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 | |
| 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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In: Biological Psychiatry, Vol. 86, No. 7, 01.10.2019, p. 545-556.
Research output: Contribution to journal › Article › Academic › peer-review
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 -