Mapping and verification of susceptibility loci for smoking quantity using permutation linkage analysis.

Nicotine dependence is the most prevalent form of drug addiction in the US and throughout the world. Epidemiological studies demonstrate that genetics accounts for at least 50% of the liability to nicotine dependence. However, there have been very limited linkage studies providing convincing evidence of susceptibility genomic loci for this disorder. In this study, we conducted genome-wide permutation linkage analyses on the smoking data collected between 1970 and 1972 of the Framingham Heart Study (FHS) to account for the abnormality associated with the smoking quantity (defined as the number of cigarettes smoked per day). We used empirical thresholds obtained from permutation tests to determine the significance of each genomic region. The variance component method implemented in SOLAR was used for the analysis. Under the empirical genome-wide thresholds determined specifically for the FHS smoking data, we found two highly or near-highly significant linkages of nicotine dependence on chromosomes 1 and 4 (P=0.001) and eight significant linkages on chromosomes 3, 7, 8, 9, 11, 16, 17, and 20 (P<0.05). These findings strongly indicate that some of these regions may harbor susceptibility loci for nicotine dependence. Further analysis of these positive regions by fine mapping and/or association analysis is warranted. To our knowledge, this study presents the most convincing linkage evidence for nicotine dependence in the field.