The effect of rs1076560 (DRD2) and rs4680 (COMT) on tardive dyskinesia and cognition in schizophrenia subjects

Abstract

Objective The aim of the study is to test the association of a functional variant each in DRD2 and COMT genes with schizophrenia and its endophenotypes. Basic methods Effect of two functional variants rs1076560 in DRD2 and rs4680 in COMT on (1) schizophrenia (502 cases, 448 controls) diagnosed by Diagnostic and Statistical Manual of Mental Disorders-IV criteria and in subsets with (2) tardive dyskinesia (80 positive, 103 negative), assessed by Abnormal Involuntary Movement Scale (AIMS), positive and negative symptoms assessed by Positive and Negative Syndrome Scale (PANSS) and (3) cognition (299 cases, 245 controls), estimated by Penn Computerized Neurocognitive Battery, were analysed either using analysis of variance (ANOVA) or regression analysis. Main results No association of two SNPs with schizophrenia, but association of rs4680 (P < 0.05) with tardive dyskinesia was observed. On ANOVA, main effect of smoking [F(2,148) = 16.3; P = 3.9 × 10-7]; rs4680 [F(2,148) = 3.3; P = 0.04] and interaction effect of tardive dyskinesia-status∗Smoking [F(2,148) = 5.4, P = 0.006]; Smoking∗rs1076560 [F(3,148) = 3.6; P = 0.01]; Smoking∗rs4680 [F(4,148) = 5.3; P = 4.7 × 10-4] were significant with AIMS tardive dyskinesia score. The main effect of rs1076560 [F(2,148) = 4.5; P = 0.013] and rs4680 [F(2,148) = 4.0; P = 0.02] were significant with limb truncal tardive dyskinesia. Allelic/genotypic (P = 0.004/P = 0.01) association of rs1076560 with negative scale of PANSS in tardive dyskinesia-negative; diminished expression factor of PANSS in tardive dyskinesia-negative subcohort (allelic/genotypic P = 3.3 × 10-5/6.6 × 10-5) and tardive dyskinesia cohorts (P = 0.003/0.002); genotypic association (P = 0.05) with disorganised/concrete factor in tardive dyskinesia-positive subcohorts were observed by regression analysis using gPLINKv2.050. Further allelic/genotypic (P = 0.02) association of rs4680 with depressed factor of PANSS in tardive dyskinesia cohort was observed. Allelic/genotypic association of rs1076560 with abstraction and mental flexibilityaccuracy(P = 0.03/0.04), abstraction and mental flexibilityefficiency(P = 0.01/0.02); allelic association with spatial abilityprocessing speed(P = 0.03), emotionefficiency(P = 0.05); and with spatial abilityefficiency(genotypic, P = 0.05) in healthy controls and allelic association of rs4680 with emotionefficiencyin cases with schizophrenia (P = 0.04) were notable. Principal conclusion Dopaminergic genes seem to contribute to tardive dyskinesia and cognition warranting replication.