This study is the first extensive examination of the association between the neuropeptide Y system and alcohol dependence, alcohol withdrawal and cocaine dependence. We took a systems approach and analyzed not only the NPY gene but also three of its receptor genes. The strongest association we found was between a haplotype in NPY2R with alcohol dependence as well as with several subphenotypes, including alcohol withdrawal symptoms, alcohol dependence without comorbid cocaine dependence, comorbid alcohol and cocaine dependence, and cocaine dependence. For each of the phenotypes analyzed, the same haplotype was preferentially transmitted to alcohol dependent individuals, with the strongest association being with all alcohol dependent individuals (the numerically largest group) and those suffering from alcohol withdrawal. Due to ascertainment criteria for the sample, we had insufficient power to test for an association of NPY2R and cocaine dependence in subjects who were not also alcohol dependent. Our results suggest that sequence variations in the NPY system, specifically in NPY2R, are associated with alcohol dependence characterized by severe withdrawal, as was reported in humans by Koehnke et al (2002) and Okubo and
