A Cross-Matrix Peripheral Transcriptional Signature in Suicide Attempt: NR3C2 Downregulation in Blood and Buccal Swab Samples

The biological basis of suicidal behavior extends beyond psychiatric diagnosis, and alterations in stress-response regulation, monoaminergic signaling, and GABAergic function may contribute to suicide risk. We enrolled 69 adults presenting to the emergency department after a suicide attempt episode and 72 controls. Expression of eight candidate genes (SLC6A3, SLC6A4, NR3C1, NR3C2, DRD2, MAOA, GABRA2, and GABBR2) was measured by qRT-PCR in paired peripheral blood and buccal swab samples, with GAPDH as the reference gene. Multiple testing was addressed with the Benjamini—Hochberg false discovery rate. NR3C2, which encodes the mineralocorticoid receptor, was the only gene downregulated in both sample types after FDR correction (blood: q = 0.0007; swab: q = 0.0004). Blood additionally showed changes in SLC6A4 (↓), DRD2 (↑), and GABBR2 (↑). In buccal swabs, every gene that reached significance—SLC6A3, NR3C1, GABRA2, and GABBR2—was downregulated. No gene achieved AUC ≥ 0.90 in ROC analysis. Gene-by-biochemistry correlations did not survive FDR correction, suggesting transcriptional changes independent of acute metabolic status. Overall, peripheral expression was matrix-dependent, and NR3C2 downregulation stood out as the one signal that replicated across both. Blood and buccal swabs captured complementary biological information, together pointing to impaired HPA-axis buffering. Because group-level confounders could not be adjusted for, these findings should be read as hypothesis-generating and warrant confounder-controlled, longitudinal validation.