Genetic Variation in the Vesicular Monoamine Transporter 1 (VMAT1/SLC18A1) Gene and Alcohol Withdrawal Severity

Alcohol withdrawal (AW) can be a serious consequence of alcohol dependence and consists of various neurochemical adaptations in the brain. One such neuroadaptation occurs in the monoamine neurotransmitter system. Recently, a functional variant in the presynaptic vesicular monoamine transporter gene (VMAT1/SLC18A1-Thr136Ile-rs1390938) was found to significantly increase transport of monoamines into synaptic vesicles in vitro. We hypothesize that the alteration of magnitude of monoamine release contributes to severity of AW symptoms.

Alcohol-dependent individuals (n = 609; European American n = 340; African American n = 216; other n = 53) were administered the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) questionnaire at the time of inpatient admission. Patients were subsequently genotyped for 12 single nucleotide polymorphism (SNP) markers in VMAT1. Association analyses were conducted on the combined sample and separated by ethnicity.

Single marker association tests revealed a significant association between 3 VMAT1 markers and CIWA-Ar scores in the EA sample. The minor alleles of rs1390938 (A) and rs952859 (C) were significantly associated with lower CIWA-Ar scores (p = 0.0006; p = 0.0007), whereas the minor allele of rs3779672 (G) was significantly associated with higher scores (p = 0.006). Additionally, these 3 SNPs were found in a haplotype block that was significantly associated with lower CIWA-Ar scores after haplotype analyses were run (p = 0.009).

This study shows that genetic variants in VMAT1, including the functional SNP rs1390938, contribute to the severity of AW in patients of European descent. Our data show for the first time a role of presynaptic neurotransmitter release in AW severity. This finding could contribute to identifying patients at risk for severe AW and shed light into the pathophysiology of AW and its treatment.