1. ¹Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia, USA
2. ²Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia, USA
3. ³Institute of Bioinformatics, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China

Correspondence: Professor MD Li, Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, 1670 Discovery Drive, Suite 110, Charlottesville, VA 22911, USA. Tel: +1 434 243 0570; Fax: +1 434 973 7031; E-mail: Ming_Li@virginia.edu

Received 7 January 2009; Revised 28 April 2009; Accepted 11 May 2009; Published online 24 June 2009.

Abstract

Substance P (SP), a neurotransmitter in stress pathways, exerts its effects mainly through the neurokinin-1 receptor (NK1R). Genetic and pharmacological studies show that binding of ligands to NK1R decreases anxiety-related behaviors, and therefore, self-administration of alcohol in mice and craving for alcohol in humans. As genetic variants may result in differential expression of the receptor through various molecular mechanisms, we examined whether allelic variations in the NK1R gene are associated with alcohol dependence (AD) by genotyping 11 single-nucleotide polymorphisms (SNPs) across NK1R in alcoholic (n=271) and healthy control (n=337) participants of Caucasian descent. The AD was diagnosed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Associations of the SNPs with AD were assessed at both the individual SNP and haplotype levels. We found that genotype and allele frequencies of rs6715729, a synonymous SNP in exon 1, differed significantly in alcoholics and in controls (p=0.0006; OR (odds ratio)=6.13; 95% CI=4.06, 9.23). Haplotype analyses indicated two risk haplotypes for AD in the 5' end of the gene, formed by the three-SNP combinations rs6715729–rs735668–rs6741029. Taken together, we conclude that polymorphisms of NK1R are significantly associated with the development of AD in Caucasian individuals. Additional studies are needed to replicate these results in other samples and to elucidate the mechanism(s) by which these polymorphisms affect NK1R function in the brain.