White matter microstructure in relatives of people with schizophrenia or bipolar disorder: an ENIGMA meta-analysis

Bipolar and psychotic disorders are highly heritable and associated with widespread white matter microstructure abnormalities. In this project, we compare white matter microstructure of unaffected first-degree relatives of individuals with bipolar disorder (FDR-BD) or psychotic disorder (FDR-SZ) to that of control participants. As secondary, exploratory aims, we examined the associations of childhood traumatic experiences and working memory with white matter microstructure across relatives and controls. Finally, we compared participants with BD or SZ to controls. We combined 11 samples from 9 institutions with 408 FDR-BD, 542 FDR-SZ, 841 controls, 255 BD and 464 SZ. Analysis of the diffusion-weighted imaging data followed the ENIGMA pipeline protocols, resulting in mean fractional anisotropy (FA). Sample-level analyses were linear mixed-effects models with group as the main predictor, adjusting for age and sex and correcting for dependence between family members. Samples were combined using random-effects meta-analysis. FDR-BD showed higher FA in the posterior limb of the internal capsule (PLIC) than controls. FDR-SZ did not demonstrate any FA differences from controls. Participants with BD or SZ diagnoses from the same samples did show the expected lower FA than controls in several tracts. Working memory scores were more positively related to FA in the PLIC in FDR-SZ than in controls. The level of childhood traumatic experiences was not related to FA. White matter deficits observed in people with SZ and BD were not detected in FDR-BD and FDR-SZ, suggesting that these findings in patients are not due to familial risk but may pertain to illness itself.

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Journal
Molecular Psychiatry
Published
2026-05-21
DOI
https://doi.org/10.1038/s41380-026-03628-x
Primary Topic
Advanced Neuroimaging Techniques and Applications
Type
article
Field-Weighted Citation Impact
0.00

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article

White matter microstructure in relatives of people with schizophrenia or bipolar disorder: an ENIGMA meta-analysis

Simon R. Poortman, Janice M. Fullerton, Marjolein E.A. Barendse, Manon Hillegers et al.
Molecular Psychiatry
Advanced Neuroimaging Techniques and Applications
article

White matter microstructure in relatives of people with schizophrenia or bipolar disorder: an ENIGMA meta-analysis

Simon R. Poortman, Janice M. Fullerton, Marjolein E.A. Barendse, Manon Hillegers, Scott Sponheim, Marta Pena, Camille Piguet, Bryon A. Mueller, Aysegul Ozerdem, Elena de la Serna, Christopher R. K. Ching, Nabi Zorlu, W. Cahn, Dara M. Cannon, Josefina Castro-Fornieles, Gisela Sugranyes, Luigi F. Saccaro, Philip B. Mitchell, Colm McDonald, Paul M. Thompson, Farnaz Delavari, Neeltje E. M. van Haren, Gloria Roberts, Lei Xuan, Aybala Saricicek Aydogan
article en

Abstract

Bipolar and psychotic disorders are highly heritable and associated with widespread white matter microstructure abnormalities. In this project, we compare white matter microstructure of unaffected first-degree relatives of individuals with bipolar disorder (FDR-BD) or psychotic disorder (FDR-SZ) to that of control participants. As secondary, exploratory aims, we examined the associations of childhood traumatic experiences and working memory with white matter microstructure across relatives and controls. Finally, we compared participants with BD or SZ to controls. We combined 11 samples from 9 institutions with 408 FDR-BD, 542 FDR-SZ, 841 controls, 255 BD and 464 SZ. Analysis of the diffusion-weighted imaging data followed the ENIGMA pipeline protocols, resulting in mean fractional anisotropy (FA). Sample-level analyses were linear mixed-effects models with group as the main predictor, adjusting for age and sex and correcting for dependence between family members. Samples were combined using random-effects meta-analysis. FDR-BD showed higher FA in the posterior limb of the internal capsule (PLIC) than controls. FDR-SZ did not demonstrate any FA differences from controls. Participants with BD or SZ diagnoses from the same samples did show the expected lower FA than controls in several tracts. Working memory scores were more positively related to FA in the PLIC in FDR-SZ than in controls. The level of childhood traumatic experiences was not related to FA. White matter deficits observed in people with SZ and BD were not detected in FDR-BD and FDR-SZ, suggesting that these findings in patients are not due to familial risk but may pertain to illness itself.

Molecular Psychiatry
University of Geneva (CH), University of Southern California (US), The University of Sydney (AU), Mayo Clinic (US), Izmir Kâtip Çelebi University (TR), Instituto de Salud Carlos III (ES), Erasmus MC (NL), WinnMed (US), University Medical Center Utrecht (NL), UNSW Sydney (AU), Centro de Investigación Biomédica en Red de Salud Mental (ES), University Hospital of Geneva (CH), Hospital Clínic de Barcelona (ES), Minneapolis VA Health Care System (US), University of Minnesota Medical Center (US), Cognitive Neuroimaging Lab (FR), École Polytechnique Fédérale de Lausanne (CH), Universitat de Barcelona (ES), Neuroscience Research Australia (AU), Erasmus University Rotterdam (NL)
Eli Lilly and Company, AstraZeneca, Fundación Alicia Koplowitz, National Alliance for Research on Schizophrenia and Depression, National Institute for Health and Care Research, King's College London, European Commission, ZonMw, Universiteit Maastricht, Generalitat de Catalunya, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, GGZ inGeest, Rivierduinen, GGZ Friesland, GGZ Drenthe, Dokuz Eylül Üniversitesi, H. Lundbeck A/S, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, National Institute of Mental Health, Cilag
Openalex Percentile: Top 6%
Advanced Neuroimaging Techniques and Applications
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