A STUDY ON THE ASSOCIATION OF POLYMORPHISMS AND METHYLATION STATUS OF DOPAMINE PATHWAY GENES IN ALCOHOL DEPENDENCE

Background Alcohol Dependence (AD), a chronic relapsing disorder, is a serious social and public health concern globally. Risk of AD is reportedly increased due to polymorphisms and methylation changes affecting transcription of the genes involved in various dopamine neurotransmitter gene pathways. The aim of this study was to identify polymorphisms and methylation changes in the SNCA and DAT genes of dopamine pathway in subjects with AD. Methods A total of 145 AD subjects from the outpatient department of Psychiatry and 110 healthy volunteers were recruited for the study. All subjects were interviewed with a semi-structured and WHO assist questionnaire. Blood samples drawn were subjected to DNA extraction, followed by sodium bisulphite modification and methylation specific PCR of the SNCA and DAT genes. DNA was also used to screen six polymorphisms of the dopamine pathway namely DRD4 120 bp duplication, DRD3 Ser9Gly, DRD2 Taq1α, COMT rs4680, COMT-287A>G and DRD4 -521C/T by PCR/RFLP. Genotype frequencies were calculated and their significance assessed using chi-square test and correlated with duration of alcohol use, age at onset of alcohol use, quantity of alcohol consumed (gms/day) and liver function. Statistical analysis was done through SPSS software V21.0. Results Of all the polymorphisms studied COMT Val158Met (rs4680) showed significant association with AD (p-0.03) compared to the others. SNCA gene methylation levels were significantly different between AD subjects and controls (p Discussion In the present study, significant difference between COMT rs4680 was observed between cases and controls. More heterozygosity was observed in cases which imply presence of low activity allele of COMT gene which affects the activity of enzyme and makes the individual more vulnerable to alcohol dependence. However, increased methylation at promoter region of DAT gene with both age and duration of alcohol use may lead to less re-uptake of dopamine from the synapse. Whereas, decreased methylation at promoter region of SNCA gene may help in the formation of synapse and hence increased dopamine neurotransmission. Therefore, this preliminary report suggests association of COMT rs4680 and methylation changes of SNCA and DAT genes with alcohol dependence.