Site-specific CHRNA7 promoter hypomethylation associates with executive dysfunction in first-episode schizophrenia

Schizophrenia is characterized by persistent cognitive deficits that are largely refractory to current treatments. The CHRNA7 gene, encoding the α7 nicotinic acetylcholine receptor (α7 nAChR), has been implicated in both cognitive function and Schizophrenia susceptibility; however, its epigenetic regulation remains poorly defined. Here, we quantified DNA methylation (DNAm) at 14 CpG sites within the CHRNA7 promoter in 108 patients with first-episode Schizophrenia (FES) and 60 healthy controls (HCs). Cognitive performance was assessed using the Wisconsin Card Sorting Test (WCST), and clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS). FES patients exhibited promoter-wide hypomethylation, with significant reductions at CpG7/CpG14, and CpG10. CpG-resolved analyses revealed bidirectional associations with executive function: higher methylation at CpG2 and CpG6 correlated with improved performance, whereas hypermethylation at CpG7/CpG14 was associated with impaired cognitive flexibility and concept formation. In addition, CpG-specific methylation patterns were associated with symptom dimensions, including excitement and negative symptoms. Receiver operating characteristic (ROC) analyses showed that CpG3/CpG13, and CpG7/CpG14 discriminated FES patients from controls with moderate accuracy (AUC ≈ 0.791-0.803). Collectively, these findings identify site-specific alterations in CHRNA7 promoter methylation at disease onset and support a model in which CpG-resolved epigenetic variation contributes to cognitive heterogeneity in FES. These loci may represent candidate peripheral biomarkers and potential entry points for targeting cholinergic dysfunction.