Longitudinal exome-focused GWAS for alcohol use in a cohort with and without HIV

描述（由申请人提供）：由于表型异质性和复杂的遗传结构，酒精使用障碍（AUD）的基因定位一直具有挑战性。传统的全基因组关联研究（GWAS）主要集中在病例对照样本中常见的单核苷酸变异（SNV）。为了解决这些局限性，我们建议通过在有和没有HIV感染的患者的纵向队列中应用以外显子组为中心的分析来检测AUD的基因。我们将对来自退伍军人老龄化队列研究（VACS）的2，470名退伍军人进行纵向GWAS（LGWAS）。我们在该人群中确定了3种AUD轨迹（无AUD、中度AUD和重度AUD）。我们将应用一种具有成本效益和强大的方法来进行纵向GWAS基因检测。我们将使用Illumina HumanCoreExome Beadchip，其鉴定560 K低频推定功能SNV和共同标签SNV。我们已经成功地使用该阵列对2,470个DNA样本中的1,000个进行了基因分型。此外，我们还开发了一种新的统计方法来分析该项目中基于基因的LGWAS。在这项研究中，我们的目标是1）通过使用纵向队列来确定AUD轨迹的遗传风险。我们假设基因中的低频变异共同有助于与AUD相关，并且可以在中等样本量中通过LGWAS检测到; 2）进行基因集富集分析（GSEA）以识别与AUD轨迹相关的生物学途径。GSEA方法能够检测边缘显著的遗传效应。另外我们 将研究基因和HIV状态在AUD进展中的相互作用。我们假设HIV暴露对AUD表现出边际遗传变异效应，并且通过测试基因和HIV状态的相互作用将揭示新基因的子集。长期目标：我们的目标是识别AUD进展的风险个体。我们将评估从这项研究中确定的变体和途径的神经生物学机制。希望能为今后的药物开发和个体化护理提供生物学依据。

DESCRIPTION (provided by applicant): Gene mapping for alcohol use disorder (AUD) has been challenging due to phenotype heterogeneity and complicated genetic architecture. Traditional genome-wide association study (GWAS) has focused on common single nucleotide variant (SNV) in case-control sample. To address these limitations, we propose to detect genes for AUD by applying the exome-focused analysis in a longitudinal cohort of patients with and without HIV infection. We will conduct a longitudinal GWAS (LGWAS) in 2,470 veterans from the Veterans Aging Cohort Study (VACS). We have identified 3 AUD trajectories in this population (No AUD; Moderate AUD, and Severe AUD). We will apply a cost-effective and powerful approach to conduct a longitudinal GWAS for gene detection. We will use the Illumina HumanCoreExome Beadchip that compasses 560K low-frequency putative functional SNVs and common tag SNVs. We have successfully genotyped 1,000 out of 2,470 DNA samples using this array. Additionally, we have developed a novel statistical method to analyze gene-based LGWAS for this project. In this study, we aim 1) to identify genetic risks for AUD trajectory by using a longitudinal cohort. We hypothesize that low-frequency variant in a gene collectively contribute to associate to AUD and can be detected by LGWAS in a moderate sample size; 2) to perform gene set enrichment analysis (GSEA) to identify biological pathways related to AUD trajectories. GSEA approach is able to detect marginal significant genetic effects. In addition, we will examine the interaction of genes and HIV status in AUD progression. We hypothesize that HIV exposure manifests marginal genetic variant effects on AUD and a subset of novel genes will be revealed through testing the interaction of genes and HIV status. Long-term objectives: Our goal is to identify risk individuals for AUD progression. We will evaluate neurobiological mechanisms of identified variants and pathways from this study. We hope to provide biological evidence for future medication development and individualized care.