Intelligence, educational attainment, and brain structure in those at familial high-risk for schizophrenia or bipolar disorder

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)414-430
Number of pages17
JournalHuman Brain Mapping
Issue number1
StatePublished - Jan 2022
Externally publishedYes


  • bipolar disorder
  • education
  • intelligence
  • neuroimaging
  • relatives
  • schizophrenia

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Radiological and Ultrasound Technology
  • Radiology Nuclear Medicine and imaging
  • Anatomy


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