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

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.