A Genome Wide Association Study of Severe Alcohol Use Disorder

酒精使用障碍(AUD)是一种本质上可遗传的综合征，对公共健康的影响很高。 对于这一点，人们仍然知之甚少。在过去的十年里，全基因组关联研究(GWAS)已经 成功地应用于越来越多的复杂生物医学和神经精神综合征 对生物因果路径的重要洞察。结果一致表明，这些障碍是 影响大小风险变异较小的多基因较高。然而，分子遗传解剖的进展 由于缺乏特征明确的严重疾病病例的足够样本量，澳大利亚发展缓慢。作为回应 针对这一关切，NIAAA于17年4月3日发布了Not-AA-17-002“提交包含基因组- 广泛的协会研究。“这项建议旨在满足NIAAA在以下方面制定的目标 公告。由于招聘成本低，其可行性已通过试点研究进行测试，我们 在R0-1预算范围内，可以评估12,000例严重DSM-5 AUD病例并进行基因分型。 然而，这一应用程序不应该仅仅被视为一个独立的项目，而应该被视为NIAAA计划的一部分 将在这一倡议下资助的多项研究的结果与精神科医生正在进行的努力结合起来 基因组学联盟(PGC)为分子分析获得足够的总样本量。评估 AUD的完整DSM-5标准，相关的关键共病(抑郁、药物滥用、反社会 个性)和其他风险因素(例如个性)将由化身辅助平板电脑/网络程序执行。 我们将从两个临床数据收集网络(Hazelden- 贝蒂·福特和巴尔的摩治疗网络)，并通过网络从面孔和康复之声。 科学目标包括：i)从公共来源确定种族匹配的筛选暴露的酒精 通过GWAS进行控制，ii)完成对基因数据的归因和质量控制检查，iii)执行 对每一超群体的GWAS分析和跨种族样本的荟萃分析，四)建立 与PGC和其他NIAAA项目建立协作联系，以实施交叉样本分析，v) 执行基因和基因集分析，以寻求对AUD，vi)检查风险途径的进一步了解 使用我们丰富的症状学、个性和 这些亚型的共病和尝试的分子验证以及vii)使用多基因风险评分(与 我们的研究同时作为测试和训练样本)和遗传相关性，以更好地理解 AUD与其他主要精神疾病和物质使用障碍之间遗传风险的共性。有了这个 和平行的类似项目，将确定足够的澳大利亚急性呼吸衰竭病例和相关对照的样本量 为了识别风险SNP，追踪这些SNP到它们相关的风险基因，并使用这些汇总的发现来提供 洞察AUD风险的生物致病途径。这样的途径可以带来新的潜在治疗方法。 以及对AUD这一严重但知之甚少的综合征的预防策略。

Alcohol Use Disorder (AUD) is substantially heritable syndrome with high public-health impact the etiology of which remains poorly understood. Over the last decade, genome-wide association studies (GWAS) have been successfully applied to an increasing number of complex biomedical and neuropsychiatric syndromes leading to important insights into biological causal pathways. Results have uniformly shown these disorders to be higher polygenic with small effect-size risk variants. However, progress in the molecular genetic dissection of AUD has been slow due to lack of adequate sample sizes of well-characterized severely ill cases. In response to this concern, NIAAA issued on 4/3/17 NOT-AA-17-002 “Submission of Applications Containing Genome- Wide Association Studies.” This proposal was designed to meet the goals laid out by NIAAA in this announcement. Because of low recruitment costs, the viability of which have been tested by pilot studies, we can, within the confines of an R0-1 budget, assess and genotype 12,000 cases of severe DSM-5 AUD. However, this application should not be viewed as only a “stand-alone” project, but as part of NIAAA’s plan to combine results across multiple studies funded under this initiative and ongoing efforts of the Psychiatric Genomics Consortium (PGC) to gain sufficient aggregate sample size for molecular analysis. Assessment of complete DSM-5 criteria for AUD, associated key co-morbidities (depression, drug abuse, antisocial personality) and other risk factors (e.g. personality) will be performed by an avatar aided tablet/web program. We will collect a severe and ethnically diverse sample from two clinical data collection networks (Hazelden- Betty Ford and Baltimore Treatment Network) and via the web from the Faces and Voices of Recovery. Scientific aims include i) identification, from public sources, of ethnically matched screened alcohol-exposed controls with GWAS, ii) complete imputation and quality control checks of genotype data, iii) performance of GWAS analyses of each super-population and a meta-analysis across ethnic samples, iv) establishment of collaborative links with the PGC and other NIAAA projects to implement cross-samples analyses, v) performance of gene and geneset analyses to seek further insights into risk pathways to AUD, vi) examination of phenotypic heterogeneity within AUD using our rich measures of symptomatology, personality, and comorbidity and attempted molecular validation of these subtypes and vii) use of polygenic risk scores (with our study serving as both a test and training sample) and genetic correlations to better understand the commonality of genetic risk between AUD and other key psychiatric and substance using disorders. With this and parallel similar projects, sufficient sample sizes of AUD cases and associated controls will be ascertained to identify risk SNPs, trace these to their relevant risk genes and use these aggregate findings to provide insight into biological etiologic pathways to AUD risk. Such pathways can then lead to new potential treatment and prevention strategies for the critical but poorly understood syndrome of AUD.