding Information: SydneyBipolarGroup: The Australian cohort collection was supported by the Australian National Health and Medical Research Council Program Grants (Grant No. 510135 [to PBM] and Grant No. 1037196 [to PBM and PRS]) and Project Grants (Grant No. 1063960 [to JMF and PRS] and Grant No. 1066177 [to JMF]). Funding Information: C-SFS: This work was supported by Canadian Institutes of Health Research . Funding Information: The researchers and studies included in this article were supported by the Research Council of Norway (Grant No. 223273 ), National Institutes of Health (NIH) (Grant No. R01 MH117601 [to NJ], Grant Nos. R01 MH116147 , R01 MH111671 , and P41 EB015922 [to PMT], Grant Nos. 5T32MH073526 and U54EB020403 [to CRKC], and Grant No. R03 MH105808 [to CEB and SCF]) and National Institute on Aging (NIA) (Grant No. T32AG058507 [to CRKC]). Funding Information: DEU: This work was supported by Dokuz Eylul University Department of Scientific Research Projects Funding (Grant No. 2012.KB.SAG.062 ). This report represents independent research funded by the National Institute for Health Research ( NIHR ) Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King{\textquoteright}s College London . The views expressed are those of the authors and not necessarily those of the National Health Service , NIHR , or Department of Health . Funding Information: EGEU: This work was supported by the Ege University School of Medicine Research Foundation (Grant No. 2009-D-00017 ). Funding Information: IDIBAPS: This work was supported by the Spanish Ministry of Economy and Competitiveness / Instituto de Salud Carlos III (Grant Nos. PI070066 , PI1100683 , and PI1500467 ) and Fundacio Marato TV3 (Grant No. 091630 ), co-financed by ERDF Funds from the European Commission (“A Way of Making Europe”), Brain and Behaviour Research Foundation ( NARSAD Young Investigator Award), and Alicia Koplowitz Foundation . Funding Information: IoP-SZ: This work was supported by a Wellcome Trust Research Training Fellowship (Grant No. 064971 to MMP), NARSAD Young Investigator Award (to TT), and European Community{\textquoteright}s Sixth Framework Programme through a Marie Curie Training Network called the European Twin Study Network on Schizophrenia. Funding Information: UMCU: This work was supported by NARSAD (Grant No. 20244 [to MHJH]), ZonMw (Grant No. 908-02-123 [to HEHP]), VIDI (Grant No. 452-11-014 [to NEMvH] and Grant No. 917-46-370 [to HEHP]), and Stanley Medical Research Institute . Publisher Copyright: {\textcopyright} 2019 Society of Biological Psychiatry",

year = "2019",

month = oct,

day = "1",

doi = "10.1016/j.biopsych.2019.03.985",

language = "English",

volume = "86",

pages = "545--556",

journal = "Biological Psychiatry",

issn = "0006-3223",

publisher = "Elsevier Science",

number = "7",

}

de Zwarte, SMC, Brouwer, RM, Agartz, I, Alda, M, Aleman, A, Alpert, KI, Bearden, CE, Bertolino, A, Bois, C, Bonvino, A, Bramon, E, Buimer, EEL, Cahn, W, Cannon, DM, Cannon, TD, Caseras, X, Castro-Fornieles, J, Chen, Q, Chung, Y, De la Serna, E, Di Giorgio, A, Doucet, GE, Eker, MC, Erk, S, Fears, SC, Foley, SF, Frangou, S, Frankland, A, Fullerton, JM, Glahn, DC, Goghari, VM, Goldman, AL, Gonul, AS, Gruber, O, de Haan, L, Hajek, T, Hawkins, EL, Heinz, A, Hillegers, MHJ, Pol, HEH, Hultman, CM, Ingvar, M, Johansson, V, Jonsson, EG, Kane, F, Kempton, MJ, Koenis, MMG, Kopecek, M, Krabbendam, L, Kraemer, B, Lawrie, SM, Lenroot, RK, Marcelis, M, Marsman, J-BC, Mattay, VS, McDonald, C, Meyer-Lindenberg, A, Michielse, S, Mitchell, PB, Moreno, D, Murray, RM, Mwangi, B, Najt, P, Neilson, E, Newport, J, van Os, J, Overs, B, Ozerdem, A, Picchioni, MM, Richter, A, Roberts, G, Aydogan, AS, Schofield, PR, Simsek, F, Soares, JC, Sugranyes, G, Toulopoulou, T, Tronchin, G, Walter, H, Wang, L, Weinberger, DR, Whalley, HC, Yalin, N, Andreassen, OA, Ching, CRK, van Erp, TGM, Turner, JA, Jahanshad, N, Thompson, PM, Kahn, RS & van Haren, NEM 2019, 'The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder', Biological Psychiatry, vol. 86, no. 7, pp. 545-556. https://doi.org/10.1016/j.biopsych.2019.03.985

TY - JOUR

T1 - The Association Between Familial Risk and Brain Abnormalities Is Disease Specific

T2 - An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder

AU - de Zwarte, Sonja M. C.

AU - Brouwer, Rachel M.

AU - Agartz, Ingrid

AU - Alda, Martin

AU - Aleman, Andre

AU - Alpert, Kathryn I.

AU - Bearden, Carrie E.

AU - Bertolino, Alessandro

AU - Bois, Catherine

AU - Bonvino, Aurora

AU - Bramon, Elvira

AU - Buimer, Elizabeth E. L.

AU - Cahn, Wiepke

AU - Cannon, Dara M.

AU - Cannon, Tyrone D.

AU - Caseras, Xavier

AU - Castro-Fornieles, Josefina

AU - Chen, Qiang

AU - Chung, Yoonho

AU - De la Serna, Elena

AU - Di Giorgio, Annabella

AU - Doucet, Gaelle E.

AU - Eker, Mehmet Cagdas

AU - Erk, Susanne

AU - Fears, Scott C.

AU - Foley, Sonya F.

AU - Frangou, Sophia

AU - Frankland, Andrew

AU - Fullerton, Janice M.

AU - Glahn, David C.

AU - Goghari, Vina M.

AU - Goldman, Aaron L.

AU - Gonul, Ali Saffet

AU - Gruber, Oliver

AU - de Haan, Lieuwe

AU - Hajek, Tomas

AU - Hawkins, Emma L.

AU - Heinz, Andreas

AU - Hillegers, Manon H. J.

AU - Pol, Hilleke E. Hulshoff

AU - Hultman, Christina M.

AU - Ingvar, Martin

AU - Johansson, Viktoria

AU - Jonsson, Erik G.

AU - Kane, Fergus

AU - Kempton, Matthew J.

AU - Koenis, Marinka M. G.

AU - Kopecek, Miloslav

AU - Krabbendam, Lydia

AU - Kraemer, Bernd

AU - Lawrie, Stephen M.

AU - Lenroot, Rhoshel K.

AU - Marcelis, Machteld

AU - Marsman, Jan-Bernard C.

AU - Mattay, Venkata S.

AU - McDonald, Colm

AU - Meyer-Lindenberg, Andreas

AU - Michielse, Stijn

AU - Mitchell, Philip B.

AU - Moreno, Dolores

AU - Murray, Robin M.

AU - Mwangi, Benson

AU - Najt, Pablo

AU - Neilson, Emma

AU - Newport, Jason

AU - van Os, Jim

AU - Overs, Bronwyn

AU - Ozerdem, Aysegul

AU - Picchioni, Marco M.

AU - Richter, Anja

AU - Roberts, Gloria

AU - Aydogan, Aybala Saricicek

AU - Schofield, Peter R.

AU - Simsek, Fatma

AU - Soares, Jair C.

AU - Sugranyes, Gisela

AU - Toulopoulou, Timothea

AU - Tronchin, Giulia

AU - Walter, Henrik

AU - Wang, Lei

AU - Weinberger, Daniel R.

AU - Whalley, Heather C.

AU - Yalin, Nefize

AU - Andreassen, Ole A.

AU - Ching, Christopher R. K.

AU - van Erp, Theo G. M.

AU - Turner, Jessica A.

AU - Jahanshad, Neda

AU - Thompson, Paul M.

AU - Kahn, Rene S.

AU - van Haren, Neeltje E. M.

N1 - Funding Information: MSSM: This work was supported by NIMH (Grant Nos. R01 MH116147 and R01 MH113619 ). Funding Information: MFS: The Maudsley Family Study cohort collection was supported by the Wellcome Trust (Grant Nos. 085475/B/08/Z and 085475/Z/08/Z ), NIHR Biomedical Research Centre at University College London Hospital, Medical Research Council (Grant No. G0901310 ), and British Medical Association Margaret Temple Fellowship 2016. Funding Information: The researchers and studies included in this article were supported by the Research Council of Norway (Grant No. 223273), National Institutes of Health (NIH) (Grant No. R01 MH117601 [to NJ], Grant Nos. R01 MH116147, R01 MH111671, and P41 EB015922 [to PMT], Grant Nos. 5T32MH073526 and U54EB020403 [to CRKC], and Grant No. R03 MH105808 [to CEB and SCF]) and National Institute on Aging (NIA) (Grant No. T32AG058507 [to CRKC]). C-SFS: This work was supported by Canadian Institutes of Health Research. Cardiff: This work was supported by the National Centre for Mental Health, Bipolar Disorder Research Network, 2010 National Alliance for Research on Schizophrenia and Depression (NARSAD) Young Investigator Award (Grant No. 17319). DEU: This work was supported by Dokuz Eylul University Department of Scientific Research Projects Funding (Grant No. 2012.KB.SAG.062). This report represents independent research funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the National Health Service, NIHR, or Department of Health. EGEU: This work was supported by the Ege University School of Medicine Research Foundation (Grant No. 2009-D-00017). EHRS: The Edinburgh High Risk Study was supported by the Medical Research Council. GROUP: The infrastructure for the GROUP study was supported by the Geestkracht program of the Netherlands Organisation for Health Research and Development (Grant No. 10-000-1002). ENBD_UT/BPO_FLB: This work was supported by the National Institute of Mental Health (Grant No. R01 MH 085667). HHR/PHHR: This work was supported by the Canadian Institutes of Health Research (Grant Nos. 103703, 106469, and 341717), Nova Scotia Health Research Foundation, Dalhousie Clinical Research Scholarship (to TH), 2007 Brain and Behavior Research Foundation Young Investigator Award (to TH), and Ministry of Health of the Czech Republic (Grant Nos. NR8786 and NT13891). HUBIN: This work was supported by the Swedish Research Council (Grant Nos. K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3), regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, Knut and Alice Wallenberg Foundation, and HUBIN project. IDIBAPS: This work was supported by the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI070066, PI1100683, and PI1500467) and Fundacio Marato TV3 (Grant No. 091630), co-financed by ERDF Funds from the European Commission (?A Way of Making Europe?), Brain and Behaviour Research Foundation (NARSAD Young Investigator Award), and Alicia Koplowitz Foundation. IoP-BD: The Maudsley Bipolar Twin Study was supported by the Stanley Medical Research Institute and NARSAD. IoP-SZ: This work was supported by a Wellcome Trust Research Training Fellowship (Grant No. 064971 to MMP), NARSAD Young Investigator Award (to TT), and European Community's Sixth Framework Programme through a Marie Curie Training Network called the European Twin Study Network on Schizophrenia. Lieber Institute for Brain Development (LIBD): This work was supported by the NIMH Intramural Research Program (to DRW's laboratory). LIBD is a nonprofit research institute located in Baltimore, MD. The work performed at LIBD was performed in accordance with an NIMH material transfer agreement with LIBD. MFS: The Maudsley Family Study cohort collection was supported by the Wellcome Trust (Grant Nos. 085475/B/08/Z and 085475/Z/08/Z), NIHR Biomedical Research Centre at University College London Hospital, Medical Research Council (Grant No. G0901310), and British Medical Association Margaret Temple Fellowship 2016. MooDS: This work was supported by the German Federal Ministry for Education and Research grants NGFNplus MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) and Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med program (Grant Nos. O1ZX1314B and O1ZX1314G) and Deutsche Forschungsgemeinschaft (Grant No. 1617 [to AH]). MSSM: This work was supported by NIMH (Grant Nos. R01 MH116147 and R01 MH113619). NU: This work was supported by NIH (Grant Nos. U01 MH097435, R01 MH084803, and R01 EB020062) and National Science Foundation (Grant Nos. 1636893 and 1734853). OLIN: This work was supported by NIH (Grant No. R01 MH080912). STAR: This work was supported by NIH (Grant No. R01 MH052857). SydneyBipolarGroup: The Australian cohort collection was supported by the Australian National Health and Medical Research Council Program Grants (Grant No. 510135 [to PBM] and Grant No. 1037196 [to PBM and PRS]) and Project Grants (Grant No. 1063960 [to JMF and PRS] and Grant No. 1066177 [to JMF]). UMCU: This work was supported by NARSAD (Grant No. 20244 [to MHJH]), ZonMw (Grant No. 908-02-123 [to HEHP]), VIDI (Grant No. 452-11-014 [to NEMvH] and Grant No. 917-46-370 [to HEHP]), and Stanley Medical Research Institute. CliNG: We thank Anna Fanelli, Kathrin Jakob, and Maria Keil for help with data acquisition. All authors have contributed to and approved the contents of this manuscript. GS has received research and travel support from Janssen Pharmaceutica and Otsuka Pharmaceutical and honoraria from Adamed Pharma. NY has been an investigator in clinical studies conducted together with Janssen-Cilag, Corcept Therapeutics, and COMPASS Pathways in the last 3 years. AM-L has received consultant fees from Boehringer Ingelheim, BrainsWay, Elsevier, Lundbeck International Neuroscience Foundation, and Science Advances. CRKC has received partial research support from Biogen, Inc. (Boston, MA) for work unrelated to the topic of this manuscript. The remaining authors report no biomedical financial interests or potential conflicts of interest. Funding Information: MooDS: This work was supported by the German Federal Ministry for Education and Research grants NGFNplus MooDS (Systematic Investigation of the Molecular Causes of Major Mood Disorders and Schizophrenia) and Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med program (Grant Nos. O1ZX1314B and O1ZX1314G ) and Deutsche Forschungsgemeinschaft (Grant No. 1617 [to AH]). Funding Information: GS has received research and travel support from Janssen Pharmaceutica and Otsuka Pharmaceutical and honoraria from Adamed Pharma. NY has been an investigator in clinical studies conducted together with Janssen-Cilag, Corcept Therapeutics, and COMPASS Pathways in the last 3 years. AM-L has received consultant fees from Boehringer Ingelheim , BrainsWay , Elsevier , Lundbeck International Neuroscience Foundation, and Science Advances. CRKC has received partial research support from Biogen, Inc. (Boston, MA) for work unrelated to the topic of this manuscript. The remaining authors report no biomedical financial interests or potential conflicts of interest. Funding Information: Cardiff: This work was supported by the National Centre for Mental Health , Bipolar Disorder Research Network , 2010 National Alliance for Research on Schizophrenia and Depression ( NARSAD ) Young Investigator Award (Grant No. 17319 ). Funding Information: HHR/PHHR: This work was supported by the Canadian Institutes of Health Research (Grant Nos. 103703 , 106469 , and 341717 ), Nova Scotia Health Research Foundation , Dalhousie Clinical Research Scholarship (to TH), 2007 Brain and Behavior Research Foundation Young Investigator Award (to TH), and Ministry of Health of the Czech Republic (Grant Nos. NR8786 and NT13891 ). Funding Information: OLIN: This work was supported by NIH (Grant No. R01 MH080912 ). Funding Information: GROUP: The infrastructure for the GROUP study was supported by the Geestkracht program of the Netherlands Organisation for Health Research and Development (Grant No. 10-000-1002 ). Funding Information: HUBIN: This work was supported by the Swedish Research Council (Grant Nos. K2007-62X-15077-04-1 , K2008-62P-20597-01-3 , K2010-62X-15078-07-2 , K2012-61X-15078-09-3 ), regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, Knut and Alice Wallenberg Foundation, and HUBIN project. Funding Information: ENBD_UT/BPO_FLB: This work was supported by the National Institute of Mental Health (Grant No. R01 MH 085667 ). Funding Information: STAR: This work was supported by NIH (Grant No. R01 MH052857 ). Funding Information: NU: This work was supported by NIH (Grant Nos. U01 MH097435 , R01 MH084803 , and R01 EB020062 ) and National Science Foundation (Grant Nos. 1636893 and 1734853 ). Funding Information: SydneyBipolarGroup: The Australian cohort collection was supported by the Australian National Health and Medical Research Council Program Grants (Grant No. 510135 [to PBM] and Grant No. 1037196 [to PBM and PRS]) and Project Grants (Grant No. 1063960 [to JMF and PRS] and Grant No. 1066177 [to JMF]). Funding Information: C-SFS: This work was supported by Canadian Institutes of Health Research . Funding Information: The researchers and studies included in this article were supported by the Research Council of Norway (Grant No. 223273 ), National Institutes of Health (NIH) (Grant No. R01 MH117601 [to NJ], Grant Nos. R01 MH116147 , R01 MH111671 , and P41 EB015922 [to PMT], Grant Nos. 5T32MH073526 and U54EB020403 [to CRKC], and Grant No. R03 MH105808 [to CEB and SCF]) and National Institute on Aging (NIA) (Grant No. T32AG058507 [to CRKC]). Funding Information: DEU: This work was supported by Dokuz Eylul University Department of Scientific Research Projects Funding (Grant No. 2012.KB.SAG.062 ). This report represents independent research funded by the National Institute for Health Research ( NIHR ) Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London . The views expressed are those of the authors and not necessarily those of the National Health Service , NIHR , or Department of Health . Funding Information: EGEU: This work was supported by the Ege University School of Medicine Research Foundation (Grant No. 2009-D-00017 ). Funding Information: IDIBAPS: This work was supported by the Spanish Ministry of Economy and Competitiveness / Instituto de Salud Carlos III (Grant Nos. PI070066 , PI1100683 , and PI1500467 ) and Fundacio Marato TV3 (Grant No. 091630 ), co-financed by ERDF Funds from the European Commission (“A Way of Making Europe”), Brain and Behaviour Research Foundation ( NARSAD Young Investigator Award), and Alicia Koplowitz Foundation . Funding Information: IoP-SZ: This work was supported by a Wellcome Trust Research Training Fellowship (Grant No. 064971 to MMP), NARSAD Young Investigator Award (to TT), and European Community’s Sixth Framework Programme through a Marie Curie Training Network called the European Twin Study Network on Schizophrenia. Funding Information: UMCU: This work was supported by NARSAD (Grant No. 20244 [to MHJH]), ZonMw (Grant No. 908-02-123 [to HEHP]), VIDI (Grant No. 452-11-014 [to NEMvH] and Grant No. 917-46-370 [to HEHP]), and Stanley Medical Research Institute . Publisher Copyright: © 2019 Society of Biological Psychiatry

PY - 2019/10/1

Y1 - 2019/10/1

N2 - BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.RESULTS: FDRs-BD had significantly larger ICV (d = +10.16, q <.05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q <.05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d <-0.09, q <.05 corrected); and third ventricle was larger (d = +0.15, q <.05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

AB - BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.RESULTS: FDRs-BD had significantly larger ICV (d = +10.16, q <.05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q <.05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d <-0.09, q <.05 corrected); and third ventricle was larger (d = +0.15, q <.05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.

KW - Bipolar disorder

KW - Familial risk

KW - Imaging

KW - Meta-analysis

KW - Neurodevelopment

KW - Schizophrenia

KW - GRAY-MATTER VOLUME

KW - VOXEL-BASED MORPHOMETRY

KW - HIGH GENETIC RISK

KW - SOCIOECONOMIC-STATUS

KW - SCHOOL PERFORMANCE

KW - TWINS DISCORDANT

KW - PREMORBID IQ

KW - METAANALYSIS

KW - CHILDHOOD

KW - PREDISPOSITION

U2 - 10.1016/j.biopsych.2019.03.985

DO - 10.1016/j.biopsych.2019.03.985

M3 - Article

C2 - 31443932

SN - 0006-3223

VL - 86

SP - 545

EP - 556

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 7

ER -

The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder

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