Peripheral GRM2 and GRM3 mRNA Alterations and Clinical Correlates in Insomnia Disorder: A Case–Control Pilot Study

Liqing Zhang,1,2 Fangyi Deng,1,3,* Jiaheng Lin,1,4 Jiwu Liao,1 Jiyang Pan11Department of Psychiatry, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, People’s Republic of China; 2Department of Psychiatry, The Third Affiliated Hospital, Southern Medical University, Guangzhou, 510630, People’s Republic of China; 3Wuhan Children’s Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, 430010, People’s Republic of China; 4Department of Gastrointestinal Surgery, The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510700, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiyang Pan, Department of Psychiatry, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, People’s Republic of China, Email [email protected]; [email protected]; Liqing Zhang, Department of Psychiatry, The First Affiliated Hospital of Jinan University, Guangzhou, 510632, People’s Republic of China, Email [email protected]: This pilot study examined whether peripheral GRM2/GRM3 mRNA expression differed between chronic insomnia disorder (ID) and healthy controls (HCs) and correlated with emotional and polysomnographic (PSG) features.Methods: After PSG screening, 43 patients with chronic ID meeting DSM-5-TR criteria and 34 HCs with comparable age and sex distributions were included. Mood, sleep, and PSG parameters were assessed, and peripheral GRM2/GRM3 mRNA was quantified by RT-qPCR. Statistical analyses comprised group comparisons, age- and sex-adjusted regression, partial correlations with false discovery rate (FDR) correction, Bayesian analyses, sensitivity analyses, and exploratory receiver operating characteristic (ROC) analyses.Results: Compared with HCs, ID patients showed greater depressive and anxiety symptoms, poorer subjective sleep quality, and altered sleep architecture. Peripheral GRM2 and GRM3 mRNA expression was lower in ID patients, with both differences remaining significant after adjustment for age and sex (P=0.001; P=0.029). The apparent area under the curves (AUCs) were 0.744, 0.666, and 0.769 for GRM2, GRM3, and the combined model, respectively; corresponding cross-validated mean AUCs were 0.745, 0.645, and 0.732. Both GRM2 and GRM3 showed associations with emotional and sleep measures; the GRM3–PHQ-9 association remained significant after FDR correction (r=− 0.373, Padj=0.020), while the GRM2–REM association showed Bayesian support (BF=4.473). These associations were attenuated after further adjustment for diagnostic group.Conclusions: Lower peripheral GRM2 and GRM3 expression was associated with chronic ID, with exploratory associations with selected emotional and sleep measures. These findings identify peripheral GRM2/GRM3 as candidate molecular correlates of ID. Independent external validation is required before clinical diagnostic application.Keywords: GRM2, GRM3, RT-qPCR, polysomnography, insomnia disorder