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    The Association Between Familial Risk and Brain Abnormalities Is Disease Specific: An ENIGMA-Relatives Study of Schizophrenia and Bipolar Disorder
    (Elsevier Science Inc, 2019) de Zwarte, Sonja M. C.; Brouwer, Rachel M.; Agartz, Ingrid; Alda, Martin; Aleman, Andre; Alpert, Kathryn I.; Bearden, Carrie E.; Bertolino, Alessandro; Bois, Catherine; Bonvino, Aurora; Bramon, Elvira; Buimer, Elizabeth E. L.; Cahn, Wiepke; Cannon, Dara M.; Cannon, Tyrone D.; Caseras, Xavier; Castro-Fornieles, Josefina; Chen, Qiang; Chung, Yoonho; De la Serna, Elena; Di Giorgio, Annabella; Doucet, Gaelle E.; Eker, Mehmet Cagdas; Erk, Susanne; Fears, Scott C.; Foley, Sonya F.; Frangou, Sophia; Frankland, Andrew; Fullerton, Janice M.; Glahn, David C.; Goghari, Vina M.; Goldman, Aaron L.; Gonul, Ali Saffet; Gruber, Oliver; de Haan, Lieuwe; Hajek, Tomas; Hawkins, Emma L.; Heinz, Andreas; Hillegers, Manon H. J.; Pol, Hilleke E. Hulshoff; Hultman, Christina M.; Ingvar, Martin; Johansson, Viktoria; Jonsson, Erik G.; Kane, Fergus; Kempton, Matthew J.; Koenis, Marinka M. G.; Kopecek, Miloslav; Krabbendam, Lydia; Kraemer, Bernd; Lawrie, Stephen M.; Lenroot, Rhoshel K.; Marcelis, Machteld; Marsman, Jan-Bernard C.; Mattay, Venkata S.; McDonald, Colm; Meyer-Lindenberg, Andreas; Michielse, Stijn; Mitchell, Philip B.; Moreno, Dolores; Murray, Robin M.; Mwangi, Benson; Najt, Pablo; Neilson, Emma; Newport, Jason; van Os, Jim; Overs, Bronwyn; Ozerdem, Aysegul; Picchioni, Marco M.; Richter, Anja; Roberts, Gloria; Aydogan, Aybala Saricicek; Schofield, Peter R.; Simsek, Fatma; Soares, Jair C.; Sugranyes, Gisela; Toulopoulou, Timothea; Tronchin, Giulia; Walter, Henrik; Wang, Lei; Weinberger, Daniel R.; Whalley, Heather C.; Yalin, Nefize; Andreassen, Ole A.; Ching, Christopher R. K.; van Erp, Theo G. M.; Turner, Jessica A.; Jahanshad, Neda; Thompson, Paul M.; Kahn, Rene S.; van Haren, Neeltje E. M.
    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.
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    The Role of Educational Attainment and Brain Morphology in Major Depressive Disorder: Findings From the ENIGMA Major Depressive Disorder Consortium
    (Amer Psychological Assoc, 2022) Whittle, Sarah; Rakesh, Divyangana; Schmaal, Lianne; Veltman, Dick J.; Thompson, Paul M.; Singh, Aditya; Gonul, Ali Saffet
    Brain structural abnormalities and low educational attainment are consistently associated with major depressive disorder (MDD), yet there has been little research investigating the complex interaction of these factors. Brain structural alterations may represent a vulnerability or differential susceptibility marker, and in the context of low educational attainment, predict MDD. We tested this moderation model in a large multisite sample of 1958 adults with MDD and 2921 controls (aged 18 to 86) from the ENIGMA MDD working group. Using generalized linear mixed models and within-sample split-half replication, we tested whether brain structure interacted with educational attainment to predict MDD status. Analyses revealed that cortical thickness in a number of occipital, parietal, and frontal regions significantly interacted with education to predict MDD. For the majority of regions, models suggested a differential susceptibility effect, whereby thicker cortex was more likely to predict MDD in individuals with low educational attainment, but less likely to predict MDD in individuals with high educational attainment. Findings suggest that greater thickness of brain regions subserving visuomotor and social-cognitive functions confers susceptibility to MDD, dependent on level of educational attainment. Longitudinal work, however, is ultimately needed to establish whether cortical thickness represents a preexisting susceptibility marker. General Scientific Summary Findings from this study provide support for a complex interplay of biological and environmental factors being important in predicting major depressive disorder. Findings suggest that alterations in brain structure may not predict depression in all individuals; rather, such alterations may only predict depression in the context of adverse environmental experiences. Conversely, these same alterations may protect against depression in the context of positive environmental experiences.