An Association Study on the Glutamate Pathway GRIN2A Gene Polymorphisms with Heroin Dependence

Abstract

Background: Heroin dependence (HD) is a complex disorder characterized by disruption in particular circuits of the brain and influenced by environmental and genetic factors. Glutamate pathway plays a role in normal brain functions including learning, memory, and cognition. Disturbances in Glutamate pathways are implicated in many psychiatric disorders, including heroin dependence, and polymorphisms present in these pathway genes are reported to increase the risk of developing heroin dependence. Aim: To identify association of single nucleotide polymorphisms (SNPs) of Glutamate pathway genes with heroin dependence and correlate with heroin use parameters. Method: A total of 103 HD patients were recruited as per DSM IV criteria from the Department of Psychiatry, and 100 healthy volunteers from the general population. Genomic DNA from peripheral blood samples was processed for PCR followed by restriction digestion to screen for presence of GRIN2A polymorphisms in the glutamate pathway. GRIN2A SNPs i.e. rs11866328, rs1071502, rs1375067, rs1530669, rs12325652, rs16966381, rs1104068, rs16966448, rs9927871 and rs1366076 were selected based on the Hap Map project and Tagger program (r2 ≥ 0.8). Genotype and allele frequencies were estimated and the difference between patient and control groups were assessed by chi-square test of significance and the results correlated with duration, age at onset of heroin use, the quantity of heroin consumed and WHO ASSIST score. Statistical analysis was done using Haploview v4.1 and SPSSv21.0. Results: Haplotype analyses revealed three SNPs (rs1071502-rs1366076-rs1104068) with alleles A-T-A to confer risk while the haplotypes A-T-G had a protective effect on HD. Another haplotype (rs1530669-rs9927871) was also found significantly associated with heroin dependence (p=0.039). Conclusion: The study reports for the first time, a possible association of GRIN2A SNPs with age at onset of heroin use, duration and quantity of use, and also suggests an important role in severity of heroin dependence.