RhoA, encoding a Rho GTPase, is associated with smoking initiation

We used microarray analysis of acute nicotine responses in mouse brain to choose rationale candidates for human association studies on tobacco smoking and nicotine dependence (ND). Microarray studies on the time-course of acute response to nicotine in mouse brain identified 95 genes regulated in ventral tegmental area. Among these, 30 genes were part of a gene network, with functions relevant to neural plasticity. On this basis and their known roles in drug abuse or synaptic plasticity, we chose the genes RhoA and Ywhag as candidates for human association studies. A synteny search identified human orthologs and we investigated their role in tobacco smoking and ND in a human case-control association study. We genotyped five and three single nucleotide polymorphisms from the RhoA and Ywhag genes, respectively. Both single marker and haplotype analyses were negative for the Ywhag gene. For the RhoA gene, rs2878298 showed highly significant genotypic association with both smoking initiation (SI) and ND (P = 0.00005 for SI and P = 0.0007 for ND). In the allelic analyses, rs2878298 was only significant for SI. In the multimarker haplotype analyses, significant association with SI was found for the RhoA gene (empirical global P values ranged from 9 x 10(-5) to 10(-5)). In all multimarker combinations analyzed, with or without inclusion of the single most significant marker rs2878298, identical risk and protective haplotypes were identified. Our results indicated that the RhoA gene is likely involved in initiation of tobacco smoking and ND. Replication and future model system studies will be needed to validate the role of RhoA gene in SI and ND.