Virtual Ontogeny of Cortical Growth Preceding Mental Illness

Abstract

Background: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life.

Methods: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed.

Results: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth.

Conclusions: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy.

Keywords: Cortical growth; Cortical surface area; Mental illness; Neurodevelopment; Neurogenesis; Psychiatric disorders.

Figure 1.

Methodological workflow for virtual ontogeny. Step 1 (top left): identify top 200 cell-specific genes from single-cell RNA sequencing data of the developing neocortex (30). Step 2 (top right): quantify median gene expression (bulk RNA) across donors for each of 11 cortical regions sampled from the PsychENCODE dataset (33). Cell specificity was defined as the ratio of expression of a gene in a given cell type divided by the expression across all cells. For instance, the gene SLC1A3 was in the top 200 specific genes for the radial-glia panel. The expression of this gene is plotted in step 2 (top right). Step 3 (bottom left): quantify meta-analytic group differences in surface area between cases and controls across the 11 cortical regions sampled in the PsychENCODE dataset. Group differences for SCZ are plotted as an example. Step 4 (bottom right, top half): correlation between cell-specific gene expression and an MRI-derived profile, in this case, SLC1A3 expression and case-control differences for SCZ. This is repeated for all 200 genes specific to a cell type (in this case, radial glia) to create a distribution of correlation coefficients in step 5 (bottom right, bottom half). A1C, primary auditory cortex; ABCD, Adolescent Brain Cognitive Development; AMY, amygdala; CBC, cerebral cortex; DFC, dorsal frontal cortex; ENIGMA, Enhancing Neuro Imaging Genetics through Meta Analysis; HIP, hippocampus; IPC, inferior parietal cortex; IPCs, intermediate progenitor cells; ITC, inferior temporal cortex; M1C, primary motor cortex; MD, mediodorsal nucleus of thalamus; MDD, major depressive disorder; MFC, medial frontal cortex; MRI, magnetic resonance imaging; OFC, orbitofrontal cortex; OPC, oligodendrocyte progenitor cell; PCW, postconception week; S1C, primary somatosensory cortex; SCZ, schizophrenia; STC, superior temporal cortex; STR, striatum; V1C, primary visual cortex; VFC, ventral frontal cortex.

Figure 2.

Regional differences in cortical surface area across multiple psychiatric conditions. (A) Meta-analytic estimates of group differences in cortical surface between cases and controls. Contrast shown as controls minus cases, where positive values indicate smaller surface area in cases. (B) Schematic location of regions of interest from which surface area was quantified. (C) Cross-disorder correlation matrix of profiles from panel (A). *Nominal p < .05; ***false discovery rate–corrected p < .05. A1C, primary auditory cortex; ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; BD, bipolar disorder; CBCL, Child Behavior Checklist; DFC, dorsal frontal cortex; IPC, inferior parietal cortex; ITC, inferior temporal cortex; M1C, primary motor cortex; MDD, major depressive disorder; MFC, medial frontal cortex; OFC, orbitofrontal cortex; SA, surface area; S1C, primary somatosensory cortex; SCZ, schizophrenia; STC, superior temporal cortex; V1C, primary visual cortex; VFC, ventral frontal cortex.

Figure 3.

Virtual ontogeny. (A) Distribution of correlation coefficients between prenatal cell-specific gene expression and postnatal group differences in cortical surface area. Gray box around zero represents 99% confidence intervals from the null distribution generated through 10,000 resamplings of gene expression and group-difference profiles. Black vertical line represents the mean correlation coefficient (biweight midcorrelation) of the distribution, also plotted in panel (B). *False discovery rate–corrected p value < .01. ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; BD, bipolar disorder; bicor, biweight midcorrelation; CBCL, Child Behavior Checklist; IPC, intermediate progenitor cell; MDD, major depressive disorder; OPC, oligodendrocyte progenitor cell; SCZ, schizophrenia.

Figure 4.

Differences in cortical surface area cluster into associative and primary/unimodal cortex. (A) Hierarchical clustering dendrogram of group differences in cortical surface area with k = 2 clusters. (B) Boxplot depicting group differences between clusters for each of the six profiles investigated. (C) LOESS model fits of cell-specific gene expression trajectories stratified by cortical cluster. Expression (y-axis) is unit scaled. Shaded gray region around the model fit represents 95% confidence intervals. Vertical black dashed lines represent prominent windows of neurodevelopment reported previously (33). A1C, primary auditory cortex; ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; BD, bipolar disorder; CBCL, Child Behavior Checklist; DFC, dorsal frontal cortex; IPC, intermediate progenitor cell; IPC, inferior parietal cortex; ITC, inferior temporal cortex; M1C, primary motor cortex; MDD, major depressive disorder; MFC, medial frontal cortex; OFC, orbitofrontal cortex; OPC, oligodendrocyte progenitor cell; PCW, postconception week; S1C, primary somatosensory cortex; SCZ, schizophrenia; STC, superior temporal cortex; V1C, primary visual cortex; VFC, ventral frontal cortex.

Figure 5.

Enrichment of cell-specific gene panels. (A) Principal component analysis plot of regional loadings of PC1 and PC2. (B) Correlation between disorder-specific profiles and PC1/PC2 loadings. (C) Virtual ontogeny analysis depicting distributions of correlation between interregional variation in cell-specific gene expression and PC1 loadings (across the 11 regions). *FDR p < .01. (D–F) Gene Ontology enrichment analysis of coexpressed cell-specific gene panels. Gene ratio represents the proportion of genes in the cell-specific panel that intersect with a Gene Ontology term with the total size of the gene set. (G) Enrichment analysis for disorder-associated genes for the three disorders loading strongest on PC1 (SCZ, ADHD, and ASD) and for (H) cortical surface area–associated genes of clusters 1 and 2. A1C, primary auditory cortex; ADHD, attention-deficit/hyperactivity disorder; ASD, autism spectrum disorder; BD, bipolar disorder; CBCL, Child Behavior Checklist; DFC, dorsal frontal cortex; FDR, false discovery rate; IPC, intermediate progenitor cell; IPC, inferior parietal cortex; ITC, inferior temporal cortex; M1C, primary motor cortex; MDD, major depressive disorder; MFC, medial frontal cortex; OFC, orbitofrontal cortex; OPC, oligodendrocyte progenitor cell; PC, principal component; S1C, primary somatosensory cortex; SCZ, schizophrenia; STC, superior temporal cortex; V1C, primary visual cortex; VFC, ventral frontal cortex.

Figure 6.

Risk factors of psychosis with implicated cell types. (A) Z scores for pre/perinatal risk factors for psychosis from Davies et al. (39) are represented by the size of the circle, and the corresponding odds ratio is in the text below. (B) Enrichment between genes implicated in risk factors for psychosis and coexpressed cell-specific gene panels identified to be related to group differences in cortical surface area. Horizontal dashed line represents FDR < .05. FDR, false discovery rate; IPC, intermediate progenitor cell; OR, odds ratio.