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].

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.

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).

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).

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.

The authors have not supplied their declaration of competing interest.