A thalamo-cortical genetic co-expression network is associated with thalamic functional connectivity linked with familial risk for schizophrenia

Introduction The genetic architecture of schizophrenia is based on polygenic trajectories. Indeed, genes converge on molecular co-expression pathways, which may be associated with heritable characteristics of patients and their siblings, called intermediate phenotypes, such as prefrontal anomalies and thalamic dysconnectivity during attentional control [2]. Objectives Here, we investigated in healthy humans association between co-expression of genes with coordinated thalamo-prefrontal (THA-PFC) expression and functional connectivity during attentional control. Methods We used Brainspan dataset to characterize a coordinated THA-PFC expression gene list by correlating post-mortem gene expression in both areas (Kendall's Tau>.76, Bonferroni P < .05). Then, we identified a PFC co-expression network1 and tested all gene sets for THA-PFC and PGC loci [3] enrichments (P < .05). SNPs associated with the first principal component of the resulting enriched gene set were combined in a Polygenic Co-Expression Index (PCI) [1]. We conducted Independent Component Analysis (ICA) on attentional control fMRI data (n = 265) and selected Independent Components (ICs) including the thalamus and being highly correlated with an attentional control network2. Multiple regressions were conducted (predictor: PCI) using a thalamic cluster previously associated with familial risk for schizophrenia [2] as ROI (FWE P < .05). Results In one of the 8 ICs of interest there was a positive effect of PCI on thalamic connectivity strength in a cluster overlapping with our ROI (Z = 4.3). Conclusion Decreased co-expression of genes included in PCI predicts thalamic dysconnectivity during attentional control, suggesting a novel co-regulated molecular pathway potentially implicated in genetic risk for schizophrenia.