Fine mapping of alcoholism related phenotypes on chromosome 1

The goal of the Collaborative Study on the Genetics of Alcoholism (COGA) is to elucidate genetic risk factors for alcoholism and alcohol-related phenotypes. A two-stage linkage strategy has been used in large families multiply affected by alcohol dependence. A 20cM genome-wide screen was initially performed in 984 individuals from 105 families. This study reported linkage between COGA alcohol dependence and markers on chromosome 1, 2 and 7. These regions were followed up in the initial sample and in a replication sample of 1295 individuals in 157 families. Here we report replication of the linkage between COGA alcohol dependence and markers on the long arm of chromosome 1. Further, we report co-localization of linkage signals for marijuana dependence, cocaine dependence, alcohol dependence or depression, low level of response to alcohol and amplitude of the EEG alpha wave. All phenotypes showed linkage to markers in a 20cM region between D1S2613 and D1S1588. We are now using fine mapping and positional candidate gene analysis to search for the genetic risk factor(s) detected by these linkage results. At least thirty genes are already known to map to this interval including the phosphodiesterase 4B (PDE4B) gene, a human homologue of the Drosophila gene, dunce. Dunce is known to be involved in an ethanol responsive pathway in fruit flies. We have identified several single nucleotide polymorphisms within the human homologue of dunce and have analyzed these polymorphisms in the COGA families.