Investigating the association between common DRD2/ANKK1 genetic polymorphisms and schizophrenia: a meta-analysis

Genetic factors play an important role in the pathogenesis of schizophrenia. Dysregulations in the dopaminergic system have long been known to play an influential role in the development of this disorder. Although a large number of studies have investigated the association between genetic polymorphisms in the genes involved in this system and the risk of schizophrenia, the results have been inconsistent. In this meta-analysis, we searched for publications in Ovid Medline, Embase, Web of Science (science citation index expanded), and PsycNET for articles published until January 2020. We identified case-control studies investigating the association between four common genetic polymorphisms (rs6277, rs1799732, rs1800497, and rs1801028) and the risk of schizophrenia. The studies were subsequently selected according to the predefined inclusion and exclusion criteria. The data extraction was conducted according to the PRISMA guidelines. We also assessed the quality of the studies and investigated publication bias using funnel plot and Egger's regression test. The association analysis was conducted in allelic, dominant, and recessive genetic models. Subsequently, bioinformatics analysis of the effect of the polymorphisms found to be significantly associated with schizophrenia on protein stability, posttranslational modifications, and 3D protein structure was conducted. This meta-analysis showed that Taq1A (allelic model: OR, 0.856, 95% CI, 0.734-0.998) has a protective effect against the development of schizophrenia. Further, it was found that this variant may decrease ANKK1 protein stability. Further, this polymorphism was found to lead to the gain of modifications sites for ubiquitination (Ubi. score = -1.894) and methylation (Meth. score = -0.834). Several genetic factors contribute to the susceptibility of schizophrenia. The updated knowledge emerging from this meta-analysis showing the protective effect of rs1800497 polymorphism (Taq1A) can shed light on the role of Taq1A polymorphism in the susceptibility to schizophrenia and also pave way for further functional studies investigating the role of ANKK1 protein in the pathogenesis of schizophrenia.