Susceptibility genes for nicotine dependence: a genome scan and followup in an independent sample suggest that regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study

(C)igarette smoking is associated with considerable morbidity, mortality, a nd public health costs. Genetic factors influence both smoking initiation a nd nicotine dependence, but none of the genes involved have been identified . A genome scan using 451 markers was conducted to identify chromosomal reg ions linked to nicotine dependence in a collection of 130 families containi ng 343 genotyped individuals (308 nicotine-dependent) from Christchurch, Ne w Zealand. By pairwise analysis, the best result was with marker D2S1326 wh ich gave a rod score under heterogeneity (H-LOD) of 2.63 (P = 0.0012) and a nonparametric linkage (NPL, Z(all)) score of 2.65 (P = 0.0011). To identif y regions that warranted further study, rather than comparing the pairwise scores from the scan to theoretical thresholds, we compared them to an em p irical baseline, found here to be H-LOD scores of 0.5 and Z(all) scores of 1.0. We also found a number of targe (31-88 cM) regions where many (8-16) c onsecutive markers yielded small but positive Z(all) scores. Selected regio ns of chromosomes 2, 4, 10, 16, 17 and 18 were investigated further by addi tional genotyping of the Christchurch sample and an independent sample from Richmond, Virginia (91 families with 264 genotyped individuals, 211 nicoti ne-dependent). Multipoint nonparametric analysis showed the following maxim ums for the Christchurch sample: Chr. 2 (Z(lr) = 2.61, P = 0.005), Chr. 4 ( Z(lr) = 1.36, P = 0.09), Chr. 10 (Z(lr) = 2.43, P = 0.008), Chr. 16 (Z(lr) = 0.85, P = 0.19), Chr. 17 (Z(lr) = 1.64, P = 0.05), Chr. 18 (Z(lr) = 1.54, P = 0.06). Analysis of the Richmond sample showed the following maximums: Chr. 2 (Z(lr) = 1.00, P = 0.15), Chr. 4 (Z(lr) = 0.39, P = 0.34), Chr. 10 ( Z(lr) = 1.21, P = 0.11), Chr. 16 (Z(lr) = 1.11, P = 0.13), Chr. 17 (Z(lr) = 1.60, P = 0.05), Chr. 18 (Z(lr) = 1.33, P = 0.09). It is probable that the small samples used here provided only limited power to detect linkage. It may have been difficult therefore to detect genes of small effect, or those that are influencing risk in only a small proportion of the families. When simply judged against the usual standards of linkage significance, none of the individual regions yielded strong evidence in either sample. Some or a ll of the most positive results in the genome scan of the Christchurch samp le, therefore, could be due to chance. However, the presence in the Christc hurch scan of multiple large regions containing many consecutive positive m arkers, coupled with the relatively positive results in these same regions in the Richmond sample, suggests that some of these regions may contain gen es influencing nicotine dependence and therefore deserve further study.