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

项目总结 尼古丁和酒精依赖是全球主要的健康问题，是可预防的主要原因 发病率和死亡率。尽管它们在全球造成负担，但总的来说，药物治疗的选择是有限的。 部分原因是它们的分子机制尚不清楚。吸烟和饮酒的特征是 可遗传的和全基因组的关联研究为常见的变异提供了强有力的证据 在近400个影响吸烟和/或饮酒特征的基因组区域。然而，绝大多数人 相关的变体存在于非编码的DNA中，它们的靶基因、基因网络和相关的 神经生物学机制还知之甚少。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型、 吸烟和饮酒特征，包括尼古丁依赖(ND)，每支香烟 每天(CPD)、戒烟(CS)、酒精使用障碍(AUD)和每周酒精饮料(DPW)。一旦 确定了可能的靶基因，我们将描述它们的分子功能和生物学途径。 使用基因集浓缩分析，(2)基于单细胞转录的细胞表达谱 数据集，以及(3)基于时间转录图谱的发育表达轨迹。这将是 细化分子机制、中央细胞类型和发育窗口对使用和发展至关重要 吸烟和酗酒成瘾。此外，因为我们将使用一个连贯的框架(H-岩浆) 为了破译吸烟和酒精使用特征的所有五个GWA的生物学基础，我们提议的研究 将允许对不同的GWA进行系统的描述和比较。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，这将 揭示了成瘾的核心机制。

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.