First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d = −0.42, p = 3 × 10−5), with weak evidence of IQ reductions among BD-FDRs (d = −0.23, p =.045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.
Bibliographical noteFunding 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 Neda Jahanshad], Grant Nos. R01 MH116147, R01 MH111671, and P41 EB015922 [to Paul M. Thompson], Grant No. U54EB020403 [to Paul M. Thompson, Christopher R. K. Ching, Theo G. M. van Erp and Sophia I. Thomopoulos], Grant No. R03 MH105808 [to Carrie E. Bearden and Scott C. Fears], Grant Nos. R01MH116147, and R01MH121246 [to Theo G. M. van Erp]) and National Institute on Aging (NIA) (Grant No. T32AG058507 [to Christopher R. K. Ching]). : This work was supported by Canadian Institutes of Health Research. Vina M. Goghari was supported by a Canadian Institutes of Health Research New Investigator Award. : 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). : We thank Anna Fanelli, Kathrin Jakob, and Maria Keil for help with data acquisition. : This work was supported by the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III (CPII19/00009), co‐financed by ERDF Funds from the European Commission (“A Way of Making Europe”), and the Departament de Salut de la Generalitat de Catalunya (SLT002/16/00331). Eduard Vieta thanks the support of the Spanish Ministry of Science, Innovation and Universities (PI15/00283) integrated into the Plan Nacional de I+D+I y cofinanciado por el ISCIII‐Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER); CIBERSAM; and the Comissionat per a Universitats i Recerca del DIUE de la Generalitat de Catalunya to the Bipolar Disorders Group (2017 SGR 1365) and the project SLT006/17/00357, from PERIS 2016‐2020 (Departament de Salut). CERCA Programme/Generalitat de Catalunya. : This work was supported by Dokuz Eylül Üniversitesi 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. : This work was supported by the Ege Üniversitesi School of Medicine Research Foundation (Grant No. 2009‐D‐00017). : The Edinburgh High Risk Study was supported by the Medical Research Council. : This work was supported by the National Institute of Mental Health (Grant No. R01 MH085667). : This work was supported by the Generalitat de Catalunya (2017SGR01271) and several grants funded by Instituto de Salud Carlos III co‐funded by the European Regional Development Fund/European Social Fund “Investing in your future”: Miguel Servet Research Contract (CPII16/00018 [to Edith Pomarol‐Clotet]), Sara Borrell Research Contract (CD16/00264 [to Mar Fatjó‐Vilas] and CD18/00029 [to Erick J. Canales‐Rodríguez]), and Research Projects (PI15/00277 [to Erick J. Canales‐Rodríguez], PI18/00810 [to Edith Pomarol‐Clotet] and PI18/00877 [to Raymond Salvador]). The funding organizations played no role in the study design, data collection and analysis, or manuscript approval. : The study is supported by the Swiss National Center of Competence in Research; “Synapsy: the Synaptic Basis of Mental Diseases” (No.: 51NF40‐185897), as well as a grant of the Swiss National Science Foundation (No.: 32003B_156914). : The infrastructure for the GROUP study was supported by the Geestkracht program of the ZonMw (Grant No. 10‐000‐1002). : 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 Stockholms Läns Landsting and the Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, and HUBIN project. : This work was supported by the Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III (Grant Nos. PI070066, PI1100683, and PI1500467, PI18/00976) and Fundacio Marato TV3 (Grant No. 091630), co‐financed by ERDF Funds from the European Commission (“A Way of Making Europe”), Brain and Behavior Research Foundation (NARSAD) 2017 Young Investigator Award (Grant No. 26731 [to Gisela Sugranyes]), Fundación Alicia Koplowitz and Ajut a la Recerca Pons Bartran. : The Maudsley Bipolar Twin Study was supported by the Stanley Medical Research Institute and NARSAD. : This work was supported by a Wellcome Trust Research Training Fellowship (Grant No. 064971 to Timothea Toulopoulou), NARSAD Young Investigator Award [to Timothea Toulopoulou], and European Community's Sixth Framework Programme through a Marie Curie Training Network called the European Twin Study Network on Schizophrenia. : This work was supported by the National Institute of Mental Health Intramural Research Program (to Daniel R. Weinberger's laboratory). Lieber Institute for Brain Development (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. : The Maudsley Family Study cohort was supported by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust at King’s College London and by the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and UCL. Support to Elvira Bramon: The Wellcome Trust (Grant Nos. 085475/B/08/Z and 085475/Z/08/Z), Medical Research Council (Grant No. G0901310), British Medical Association Margaret Temple Fellowship 2016, Mental Health Research UK John Grace QC award and NIHR RfPB grant (Grant No. NIHR200756).: 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 Andreas Heinz]). : This work was supported by National Institute of Mental Health (Grant Nos. R01 MH116147 and R01 MH113619). : This work was supported by NIH (Grant No. R01 MH080912). : This work was supported by the Canadian Institutes of Health Research (Grant Nos. 103703, 106469, and 142255), Nova Scotia Health Research Foundation, Dalhousie Clinical Research Scholarship [to Tomas Hajek], 2007 Brain and Behavior Research Foundation Young Investigator Award [to Tomas Hajek], and Ministry of Health of the Czech Republic (Grant Nos. NR8786 and NT13891). : This work was supported by a Department of Veterans Affairs Clinical Science Research and Development Service Merit Review Award (I01CX000227 [to Scott R. Sponheim]). : This work was supported by an NIMH Award (U01 MH108150 [to Scott R. Sponheim]) and by the NIH (P30 NS076408, 1S10OD017974‐01). : This work was supported by NIH (Grant No. R01 MH052857). : The Australian cohort collection was supported by the Australian National Health and Medical Research Council Grants (Grant No. 510135 [to Philip B. Mitchell] and Grant No. 1037196 [to Philip B. Mitchell and Peter R. Schofield] and Grant No. 1176716 [to Peter R. Schofield]) and Project Grants (Grant No. 1063960 [to Janice M. Fullerton and Peter R. Schofield] and Grant No. 1066177 [to Janice M. Fullerton and Rhoshel K. Lenroot]), the Lansdowne Foundation and the Janette Mary O'Neil Research Fellowship [to Janice M. Fullerton]. : This work was supported by National Alliance for Research on Schizophrenia and Depression (Grant No. 20244 [to Manon H. J. Hillegers]), ZonMw (Grant No. 908‐02‐123 [to Hilleke E. Hulshoff Pol]), VIDI (Grant No. 452‐11‐014 [to Neeltje E. M. van Haren] and Grant No. 917‐46‐370 [to Hilleke E. Hulshoff Pol]), and Stanley Medical Research Institute. C‐SFS Cardiff CliNG Clinic DEU EGEU EHRS ENBD_UT/BPO_FLB FIDMAG Geneva GROUP HUBIN IDIBAPS IoP‐BD IoP‐SZ LIBD MFS MooDS MSSM OLIN ORBIS Halifax and Prague samples PENS PHCP STAR SydneyBipolarGroup UMCU
Dr Yalin has been an investigator in clinical studies conducted together with Janssen‐Cilag, Corcept Therapeutics, and COMPASS Pathways in the last 3 years. Dr Cannon reports that he is a consultant to Boerhinger Ingelheim Pharmaceuticals and Lundbeck A/S. Dr Meyer‐Lindenberg has received consultant fees from Boehringer Ingelheim, BrainsWay, Elsevier, Lundbeck International Neuroscience Foundation, and Science Advances. Drs Ching, Jahanshad, and Thompson received partial research support from Biogen, Inc. (Boston, MA) for work unrelated to the topic of this manuscript. Dr Vieta has received grants and served as consultant, advisor or CME speaker for the following entities (work unrelated to the topic of this manuscript): AB‐Biotics, Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Galenica, Janssen, Lundbeck, Novartis, Otsuka, Sage, Sanofi‐Aventis, and Takeda. The remaining authors report no biomedical financial interests or potential conflicts of interest.
- bipolar disorder