Association of NPY Receptor 2 Polymorphism with Alcohol Dependence

Einleitung: Alcohol dependence (AD) contributes substantially to the global burden of disease. It's etiology involves both environmental and genetic factors with an estimated heritability of around 50%. Several lines of evidence suggest that the neuropeptide Y system plays a role in ethanol consumption: NPY knock-out mice consumed more alcohol than the wild-type, and NPY infusion reduced ethanol intake in rats. A recent study reported that activation/inhibition of the NPF system reduced/strengthened ethanol preference in drosophila. NPF receptors in drosophila are homologs of human NPY receptors. Following this rationale, we tested the genes encoding NPY and its receptors for association with AD in a large GWAS on AD.

Methode: Sample: 1333 male in-patients with severe AD according to DSM-IV and 2168 controls, all of German ancestry. Patients had been recruited from consecutive admissions to psychiatry and addiction medicine departments of German psychiatric hospitals participating in the German addiction research network. Genotyping: Illumina HumanHap550 (patients and controls), Human610Quad (patients) or Illumina Human660w Quad BeadChips (patients). Statistical Analysis: PLINK and R software packages were used for quality control (QC) and association testing. Stringent QC criteria were applied, including e.g. sample and marker call rate >= 0.98, outlier removal, conformity of markers with Hardy-Weinberg-Equilibrium, MAF >= 0.01 in all subsamples. Testing was done with logistic regression models including correction for population stratification.

Diskussion/Ergebnisse: In our systematic analysis of the NPY system the strongest association signal with AD was obtained for rs6857715 in the NPY2R gene (p = 0.0047), surviving correction for multiple testing. The 5'-region of the NPY2R gene harbouring rs6857715 is rich in functional signatures).

Schlussfolgerung: A sequence variation in the 5'-region of the NPY2R gene is significantly associated with AD. This finding replicates a previously reported association of the rs6857715 variant with AD. For genes of the NPY system other than NPY2R, no association could be detected. This is also consistent with previously reported findings. Our findings are in line with previously reported observations where genes of the NPY system were found involved in alcohol-related phenotypes in mammalian and invertebrate models of AD.