Genomewide linkage scan for nicotine dependence: Identification of a chromosome 5 risk locus
Genomewide linkage scan for nicotine dependence: Identification of a chromosome 5 risk locus
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DOI：
10.1016/j.biopsych.2006.08.023
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发表时间：
2007-01-01
影响因子：
10.6
通讯作者：
Kranzler, Henry R.
中科院分区：
文献类型：
--
作者：
Gelernter, Joel;Panhuysen, Carolien;Kranzler, Henry R.
背景：尼古丁依赖（AD）在世界范围内是一种代价昂贵的疾病，具有中等遗传性，遗传复杂，可以通过独立于先前生理假设的遗传连锁分析来识别风险位点。方法：我们完成了全基因组连锁扫描，绘制了增加DSM-IV尼古丁依赖风险的位点，并通过Fagerstrom尼古丁依赖测试（FTND）在634个小核心家庭中进行了ND的定量评估，这些家庭是基于多个受可卡因或阿片类药物依赖影响的个体确定的。其中507例至少有2例受试者患有ND。在这个样本中有两个不同的人群，欧洲裔美国人（EAs）和非洲裔美国人（AAs）。根据我们样本中AA组的FTND评分，5号染色体上的一个区域被鉴定为含有影响ND风险的基因（几率[lod]的对数为3.04；经验确定为全基因组显著，P= 0.0374；点P= 0.0001）。样品EA部分lod评分最高的是7号染色体（lod评分2.73）。在AA或EA受试者中发现了其他几个“可能的”风险位点，其中许多与先前从其他临床样本中发现的风险位点接近。在5号染色体连锁峰下的肽酰甘氨酸酰胺化单加氧酶（PAM）位点上发现了三个名义上显著的单核苷酸多态性关联，在样品的AA部分也是如此。结论：这些数据为ND风险位点的定位提供了越来越多的证据，增加了一个在AAs中重要的具有统计学意义的新位点，并表明一个基因可能有助于这种连锁信号。
Background: Nicotine dependence (AD) is costly to societies worldwide, moderately heritable, and genetically complex, Risk loci can be identified with genetic linkage analysis independent of prior physiological hypotheses.Methods: 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, 50 7 had at least two subjects affected with ND. There are two distinct populations within this sample, European-Americans (EAs) and Afiican-Americans (AAs).Results. 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 pan 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.Conclusions: 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.