Using H-MAGMA to decipher neurobiological bases of smoking and alcohol use traits

项目摘要 尼古丁和酒精依赖是全球主要的健康问题，是可预防的疾病的主要原因。 发病率和死亡率。尽管药物治疗对全球造成负担，但总体而言， 部分原因是它们的分子机制尚不清楚。吸烟和饮酒的特点是 遗传和全基因组关联研究（GWAS）为常见变异提供了有力的证据 在近400个影响吸烟和/或饮酒特征的基因组区域中。但绝大多数 相关的变异存在于非编码DNA中，它们的靶基因、基因网络和相关的 神经生物学机制知之甚少。该提案的关键第一步是确定 通过将H-MAGMA应用于一组全面的大的， 针对吸烟和饮酒特征的强有力的GWAS，包括尼古丁依赖（ND）， 日（CPD）、戒烟（CS）、酒精使用障碍（AUD）和每周饮酒量（DPW）。一旦 我们将鉴定出可能的靶基因，并描述它们的（1）分子功能和生物学途径 使用基因集富集分析，（2）基于单细胞转录组学的细胞表达谱， 数据集，以及（3）基于时间转录组图谱的发育表达轨迹。这将 完善的分子机制，中央细胞类型，和发育窗口的关键使用和开发 吸烟和酗酒成瘾。此外，由于我们将使用相干框架（H-MAGMA） 为了解释吸烟和饮酒的所有五个GWAS特征的生物学基础，我们提出的研究 将允许不同GWAS的系统表征和比较。我们的比较将导致 鉴定与香烟和酒精成瘾相关的多效性基因， 揭示成瘾的核心机制

PROJECT SUMMARY Nicotine and alcohol dependence represent major global health concerns as leading causes of preventable morbidity and mortality. Despite their global burden, pharmacological treatment options are limited, in large part because their molecular mechanisms remain unclear. Cigarette smoking and alcohol use traits are heritable, and genome-wide association studies (GWAS) have provided robust evidence for common variants in nearly 400 genomic regions that influence smoking and/or alcohol use traits. However, the vast majority of associated variants reside in non-coding DNA, and their target genes, gene networks, and relevant neurobiological mechanisms are poorly understood. The critical first step of the proposal is to identify neurobiologically-relevant target genes of known loci by applying H-MAGMA to a comprehensive set of large, well-powered GWAS for smoking and alcohol use traits, including nicotine dependence (ND), cigarettes per day (CPD), smoking cessation (CS), alcohol use disorder (AUD), and alcohol drinks per week (DPW). Once the putative target genes are identified, we will characterize their (1) molecular function and biological pathways using gene set enrichment analyses, (2) cellular expression profiles based on single cell transcriptomic datasets, and (3) developmental expression trajectories based on temporal transcriptomic atlas. This will refine the molecular mechanism, central cell type, and developmental window critical for using and developing addiction to cigarette smoking and alcohol. Further, because we will use a coherent framework (H-MAGMA) to decipher biological underpinnings of all five GWAS of smoking and alcohol use traits, our proposed study will allow the systematic characterization and comparison of different GWAS. Our comparison will result in the identification of pleiotropic genes associated with developing addiction to cigarette and alcohol, which would reveal core mechanisms underlying addiction.