This study has some limitations. First, alcohol-related traits were measured only among cases but not controls. This is not a problem for age-at-onset of AD and withdrawal, which are only meaningful in AD cases. For initial sensitivity, without information from a general population sample, our association findings have limited generalizability. It would be ideal to test for gene effects for initial sensitivity on alcohol use in the general population. Second, our association results do not directly address whether there is functional variation in the GAD genes that is related to expression level change of GAD. Addressing this question requires a different study design. Third, although the LD patterns of both GAD genes are compatible with Hapmap CEPH population data, it remains possible that we do not have a full coverage set of SNPs to detect potential association in these genes, especially rare functional polymorphisms. Finally, whereas GAD genes are our main focus in the present study, we did not include genes encoding for the downstream product GABA, and several GABA receptor genes. In future studies we plan to examine the roles of GABA receptor genes and to conduct pathway analysis for genes involved in the inhibitory neurotransmission system.
