A Genome Wide Association Study of Severe Alcohol Use Disorder

严重酒精使用障碍的全基因组关联研究

• 批准号: 10457001
• 负责人: KENNETH SEEDMAN KENDLER
• 金额: $ 69.02万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457001
• 关键词: Adoption; Affect; Alcohol Phenotype; Animal Model; Antisocial Personality Disorder; Anxiety; Baltimore; Biological; Bipolar Disorder; Budgets; Clinical Data; Collection; Complex; Computers; Consent; Core Facility; DNA; DSM-V; Data; Data Collection; Development; Disease; Dissection; Drug Addiction; Drug abuse; Etiology; Face; Funding; Genes; Genetic; Genetic Models; Genetic Risk; Genotype; Goals; Heritability; Heterogeneity; Human; Human Genetics; Internet; Lead; Link; Major Depressive Disorder; Measures; Medical; Mental Depression; Mental disorders; Meta-Analysis; Methods; Molecular; Molecular Analysis; Molecular Genetics; Morbidity - disease rate; National Institute on Alcohol Abuse and Alcoholism; Nicotine Dependence; Online Systems; Participant; Pathway interactions; Performance; Personality; Pharmacological Treatment; Phenotype; Pilot Projects; Policies; Population; Predictive Value of Tests; Prevention strategy; Preventive; Preventive measure; Psychopathology; Public Health; Quality Control; Recontacts; Recovery; Recovery Support; Research; Research Design; Research Personnel; Risk; Risk Factors; Sample Size; Sampling; Schizophrenia; Source; Standardization; Substance Use Disorder; Syndrome; Tablets; Testing; Training; Translating; Twin Studies; Universities; Validation; Variant; Voice; addiction; alcohol exposure; alcohol screening; alcohol use disorder; analysis pipeline; ancestry analysis; base; case control; cell repository; comorbidity; cost; data collection site; data repository; data sharing; design; disorder risk; disorder subtype; ethnic diversity; gene network; genetic analysis; genetic testing; genome wide association study; genome-wide; improved; innovation; insight; instrument; neuropsychiatry; novel therapeutics; phenotypic data; pilot test; polygenic risk score; population based; programs; psychiatric genomics; recruit; response; risk variant; social; socioeconomics; support network; symptomatology; tool; treatment strategy

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.

酒精使用障碍 (AUD) 是一种具有高度遗传性的综合征，对公共健康影响很大。 这仍然知之甚少。在过去的十年中，全基因组关联研究（GWAS） 成功应用于越来越多的复杂生物医学和神经精神综合征 对生物因果途径的重要见解。结果一致表明这些疾病是 具有较小效应大小风险变异的更高多基因。然而，分子遗传学解析的进展 由于缺乏充分表征的重症病例的足够样本量，澳元的进展缓慢。作为回应 针对这一问题，NIAAA 于 2017 年 4 月 3 日发布了 NOT-AA-17-002“提交包含基因组的申请 广泛的协会研究。”该提案旨在实现 NIAAA 在此方面制定的目标 公告。由于招聘成本低，其可行性已经过试点研究的检验，我们 可以在 R0-1 预算范围内对 12,000 例严重 DSM-5 AUD 病例进行评估和基因分型。 然而，该应用程序不应被视为仅仅是一个“独立”项目，而应被视为 NIAAA 计划的一部分 结合了该倡议资助的多项研究的结果以及精神科的持续努力 基因组学联盟 (PGC) 获得足够的聚合样本量以进行分子分析。评估 完整的 DSM-5 AUD 标准、相关的关键合并症（抑郁症、药物滥用、反社会行为） 个性）和其他风险因素（例如个性）将通过头像辅助平板电脑/网络程序来执行。 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）以及通过网络从恢复的面孔和声音。 科学目标包括 i) 从公共来源识别种族匹配的酒精暴露者 GWAS 控制，ii) 基因型数据的完整插补和质量控制检查，iii) 性能 对每个超级群体进行 GWAS 分析以及跨种族样本的荟萃分析，iv) 建立 与 PGC 和其他 NIAAA 项目的协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 使用我们丰富的症状学、个性和 这些亚型的共病和尝试的分子验证，以及 vii) 多基因风险评分的使用（与 我们的研究既作为测试样本，又作为训练样本）和遗传相关性，以更好地理解 AUD 与其他主要精神疾病和药物滥用疾病之间遗传风险的共性。有了这个 和平行的类似项目，将确定 AUD 案例和相关控制的足够样本量 识别风险 SNP，追踪其相关风险基因，并使用这些汇总结果来提供 深入了解 AUD 风险的生物病因学途径。这些途径可以带来新的潜在治疗方法 以及针对严重但知之甚少的 AUD 综合征的预防策略。

项目成果

Patterns and Correlates of Polysubstance Use Among Individuals With Severe Alcohol Use Disorder.

严重酒精使用障碍患者多物质使用的模式和相关性。

• DOI: 10.1093/alcalc/agac012
• 发表时间: 2022
• 期刊: Alcohol and alcoholism (Oxford, Oxfordshire)
• 作者: Stephenson,Mallory;Aggen,StevenH;Polak,Kathryn;Svikis,DaceS;Kendler,KennethS;Edwards,AlexisC
• 通讯作者: Edwards,AlexisC