A Genome Wide Association Study of Severe Alcohol Use Disorder

酒精使用障碍（AUD）是一种具有高度公共卫生影响的遗传性综合征， 这一点我们仍然知之甚少。在过去的十年中，全基因组关联研究（GWAS）已经被 成功地应用于越来越多的复杂的生物医学和神经精神综合征， 对生物因果途径的重要见解。结果一致表明，这些疾病是 高多基因与小效应大小的风险变异。然而，在分子遗传解剖的进展， AUD进展缓慢，原因是缺乏充分表征的重症病例的足够样本量。响应 为此，NIAAA于2017年4月3日发布了NOT-AA-17 - 002 "提交含有基因组的申请- 广泛的协会研究"。该提案旨在实现NIAAA在本报告中提出的目标。 公告由于招聘成本低，其可行性已通过试点研究进行了测试，我们 可以在R0 - 1预算的范围内评估12，000例重度DSM-5 AUD病例并进行基因分型。 然而，这个应用程序不应该被视为仅仅是一个“独立”的项目，而是NIAAA计划的一部分， 联合收割机将该倡议资助的多项研究的结果与精神病学委员会正在进行的努力相结合。 基因组学联盟（PGC）获得足够的聚合样本量进行分子分析。评估 AUD的完整DSM-5标准，相关的关键合并症（抑郁症、药物滥用、反社会 个性）和其他风险因素（例如个性）将由化身辅助的平板电脑/web程序来执行。 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声音的恢复。 科学目的包括i）从公共来源识别种族匹配的筛选酒精暴露者， GWAS对照，ii）基因型数据的完整插补和质量控制检查，iii） 每个超级人群的GWAS分析和跨种族样本的荟萃分析，iv）建立 与PGC和其他NIAAA项目建立合作联系，以实施跨样本分析，v） 进行基因和基因组分析，以进一步了解AUD的风险途径，vi）检查 使用我们丰富的血液学、人格和 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（具有 我们的研究既作为测试样本，也作为训练样本）和遗传相关性，以更好地了解 AUD与其他主要精神和物质使用障碍之间的遗传风险共性。与此 以及平行的类似项目，将确定AUD病例和相关对照的足够样本量 识别风险SNPs，将其追踪到相关风险基因，并使用这些汇总结果提供 深入了解AUD风险的生物学病因学途径。这样的途径可以导致新的潜在治疗 以及对严重但知之甚少的AUD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.