Brain Structure Heterogeneity Associated With Polygenic Risk in Schizophrenia

Schizophrenia was associated with increased heterogeneity in frontotemporal thickness and area and cortical, ventricle, and hippocampal volumes.

Schizophrenia is associated with increased interindividual differences in brain structure, possibly a reflection of the heterogeneity of the disease itself, gene-environment interactions, or secondary disease factors, according to study results published in JAMA Psychiatry.

Dag Alnaes, PhD, of the Norwegian Centre for Mental Disorders Research, University of Oslo, Norway, and colleagues used a case-control, polygenic risk analysis to compare magnetic resonance imaging (MRI)-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia. They tested for associations between polygenic risk score (PRS) and MRI features in a control cohort from the UK Biobank and collected data from October 27, 2004 through April 12, 2018.

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The study compared data from 1151 patients with schizophrenia and 2010 healthy controls and found higher heterogeneity in schizophrenia for cortical thickness and area (t=3.34), cortical (t=3.24) and ventricle (t range, 3.18-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In healthy controls, higher PRS correlated with thinner front and temporal cortices and smaller left Cornu Ammonis areas (2 and 3) (t=-3.00), but was not significantly associated with thickness dispersion.

Investigators suggested that the heterogeneity found in schizophrenia may reflect subtypes and symptom profiles. They noted that a higher PRS was associated with smaller volumes of the left Cornu Ammonis areas (2 and 3), suggesting a specific effect of genetic risk in this region.

The study had a number of limitations, including that heterogeneity could be associated with differences in medication status and duration of illness; diagnostic categories do not necessarily reflect biology; and as a composite score, PRS may conceal considerable genetic heterogeneity.

The investigators concluded that schizophrenia appears to be associated with widespread and increased heterogeneity in cortical thickness and cortical and hippocampal volumes. They cited the need for future longitudinal studies.


Alnaes D, Kaufmann T, van der Meer D, et al. Brain heterogeneity in schizophrenia and its association with polygenic risk [published online April 10, 2019]. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2019.0257