Gelernter Joel, Panhuysen Carolien, Weiss Roger, Brady Kathleen, Poling James, Krauthammer Michael, Farrer Lindsay, Kranzler Henry R
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06516, USA.
Biol Psychiatry. 2007 Jan 1;61(1):119-26. doi: 10.1016/j.biopsych.2006.08.023. Epub 2006 Nov 1.
Nicotine dependence (ND) is costly to societies worldwide, moderately heritable, and genetically complex. Risk loci can be identified with genetic linkage analysis independent of prior physiological hypotheses.
We completed a genomewide linkage scan to map loci increasing risk for DSM-IV ND and for a quantitative assessment of ND as measured by the Fagerstrom Test for Nicotine Dependence (FTND) in a set of 634 small nuclear families ascertained on the basis of multiple individuals affected with cocaine or opioid dependence. Of these, 507 had at least two subjects affected with ND. There are two distinct populations within this sample, European-Americans (EAs) and African-Americans (AAs).
A region on chromosome 5 was identified as containing a gene that affects risk for ND on the basis of FTND score in the AA part of our sample (logarithm of the odds [lod] score 3.04; empirically determined to be genomewide-significant, p = .0374; point p = .0001). The highest lod score observed in the EA part of the sample was on chromosome 7 (lod score 2.73). Several other "possible" risk loci were identified in either AA or EA subjects, with many of these in proximity to previously suggested risk loci from other clinical samples. Three nominally significant single-nucleotide polymorphism associations were found at the peptidylglycine alpha-amidating monooxygenase (PAM) locus under the chromosome 5 linkage peak, also in the AA part of the sample.
These data add to the growing evidence for locations for ND risk loci, add a novel statistically significant locus important in AAs, and suggest a gene that might be contributing to this linkage signal.
尼古丁依赖（ND）在全球范围内给社会带来高昂代价，具有中度遗传性且遗传机制复杂。风险基因座可通过遗传连锁分析来识别，而无需依赖先前的生理学假设。
我们完成了一项全基因组连锁扫描，以绘制增加DSM-IV尼古丁依赖风险的基因座，并通过尼古丁依赖Fagerstrom测试（FTND）对尼古丁依赖进行定量评估。该扫描基于多个受可卡因或阿片类药物依赖影响的个体，在一组634个小核家庭中进行。其中，507个家庭至少有两名受尼古丁依赖影响的受试者。该样本中有两个不同的群体，即欧裔美国人（EA）和非裔美国人（AA）。
在我们样本的非裔美国人部分，基于FTND评分，5号染色体上的一个区域被确定包含一个影响尼古丁依赖风险的基因（优势对数[lod]评分为3.04；经实证确定具有全基因组显著性，p = 0.0374；单点p = 0.0001）。在样本的欧裔美国人部分观察到的最高lod评分位于7号染色体上（lod评分为2.73）。在非裔美国人或欧裔美国人受试者中还发现了其他几个“可能的”风险基因座，其中许多与先前其他临床样本中提出的风险基因座相邻。在5号染色体连锁峰下的肽基甘氨酸α-酰胺化单加氧酶（PAM）基因座也在样本的非裔美国人部分发现了三个名义上显著的单核苷酸多态性关联。
这些数据进一步证明了尼古丁依赖风险基因座的位置，增加了一个在非裔美国人中重要的新的具有统计学显著性的基因座，并提示了一个可能导致这种连锁信号的基因。
