Utilizing Interaction to Identify Novel Genetic Factors for Nicotine Dependence

描述(申请人提供)：吸烟是癌症、心脏病、中风和肺部疾病的主要诱因，也是美国和世界范围内可预防的死亡的主要原因。尼古丁依赖(ND)和其他吸烟表型的全基因组关联研究(GWAS)已明确地发现与跨越15q25(CHRNA5-CHRNA3-CHRNB4)和8p11(CHRNB3-CHRNA6)上的烟碱型乙酰胆碱受体(NAChR)基因的单核苷酸多态(SNPs)相关。这些功能变异改变了戒烟治疗的反应，并与吸烟的健康后果独立相关。然而，他们解释了吸烟表型变异的10%。在这项研究中，我们将超越标准的GWA，进行第一项研究，应用基因-基因相互作用的联合2自由度(2DF)统计方法。这将是对新城疫最大的全基因组研究。新开发的联合2DF方法同时考虑了SNP的主要效应和相互作用，但并不侧重于检测相互作用本身。相反，该方法利用交互作用来增加SNP关联测试的能力。当考虑基因-环境交互作用时，它已被用来成功地识别在其他复杂性状的标准GWAS中遗漏的SNP关联。在这里，我们将应用联合2DF方法来同时考虑SNP主要关联及其与已建立的nAChR变体的相互作用。我们利用了我们的新城疫合作遗传研究(COGEND)、deCODE遗传学和其他可通过Fagerstrom尼古丁依赖测试(FTND)数据获得的基因型和表型数据库(DBGaP)的现有Gwas数据：23,000名参与者的集体规模。在Aim1中，我们将获得14个研究样本的全基因组SNP基因数据，并协调它们的FTND表型数据。使用COGEND和DeCODE Genetics(总N=10,319名高加索人)，我们将并行进行ND的全基因组联合2DF荟萃分析，考虑与CHRNA5-CHRNA3-CHRNB4(目标2)或CHRNB3-CHRNA6(目标3)的相互作用。来自联合2DF荟萃分析的顶级SNP将使用生物信息学分析进行优先排序，以评估它们的注释、功能和监管潜力。在目标4a中，我们将选择向上 在来自DBGaP的7个独立的高加索人样本中进行复制测试的100个顶级SNP(总N=8913)。从AIM 4a复制的SNP将使用我们的两个非裔美国人样本和三个DBGaP样本(总N=4,145)在Aim 4b中进一步测试与ND的关联。我们先前对吸烟和其他人的GWA研究发现了强大的、功能上重要的变异，这些变异也有助于戒烟治疗反应和吸烟相关疾病(例如肺癌)。这项研究利用这些早期的发现和一种新的统计方法来发现导致ND的新的变种，这可能类似地增加我们对戒烟和吸烟的健康后果的理解。

DESCRIPTION (provided by applicant): Cigarette smoking is a major contributor to cancer, heartdisease, stroke, and lung disease and is the leading cause of preventable mortality in the United States and worldwide. Genome-wide association studies (GWAS) of nicotine dependence (ND) and other smoking phenotypes have unequivocally identified associations with single nucleotide polymorphisms (SNPs) spanning the nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25 (CHRNA5-CHRNA3-CHRNB4) and on chromosome 8p11 (CHRNB3- CHRNA6). The functional variants alter cessation treatment response and are independently associated with health consequences of smoking. However, they explain <10% of the phenotypic variability for smoking. In this study, we will move beyond standard GWAS, conducting the first study to apply the joint 2 degree-of- freedom (2df) statistical method using gene-gene interaction. It will be the largest genome-wide study of ND. The newly developed joint 2df method simultaneously considers SNP main and interactive effects but does not focus on detecting interaction per se. Instead, the method leverages interaction to increase power of the SNP association test. It has been used to successfully identify SNP associations missed in standard GWAS for other complex traits when accounting for gene-environment interactions. Here, we will apply the joint 2df method to simultaneously consider SNP main associations and their interactions with the established nAChR variants. We capitalize on existing GWAS data from our Collaborative Genetic Study of ND (COGEND), deCODE Genetics, and other studies available via the Database of Genotypes and Phenotypes (dbGaP) with Fagerstrom Test for Nicotine Dependence (FTND) data: collective size of >23,000 participants. In Aim1, we will obtain genome-wide SNP genotype data from 14 study samples and harmonize their FTND phenotype data. Using COGEND and deCODE Genetics (total N=10,319 Caucasians), we will conduct genome-wide joint 2df meta-analyses of ND, in parallel, accounting for an interaction with either CHRNA5- CHRNA3-CHRNB4 (in Aim 2) or CHRNB3-CHRNA6 (in Aim 3). The top-ranking SNPs from the joint 2df meta-analyses will be prioritized using bioinformatics analyses to evaluate their annotation, functionality, and regulatory potential. In Aim 4a, we will select up to 100 top-ranking SNPs for replication testing in seven independent Caucasian samples from dbGaP (total N=8,913). Replicated SNPs from Aim 4a will be further tested for association with ND in Aim 4b using two of our African American samples and three dbGaP samples (total N=4,145). Our prior GWAS of smoking and others have identified robust, functionally important variants that also contribute to cessation treatment response and smoking-related diseases (e.g., lung cancer). This study leverages these early findings and a new statistical method to discover novel variants contributing to ND, which may similarly add to our understanding of smoking cessation and smoking's health consequences.