Overdispersed gene expression in schizophrenia

Abstract

Schizophrenia (SCZ) is a severe, highly heterogeneous psychiatric disorder with varied clinical presentations. The polygenic genetic architecture of SCZ makes identification of causal variants a daunting task. Gene expression analyses hold the promise of revealing connections between dysregulated transcription and underlying variants in SCZ. However, the most commonly used differential expression analysis often assumes grouped samples are from homogeneous populations and thus cannot be used to detect expression variance differences between samples. Here, we applied the test for equality of variances to normalized expression data, generated by the CommonMind Consortium (CMC), from brains of 212 SCZ and 214 unaffected control (CTL) samples. We identified 87 genes, including VEGFA (vascular endothelial growth factor) and BDNF (brain-derived neurotrophic factor), that showed a significantly higher expression variance among SCZ samples than CTL samples. In contrast, only one gene showed the opposite pattern. To extend our analysis to gene sets, we proposed a Mahalanobis distance-based test for multivariate homogeneity of group dispersions, with which we identified 110 gene sets with a significantly higher expression variability in SCZ, including sets of genes encoding phosphatidylinositol 3-kinase (PI3K) complex and several others involved in cerebellar cortex morphogenesis, neuromuscular junction development, and cerebellar Purkinje cell layer development. Taken together, our results suggest that SCZ brains are characterized by overdispersed gene expression-overall gene expression variability among SCZ samples is significantly higher than that among CTL samples. Our study showcases the application of variability-centric analyses in SCZ research.

Structural and Functional Features of Developing Brain Capillaries, and Their Alteration in Schizophrenia

“…Alterations in glial cells (mainly microglia and astrocytes) could contribute to this neurovascular fragility ( Figure 1 ). Growing evidence place the PFC as central in this hypothesis because multiple investigations on SCZ patients found vascular defects in this particular region, ranging from decreases in claudin-5 ( Greene et al, 2018 ), reductions in VEGF signaling ( Fulzele and Pillai, 2009 ; Huang et al, 2020 ), a less dense capillary network ( Uranova et al, 2013 ), to oversimplified angioarchitecture ( Senitz and Winkelmann, 1991 ; Uranova et al, 2010 ), and other ultrastructural defects ( Figure 1 ; Webster et al, 2001 ; Uranova et al, 2010 ; Ishizuka et al, 2017 ; Hill et al, 2020 ). As many key components of NVC are impacted by SCZ, it is not surprising that one of the most consistently observed neurovascular correlates of the illness is hypo-activity in PFC regions and in the left superior temporal gyrus, as revealed by a recent systematic review of both task and resting-state fMRI cross-sectional studies in first-episode SCZ patients ( Mwansisya et al, 2017 ).…”

Evaluation of mRNA expression level of the ATP synthase membrane subunit c locus 1 (ATP5G1) gene in patients with schizophrenia

“…Although the expanded incidence rate and incapacitating consequences of schizophrenia, little is available regarding its pathogenesis [ 17 ]. This disorder has a heterogonous genetic nature, and gene expression evaluation may expose the association between altered expressions and the pathogenesis of schizophrenia [ 18 ]. Moreover, gene expression is supposed to be the chief way genotype principally affects the disease phenotype [ 17 ].…”

The contribution of Xp22.31 gene dosage to Turner and Klinefelter syndromes and sex-biased phenotypes

“…Studies in brain tissue from individuals with developmental disorders have also not yet implicated altered expression of these genes (e.g. Chang et al, 2015;Huang et al, 2020); however, such studies are limited by small sample sizes, by sex-biased samples, by considerable heterogeneity in donors symptoms and genetics, by post mortem considerations and by treatment effects. I hypothesise that after controlling for relevant variables (e.g.…”