Intelligence, educational attainment, and brain structure in those at familial high‐risk for schizophrenia or bipolar disorder
Authors: de Zwarte Sonja M. C. , Brouwer Rachel M. , Agartz Ingrid , Alda Martin , Alonso‐Lana Silvia , Bearden Carrie E. , Bertolino Alessandro , Bonvino Aurora , Bramon Elvira , Buimer Elizabeth E. L. , Cahn Wiepke , Canales‐Rodríguez Erick J. , Cannon Dara M. , Cannon Tyrone D. , Caseras Xavier , Castro‐Fornieles Josefina , Chen Qiang , Chung Yoonho , De la Serna Elena , del Mar Bonnin Caterina , Demro Caroline , Di Giorgio Annabella , Doucet Gaelle E. , Eker Mehmet Cagdas , Erk Susanne , Fatjó‐Vilas Mar , Fears Scott C. , Foley Sonya F. , Frangou Sophia , Fullerton Janice M. , Glahn David C. , Goghari Vina M. , Goikolea Jose M. , Goldman Aaron L. , Gonul Ali Saffet , Gruber Oliver , Hajek Tomas , Hawkins Emma L. , Heinz Andreas , Hidiroglu Ongun Ceren , Hillegers Manon H. J. , Houenou Josselin , Hulshoff Pol Hilleke E. , Hultman Christina M. , Ingvar Martin , Johansson Viktoria , Jönsson Erik G. , Kane Fergus , Kempton Matthew J. , Koenis Marinka M. G. , Kopecek Miloslav , Krämer Bernd , Lawrie Stephen M. , Lenroot Rhoshel K. , Marcelis Machteld , Mattay Venkata S. , McDonald Colm , Meyer‐Lindenberg Andreas , Michielse Stijn , Mitchell Philip B. , Moreno Dolores , Murray Robin M. , Mwangi Benson , Nabulsi Leila , Newport Jason , Olman Cheryl A. , van Os Jim , Overs Bronwyn J. , Ozerdem Aysegul , Pergola Giulio , Picchioni Marco M. , Piguet Camille , Pomarol‐Clotet Edith , Radua Joaquim , Ramsay Ian S. , Richter Anja , Roberts Gloria , Salvador Raymond , Saricicek Aydogan Aybala , Sarró Salvador , Schofield Peter R. , Simsek Esma M. , Simsek Fatma , Soares Jair C. , Sponheim Scott R. , Sugranyes Gisela , Toulopoulou Timothea , Tronchin Giulia , Vieta Eduard , Walter Henrik , Weinberger Daniel R. , Whalley Heather C. , Wu Mon‐Ju , Yalin Nefize , Andreassen Ole A. , Ching Christopher R. K. , Thomopoulos Sophia I. , van Erp Theo G. M. , Jahanshad Neda , Thompson Paul M. , Kahn René S. , van Haren Neeltje E. M. 
Published: October 2020

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.