Methods to Unveil the Genetic Architecture for Nicotine Dependence via NGS data

尼古丁依赖和成瘾与公共健康密切相关，部分原因是它们诱发的风险 癌症和心血管疾病的风险。全基因组研究表明，尼古丁的使用有很强的遗传成分 协会研究和基于家庭的研究。揭示尼古丁依赖的遗传基础是非常重要的 对规范烟草使用，实行个别化治疗具有重要意义。下一代测序 使得大规模研究尼古丁依赖的遗传和基因组基础成为可能。多个大型 规模研究的重点是检测与尼古丁摄入量的直接测量或与 吸烟频率数据，如每天吸烟。迫切需要整合这些资源 使用来自Encode、GTEx等的功能基因组数据，并开发出可以促进我们的 对基因结构的理解。在这个应用中，我们提出了新的理解方法 遗传结构通过对遗传效应的分布进行建模，为每个功能类别建立不同的因果关系 变种(目标1)。为了帮助对硅胶中的基因-表型关联进行功能解释，我们还 提出综合分析尼古丁代谢物和吸烟频率数据的方法(目标2)。 这些方法将在高效和用户友好的工具中实施，这不仅有助于我们提议的 研究，但也将有助于在更广泛的研究界的研究。这些项目有可能 给尼古丁依赖的基因分析带来范式转变。方法和工具也将是 对研究其他类似的复杂性状有一定的参考价值。

Nicotine dependence and addiction have strong relevance to public health, partly due to their induced risk on cancer and cardiovascular disease risk. Nicotine use has strong genetic component as shown in genome-wide association studies and family based studies. Unveiling the genetic basis for nicotine dependence is greatly important for regulating the tobacco use, and practicing individualized treatment. Next generation sequencing has enabled large scale investigation on the genetic and genomic basis for nicotine dependence. Multiple large scale studies have focused on detecting the associations with direct measurements of nicotine intake, or with smoking frequency data such as cigarettes per day. There is a compelling need to integrate these resources with functional genomic data from ENCODE, GTEx etc, and develop methods that can advance our understanding on the genetic architecture. In this application, we propose novel methods for understanding genetic architecture through modeling the genetic effect distribution, variant causality for each functional class of variants (Aim 1). To aid in functional interpretation of genotype-phenotype associations in-silico, we also propose methods for integrating the analysis of nicotine metabolites and smoking frequency data (Aim 2). There methods will be implemented in efficient and user-friendly tools, which not only facilitate our proposed research, but will also aid in the studies in a broader research community. These projects have the potential to bring a paradigm shift to the genetic analysis of nicotine dependence. The methods and tools will also be valuable for studying other similar complex traits.