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The association between familial risk and brain abnormalities is disease-specific: an ENIGMA–Relatives study of schizophrenia and bipolar disorder

de Zwarte, Sonja, Brouwer, Rachel, Agartz, Ingrid, Alda, Martin, Aleman, André, Alpert, Kathryn, Bearden, Carrie, Bertolino, Alessandro, Bois, Catherine, Bonvino, Aurora, Bramon, Elvira, Buimer, Elizabeth, Cahn, Wiepke, Cannon, Dara, Cannon, Tyrone, Caseras, Xavier, Castro-Fornieles, Josefina, Chen, Qiang, Chung, Yoonho, De la Serna, Elena, Di Giorgio, Annabella, Doucet, Gaelle, Cagdas Eker, Mehmet, Fears, Scott, Foley, Sonya, Frangou, Sophia, Frankland, Andrew, Fullerton, Janice, Glahn, David, Goghari, Vina, Gonul, Ali, Gruber, Oliver, de Haan, Lieuwe, Hajek, Tomas, Hawkins, Emma, Hillegers, Manon, Hulshoff Pol, Hilleke, Hultman, Christina, Ingvar, Martin, Jönsson, Erik, Kane, Fergus, Kempton, Matthew, Koenis, Marinka, Kopecek, Miloslav, Krabbendam, Lydia, Krämer, Bernd, Lawrie, Stephen, Lenroot, Rhoshel, Marcelis, Machteld, Marsman, Jan-Bernard, McDonald, Colm, Michielse, Stijn, Mitchell, Philip, Moreno, Dolores, Murray, Robin, Mwangi, Benson, Najt, Pablo, Neilson, Emma, Newport, Jason, Van Os, Jim, Overs, Bronwyn, Ozerdem, Aysegul, Picchioni, Marco, Richter, Anja, Roberts, Gloria, Aydogan, Aybala, Schofiels, Peter, Simsek, Fatma, Soares, Jair, Sugranyes, Gisela, Toulopoulou, Timothea, Walter, Henrik, Wang, Lei, Weinberger, Daniel, Yalin, Nefize, Andreassen, Ole, Ching, Christopher, van Erp, Theo, Turner, Jessica, Jahanshad, Neda, Thompson, Paul, Kahn, Rene and van Haren, Neeltje 2019. The association between familial risk and brain abnormalities is disease-specific: an ENIGMA–Relatives study of schizophrenia and bipolar disorder. Biological Psychiatry 10.1016/j.biopsych.2019.03.985

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Background Schizophrenia and bipolar disorder share genetic liability and some structural brain abnormalities are common to both conditions. First-degree relatives of schizophrenia patients (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in bipolar disorder first-degree relatives (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared to controls. Methods Here, we meta-analyzed global and subcortical brain measures of 6,008 individuals (1,228 FDRs-SZ, 852 FDRs-BD, 2,246 controls, 1,016 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 controls. Results FDRs-BD had significantly larger ICV (d=+0.16, q<0.05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than controls (d=–0.12, q<0.05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD, while 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’s<–0.09, q<0.05 corrected), and third ventricle was larger (d=+0.15, q<0.05 corrected). The findings were not explained by psychopathology in the relatives or controls. Conclusions Despite shared genetic liability, first-degree relatives of patients with schizophrenia and bipolar disorder 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.

Item Type: Article
Date Type: Published Online
Status: In Press
Schools: Medicine
Publisher: Elsevier
ISSN: 0006-3223
Date of Acceptance: 24 March 2019
Last Modified: 18 Jun 2019 14:19

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