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, posttraumatic 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.
Lappalainen
Jaakko
J
Yale University School of Medicine, Department of Psychiatry, VA Connecticut Healthcare System, 950 Campbell Ave, Psychiatry 116A2, West Haven, CT 06516, USA.
Kranzler
Henry R
HR
Malison
Robert
R
Price
Lawrence H
LH
Van Dyck
Christopher
C
Rosenheck
Robert A
RA
Cramer
Joyce
J
Southwick
Steven
S
Charney
Dennis
D
Krystal
John
J
Gelernter
Joel
J
D000428:Alcohol Drinking / Q000235:genetics; D000437:Alcoholism / Q000453:epidemiology / Q000235:genetics*; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D015897:Comorbidity; D003866:Depressive Disorder / Q000453:epidemiology / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005060:Europe / Q000208:ethnology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D008297:Male; D009478:Neuropeptide Y / Q000235:genetics*; D011110:Polymorphism, Genetic; D044469:Racial Groups / Q000235:genetics; D012559:Schizophrenia / Q000453:epidemiology / Q000235:genetics; D013313:Stress Disorders, Post-Traumatic / Q000453:epidemiology / Q000235:genetics; D014481:United States / Q000453:epidemiology; D001741:Black or African American
D009478:Neuropeptide Y