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Susceptibility locus in neurokinin-1 receptor gene associated with alcohol dependence.

Seneviratne C, Ait-Daoud N, Ma JZ, Chen G, Johnson BA, Li MD - Neuropsychopharmacology (2009)

Bottom Line: Substance P (SP), a neurotransmitter in stress pathways, exerts its effects mainly through the neurokinin-1 receptor (NK1R).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia 22911, USA.

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.

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Related in: MedlinePlus

Linkage disequilibrium analysis of NK1R SNPs in Caucasian alcohol dependent and control samples. Values in squares are r2 numbers.
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Figure 1: Linkage disequilibrium analysis of NK1R SNPs in Caucasian alcohol dependent and control samples. Values in squares are r2 numbers.

Mentions: We employed Haploview to calculate pair-wise correlation coefficients (r2, the squared total linkage disequilibrium divided by the product of the allelic frequencies at both loci) to detect haplotype blocks among all 11 SNPs according to the criteria defined by Gabriel et al. (2002). As shown in Figure 1, we detected three haplotype blocks in the control sample. These blocks, each comprising two-SNP combinations, were located at the 5’ end of the gene, around exon 2, and at the 3’ end of the gene: rs2111375–rs6715729, 1 kb; rs735668-rs6741029, 17kb; rs1106855-rs881, 2kb. In contrast, we did not detect any haplotype blocks in the AD sample.


Susceptibility locus in neurokinin-1 receptor gene associated with alcohol dependence.

Seneviratne C, Ait-Daoud N, Ma JZ, Chen G, Johnson BA, Li MD - Neuropsychopharmacology (2009)

Linkage disequilibrium analysis of NK1R SNPs in Caucasian alcohol dependent and control samples. Values in squares are r2 numbers.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2743763&req=5

Figure 1: Linkage disequilibrium analysis of NK1R SNPs in Caucasian alcohol dependent and control samples. Values in squares are r2 numbers.
Mentions: We employed Haploview to calculate pair-wise correlation coefficients (r2, the squared total linkage disequilibrium divided by the product of the allelic frequencies at both loci) to detect haplotype blocks among all 11 SNPs according to the criteria defined by Gabriel et al. (2002). As shown in Figure 1, we detected three haplotype blocks in the control sample. These blocks, each comprising two-SNP combinations, were located at the 5’ end of the gene, around exon 2, and at the 3’ end of the gene: rs2111375–rs6715729, 1 kb; rs735668-rs6741029, 17kb; rs1106855-rs881, 2kb. In contrast, we did not detect any haplotype blocks in the AD sample.

Bottom Line: Substance P (SP), a neurotransmitter in stress pathways, exerts its effects mainly through the neurokinin-1 receptor (NK1R).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia 22911, USA.

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.

Show MeSH
Related in: MedlinePlus