Straub R E, Sullivan P F, Ma Y, Myakishev M V, Harris-Kerr C, Wormley B, Kadambi B, Sadek H, Silverman M A, Webb B T, Neale M C, Bulik C M, Joyce P R, Kendler K S
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-1534, USA.
Mol Psychiatry. 1999 Mar;4(2):129-44. doi: 10.1038/sj.mp.4000518.
Cigarette smoking is associated with considerable morbidity, mortality, and public health costs. Genetic factors influence both smoking initiation and nicotine dependence, but none of the genes involved have been identified. A genome scan using 451 markers was conducted to identify chromosomal regions linked to nicotine dependence in a collection of 130 families containing 343 genotyped individuals (308 nicotine-dependent) from Christchurch, New Zealand. By pairwise analysis, the best result was with marker D2S1326 which gave a lod score under heterogeneity (H-LOD) of 2.63 (P=0.0012) and a nonparametric linkage (NPL, Zall) score of 2.65 (P=0.0011). To identify regions that warranted further study, rather than comparing the pairwise scores from the scan to theoretical thresholds, we compared them to an empirical baseline, found here to be H-LOD scores of 0.5 and Zall scores of 1.0. We also found a number of large (31-88 cM) regions where many (8-16) consecutive markers yielded small but positive Zall scores. Selected regions of chromosomes 2, 4, 10, 16, 17 and 18 were investigated further by additional genotyping of the Christchurch sample and an independent sample from Richmond, Virginia (91 families with 264 genotyped individuals, 211 nicotine-dependent). Multipoint nonparametric analysis showed the following maximums for the Christchurch sample: Chr. 2 (Zlr=2.61, P=0.005), Chr. 4 (Zlr=1.36, P=0.09), Chr. 10 (Zlr=2.43, P=0.008), Chr. 16 (Zlr=0.85, P=0.19), Chr. 17 (Zlr=1.64, P=0.05), Chr. 18 (Zlr=1.54, P=0.06). Analysis of the Richmond sample showed the following maximums: Chr. 2 (Zlr=1.00, P=0.15), Chr. 4 (Zlr=0.39, P=0.34), Chr. 10 (Zlr=1.21, P=0.11), Chr. 16 (Zlr=1.11, P=0.13), Chr. 17 (Zlr=1.60, P=0.05), Chr. 18 (Zlr=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 all of the most positive results in the genome scan of the Christchurch sample, therefore, could be due to chance. However, the presence in the Christchurch scan of multiple large regions containing many consecutive positive markers, coupled with the relatively positive results in these same regions in the Richmond sample, suggests that some of these regions may contain genes influencing nicotine dependence and therefore deserve further study.
吸烟与相当高的发病率、死亡率及公共卫生成本相关。遗传因素影响吸烟行为的起始及尼古丁依赖，但相关基因均未被识别。在来自新西兰克赖斯特彻奇的130个家庭（包含343名基因分型个体，其中308名有尼古丁依赖）中，利用451个标记进行了全基因组扫描，以识别与尼古丁依赖相关的染色体区域。通过成对分析，最佳结果来自标记D2S1326，其在异质性下的对数优势分数（H-LOD）为2.63（P = 0.0012），非参数连锁（NPL，Zall）分数为2.65（P = 0.0011）。为了识别值得进一步研究的区域，我们并非将扫描得到的成对分数与理论阈值进行比较，而是与一个经验基线进行比较，此处发现经验基线为H-LOD分数0.5和Zall分数1.0。我们还发现了一些大的（31 - 88厘摩）区域，其中许多（8 - 16个）连续标记产生了小但为正的Zall分数。通过对克赖斯特彻奇样本以及来自弗吉尼亚州里士满的一个独立样本（91个家庭，264名基因分型个体，211名有尼古丁依赖）进行额外的基因分型，对染色体2、4、10、16、17和18的选定区域进行了进一步研究。多点非参数分析显示，克赖斯特彻奇样本的最大值如下：染色体2（Zlr = 2.61，P = 0.005），染色体4（Zlr = 1.36，P = 0.09），染色体10（Zlr = 2.43，P = 0.008），染色体16（Zlr = 0.85，P = 0.19），染色体17（Zlr = 1.64，P = 0.05），染色体18（Zlr = 1.54，P = 0.
