[Skip to Content]
[Skip to Content Landing]
Original Investigation
April 10, 2019

Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk

Author Affiliations
  • 1Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Norway
  • 2Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
  • 3Department of Psychological and Brain Sciences, Washington University in Saint Louis, St Louis, Missouri
  • 4Psychiatric Neuroscience Group, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
  • 5Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
  • 6Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
  • 7Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  • 8Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
  • 9Department of Psychology, University of Oslo, Oslo, Norway
JAMA Psychiatry. 2019;76(7):739-748. doi:10.1001/jamapsychiatry.2019.0257
Key Points

Question  Are schizophrenia and its polygenic risk associated with brain structural heterogeneity in addition to mean changes?

Findings  In this case-control analysis of 1151 patients and 2010 controls, schizophrenia was associated with increased heterogeneity in frontotemporal thickness and area and cortical, ventricle, and hippocampal volumes, as well as robust reductions in mean estimates. In an independent sample of 12 490 healthy controls, polygenic risk for schizophrenia was associated with thinner frontotemporal cortices and smaller CA2/3 volume of the left hippocampus, but not with heterogeneity.

Meaning  Schizophrenia appears to be associated with increased interindividual differences in brain structure, possibly reflecting clinical heterogeneity, gene-environment interactions, or secondary disease factors.


Importance  Between-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature.

Objectives  To compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls.

Design, Setting, and Participants  This case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018.

Main Outcomes and Measures  Mean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality.

Results  A comparison of 1151 patients with schizophrenia (mean [SD] age, 33.8 [10.6] years; 68.6% male [n = 790] and 31.4% female [n = 361]) with 2010 healthy controls (mean [SD] age, 32.6 [10.4] years; 56.0% male [n = 1126] and 44.0% female [n = 884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t = 3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age, 55.9 [7.5] years; 48.2% male [n = 6025] and 51.8% female [n = 6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t = −3.00) but was not significantly associated with dispersion.

Conclusions and Relevance  This study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia.