Effect of rs1108580 of DBH and rs1006737 of CACNA1C on Cognition and Tardive Dyskinesia in a North Indian Schizophrenia Cohort

Abstract

Genetic perturbations in dopamine neurotransmission and calcium signaling pathways are implicated in the etiology of schizophrenia. We aimed to test the association of a functional splice variant each in Dopamine β-Hydroxylase (DBH; rs1108580) and Calcium voltage-gated channel subunit alpha1 C (CACNA1C; rs1006737) genes in these pathways with schizophrenia (506 cases, 443 controls); Abnormal Involuntary Movement Scale (AIMS) scores in subjects assessed for tardive dyskinesia (76 TD-positive, 95 TD-negative) and Penn Computerized Neurocognitive Battery (PennCNB) scores (334 cases, 234 controls). The effect of smoking status and SNP genotypes on AIMS scores were assessed using ANOVA; health status and SNP genotypes on three performance functions of PennCNB cognitive domains were assessed by ANCOVA with age and sex as covariates. Association with Positive and Negative Syndrome Scale (PANSS) scores in the TD cohort and cognitive scores in healthy controls of the cognition cohort were tested by linear regression. None of the markers were associated with schizophrenia. Smoking status [F(2, 139) = 10.6; p = 5 × 10^-5], rs1006737 [F(2, 139) = 7.1; p = 0.001], TD status*smoking [F(2, 139) = 8.0; p = 5.0 × 10^-4] and smoking status*rs1006737 [F(4, 139) = 2.7; p = 0.03] had an effect on AIMS score. Furthermore, rs1006737 was associated with orofacial [F(2, 139) = 4.6; p = 0.01] and limb-truncal TD [(F(2, 139) = 3.8; p = 0.02]. Main effect of rs1108580 on working memory_{processing speed} [F(2, 544) = 3.8; p = 0.03] and rs1006737 on spatial ability_efficiency [F(1, 550) = 9.4; p = 0.02] was identified. Health status*rs1006737 interaction had an effect on spatial memory_{processing speed} [F(1, 550) = 6.9; p = 0.01]. Allelic/genotypic association (p = 0.01/0.03) of rs1006737 with disorganized/concrete factor and allelic association of rs1108580 (p = 0.04) with a depressive factor of PANSS was observed in the TD-negative subcohort. Allelic association of rs1006737 with sensorimotor dexterity_accuracy (p = 0.03), attention_efficiency (p = 0.05), and spatial ability_efficiency (p = 0.02); allelic association of rs1108580 with face memory_accuracy (p = 0.05) and emotion_efficiency (p = 0.05); and allelic/genotypic association with emotion_accuracy (p = 0.003/0.009) were observed in healthy controls of the cognition cohort. These association findings may have direct implications for personalized medicine and cognitive remediation.

Keywords: Cognition; Dopamine beta-hydroxylase; L-type calcium channel alpha(1C); Schizophrenia; Tardive dyskinesia; rs1006737; rs1108580.