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A Functional Neuropeptide Y Leu7Pro Polymorphism Associated With Alcohol Dependence in a Large Population Sample From the United States
Jaakko Lappalainen, MD, PhD;
Henry R. Kranzler, MD;
Robert Malison, MD;
Lawrence H. Price, MD;
Christopher Van Dyck, MD;
Robert A. Rosenheck, MD;
Joyce Cramer, BS;
Steven Southwick, MD;
Dennis Charney, MD;
John Krystal, MD;
Joel Gelernter, MD
Arch Gen Psychiatry. 2002;59:825-831.
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.
From the Department of Psychiatry, Yale University School of Medicine,
New Haven, Conn (Drs Lappalainen, Malison, Van Dyck, Rosenheck, Southwick,
Charney, Krystal, and Gelernter, and Ms Cramer), the Veterans Administration
Connecticut Healthcare System, West Haven (Drs Lappalainen, Rosenheck, Southwick,
Krystal, and Gelernter, and Ms Cramer), the Department of Psychiatry, University
of Connecticut School of Medicine, Farmington (Dr Kranzler); and Butler Hospital
and the Department of Psychiatry and Human Behavior, Brown University School
of Medicine, Providence, RI (Dr Price).
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