Children at familial high risk for schizophrenia or bipolar disorder show sex-specific differences in subcortical grey matter volumes
- 1Danish Research Centre for Magnetic Resonance, Department of Radiology and Nuclear Medicine, Copenhagen University Hospital - Amager and Hvidovre, Hvidovre, Den
Abstract
BackgroundChildren of parents with schizophrenia (SZ) or bipolar disorder (BP) are at familial high risk (FHR) of developing severe mental illnesses. Based on findings in FHR populations and adults with SZ and BP, we hypothesized that children at FHR for schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) would show sex-specific differences in subcortical grey matter volume, particularly in the thalamus, amygdala, and hippocampus, compared with population-based controls (PBC).
MethodsWe examined eight major subcortical grey matter structures in 108 FHR-SZ, 69 FHR-BP, and 120 PBC children aged 11-12 years from the Danish High Risk and Resilience Study. Structural magnetic resonance imaging (MRI) was used to estimate subcortical volumes and R1, a measure of myelin, iron, water, and macromolecular content. Sex-specific group differences were tested across regions.
ResultsThe thalamus and amygdala, but not hippocampus, showed sex-specific group differences in volume. FHR-SZ males showed smaller thalamic volumes than FHR-BP and PBC males, whereas FHR-BP females showed larger thalamic volumes compared with PBC females. FHR-BP males showed larger relative amygdala volumes (corrected for total brain volume) compared to PBC males. No significant differences were observed for subcortical R1.
ConclusionsChildren at FHR-SZ and FHR-BP exhibited sex-specific differences in subcortical brain volumes before the typical onset of SZ and BP. These differences may reflect early sex-specific neurodevelopmental correlates of familial risk and highlight the importance of modelling sex-specific effects in developmental neuropsychiatric research. Longitudinal studies are needed to determine how these volumetric differences evolve and whether they are associated with later clinical outcomes.
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BibTeX
@misc{hansen2026children,
title = {{Children at familial high risk for schizophrenia or bipolar disorder show sex-specific differences in subcortical grey matter volumes}},
author = {M. M. Hansen and W. F. C. Baare and E. Hernandez-Torres and K. M. Larsen and V. Ioakeimidis and L. K. Johnsen and N. Hemager and M. Gregersen and M. F. Krantz and N. Weye and A. Sondergaard and C. B. Knudsen and L. Veddum and A. K. Andreassen and T. E. Lund and O. Mors and A. A. E. Thorup and L. Ostergaard and M. Nordentoft and H. R. Siebner and K. S. Madsen},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.07.26362368},
url = {https://www.medrxiv.org/content/10.64898/2026.09.07.26362368v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Children at familial high risk for schizophrenia or bipolar disorder show sex-specific differences in subcortical grey matter volumes
AU - M. M. Hansen
AU - W. F. C. Baare
AU - E. Hernandez-Torres
AU - K. M. Larsen
AU - V. Ioakeimidis
AU - L. K. Johnsen
AU - N. Hemager
AU - M. Gregersen
AU - M. F. Krantz
AU - N. Weye
AU - A. Sondergaard
AU - C. B. Knudsen
AU - L. Veddum
AU - A. K. Andreassen
AU - T. E. Lund
AU - O. Mors
AU - A. A. E. Thorup
AU - L. Ostergaard
AU - M. Nordentoft
AU - H. R. Siebner
AU - K. S. Madsen
PY - 2026
DA - 2026/09/07
PB - medRxiv
DO - 10.64898/2026.09.07.26362368
UR - https://www.medrxiv.org/content/10.64898/2026.09.07.26362368v1
AB - BackgroundChildren of parents with schizophrenia (SZ) or bipolar disorder (BP) are at familial high risk (FHR) of developing severe mental illnesses. Based on findings in FHR populations and adults with SZ and BP, we hypothesized that children at FHR for schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) would show sex-specific differences in subcortical grey matter volume, particularly in the thalamus, amygdala, and hippocampus, compared with population-based controls (PBC). MethodsWe examined eight major subcortical grey matter structures in 108 FHR-SZ, 69 FHR-BP, and 120 PBC children aged 11-12 years from the Danish High Risk and Resilience Study. Structural magnetic resonance imaging (MRI) was used to estimate subcortical volumes and R1, a measure of myelin, iron, water, and macromolecular content. Sex-specific group differences were tested across regions. ResultsThe thalamus and amygdala, but not hippocampus, showed sex-specific group differences in volume. FHR-SZ males showed smaller thalamic volumes than FHR-BP and PBC males, whereas FHR-BP females showed larger thalamic volumes compared with PBC females. FHR-BP males showed larger relative amygdala volumes (corrected for total brain volume) compared to PBC males. No significant differences were observed for subcortical R1. ConclusionsChildren at FHR-SZ and FHR-BP exhibited sex-specific differences in subcortical brain volumes before the typical onset of SZ and BP. These differences may reflect early sex-specific neurodevelopmental correlates of familial risk and highlight the importance of modelling sex-specific effects in developmental neuropsychiatric research. Longitudinal studies are needed to determine how these volumetric differences evolve and whether they are associated with later clinical outcomes.
ER -