Brain Heterogeneity in Schizophrenia and Its Association With Polygenic Risk

Abstract

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.

Figure 1.. Mean and Dispersion of Cortical Thickness

All maps were thresholded using permutation testing, threshold-free cluster enhancement, and fitting the tail of the permutation distribution to a generalized Pareto distribution (500 permutations; P < .05, familywise error). A, In the t map for the schizophrenia mean model, blue shades represent areas with decreased mean thickness in schizophrenia compared with healthy controls. Schizophrenia was associated with decreased thickness globally, with the exception of the visual cortex, and with strongest effects in frontal and temporal regions, compared with healthy controls. B, In the t map for the schizophrenia dispersion model, orange and yellow shades represent areas with increased heterogeneity in schizophrenia compared with healthy controls. Interindividual variability in cortical thickness showed a spatially global increase for the schizophrenia group compared with healthy controls. C, In an independent sample of healthy adults, the mean model showed that higher polygenic risk for schizophrenia was associated with lower cortical thickness, represented by blue shades, in frontal and temporal cortices. D, Polygenic risk was not associated with cortical thickness heterogeneity in any region.

Figure 2.. Shift Function Plots

Top graphs, Marginal distributions for patients with schizophrenia and healthy controls. Lines show the amount of shift between the 2 distributions. Orange lines and boxes indicate that corresponding deciles are lower in schizophrenia compared with healthy control groups (purple shows the reverse). Bottom graphs, The magnitude of the group difference is plotted as a function of the distribution among healthy controls. A sloped line indicates a difference in the distributions between the groups. Error bars represent bootstrapped 95% CIs. A, Vertex values were extracted by masking the images by the schizophrenia dispersion significance map, and the mean was calculated across vertices and hemispheres and residualized for scanner, sex, and age. Schizophrenia was associated with reduced thickness, with larger differences between groups in the lower deciles. B, Values were residualized for scanner, sex, age, and estimated intracranial volume (eTIV). Schizophrenia was associated with larger volumes compared with controls, with the largest difference between groups in the upper deciles. C and D, Values were residualized for scanner, sex, age, and eTIV. Schizophrenia was associated with smaller volumes compared with controls, with the largest difference between groups in the upper deciles.

Figure 3.. Mean and Dispersion Values of Cortical and Subcortical Volumes

The t statistics for mean and dispersion models are shown. Filled dots mark significant effects after correction for multiple comparisons across regions (5000 permutations; permuted P < .05, familywise error, adjusted for estimated intracranial volume). A, The schizophrenia group had decreased cortical and subcortical volumes and increased ventricle, putamen, and pallidum volumes. Cortical, hippocampal, and ventricle volumes were more heterogeneous in the schizophrenia group compared with healthy controls. B, Polygenic risk for schizophrenia was not associated with mean changes or dispersion in any of the regions. CC indicates corpus callosum; GM, gray matter; Lh, left hemisphere; Rh, right hemisphere; and WM, white matter.

Figure 4.. Mean and Dispersion of Hippocampus Subfield Volumes

The t statistics for mean and dispersion models are shown. Filled dots mark significant effects after correction for multiple comparisons across regions (5000 permutations; permuted P < .05, familywise error, adjusted for intracranial volume). A, The schizophrenia group had decreased hippocampal volumes. This decrease was also evident in all subfields and accompanied by an increase of the hippocampal fissures. Whole hippocampal volumes were also more heterogeneous in the schizophrenia group, and among the subfields this effect was present in the left molecular layer, left CA1 (cornu ammonis 1), left granule cell layer of the dentate gyrus (GC-DG), left CA4, and left presubiculum. B, Polygenic risk for schizophrenia was associated with mean reductions of left dentate gyrus, left CA4, and bilateral CA2/3. Total hippocampal volumes and subfields showed no significant association between polygenic risk and volume heterogeneity. HATA indicates hippocampus-amygdala transition area.