A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States

Background: Quantitative trait locus studies, and observations in animals manipulated for the neuropeptide Y (NPY) gene suggest that variation within this gene may contribute to alcoholism. A recent population study suggested that the Pro7 allele of a functional NPY polymorphism (Leu7Pro) may be associated with increased alcohol consumption. We tested whether the Pro7 allele is associated with alcohol dependence in European Americans (EA). Methods: The design was a population study comparing the Leu7Pro allele frequencies in alcohol-dependent subjects and controls. Population stratification potential and diagnostic specificity was studied by genotyping individuals from additional populations and psychiatric diagnostic classes. We studied 2 independently collected samples of EA alcohol-dependent subjects (sample 1, n=307; sample 2, n=160) and a sample of psychiatrically screened EA controls (n=202); 8 population samples, including African Americans and European Americans (total n=551); and 4 samples of individuals with Alzheimer disease, schizophrenia, post-traumatic stress disorder, and major depression (total n=502). The main outcome measure was the difference in Leu7Pro allele frequencies between alcohol-dependent subjects and controls. Results: The frequency of the Pro7 allele was higher in the alcohol-dependent subjects (sample 1, 5.5%; sample 2, 5.0%) compared with the screened EA controls (2.0%) (sample 1 vs controls, P=.006; sample 2 vs controls, P=.03). The attributable fraction (excess morbidity) in similarly affected populations, owing to the Pro7 allele, was estimated to be 7.3%. The frequency of the Pro7 allele was equal or lower in the population samples, as compared with the screened EA controls (0%-2.2%), with 1 exception (Bedouins). We found no significant evidence that the association of the Pro7 allele with alcohol dependence was due to an association with a comorbid psychiatric disorder. Conclusions: These results suggest that the NPY Pro7 allele is a risk factor for alcohol dependence. This is only the second specific genetic mechanism ever identified that modulates risk for alcohol dependence.