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

基本信息

批准号：
9768941
负责人：
KENNETH SEEDMAN KENDLER
金额：
$ 67.76万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768941
关键词：
Adoption Affect Alcohol Phenotype Animal Model Antisocial Personality Disorder Anxiety Baltimore Biological Bipolar Disorder Budgets Cells Clinical Data Collection Comorbidity 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 Genetic screening method Genomics 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 Research Research Design Research Personnel Risk Risk Factors Sample Size Sampling Schizophrenia Site 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 base case control cost data sharing data warehouse design disorder risk disorder subtype ethnic diversity genetic analysis genome wide association study genome-wide improved innovation insight instrument neuropsychiatry novel therapeutics phenotypic data population based programs recruit response risk variant social socioeconomics support network symptomatology tool treatment strategy

Adoption Affect Alcohol Phenotype Animal Model Antisocial Personality Disorder Anxiety Baltimore Biological Bipolar Disorder Budgets Cells Clinical Data Collection Comorbidity 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 Genetic screening method Genomics 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 Research Research Design Research Personnel Risk Risk Factors Sample Size Sampling Schizophrenia Site 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 base case control cost data sharing data warehouse design disorder risk disorder subtype ethnic diversity genetic analysis genome wide association study genome-wide improved innovation insight instrument neuropsychiatry novel therapeutics phenotypic data population based programs recruit response risk variant social socioeconomics support network symptomatology tool treatment strategy

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项目摘要

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）是基本可遗传的综合症，具有很高的公共卫生影响这仍然很少理解。在过去的十年中，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症。对生物因果途径的重要见解。结果统一地表明这些疾病是较高的多基因具有小效应大小的风险变体。但是，分子遗传解剖的进展由于缺乏足够的病例疾病病例的足够样本量，AUD一直很慢。作为回应因此，NIAAA于17年4月3日发布，NOT-AA-17-002“提交包含基因组的申请广泛的协会研究。公告。由于招聘成本较低，通过试点研究已经测试了其生存能力，我们在R0-1预算的范围内，可以评估和基因型12,000例严重DSM-5 AUD。但是，该应用程序不应仅视为“独立”项目，而应将其视为NIAAA计划的一部分结合基于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）获得足够的骨料样本量用于分子分析。评估完整的DSM-5 AUD，相关关键合并症的标准（抑郁，药物滥用，反社会个性）和其他风险因素（例如个性）将由头像辅助平板电脑/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（Betty Ford）和巴尔的摩（Baltimore）治疗网络）以及通过恢复的脸和声音通过网络。科学目的包括i）从公共来源识别种族匹配的筛查酒精暴露使用GWAS的控制，ii）基因型数据的完整插补和质量控制检查，iii） GWAS分析每个超级人群和跨种族样本的荟萃分析，iv）建立与PGC和其他NIAAA项目的协作链接以实施跨样本分析，v）基因和基因组分析的性能，以寻求进一步了解AUD的风险途径，VI）检查使用我们丰富的症状，人格和人格和这些亚型和VII的合并症和尝试的分子验证）使用多基因风险评分（与我们的研究既是测试和训练样本）和遗传相关性，以更好地了解使用疾病与其他关键精神病和物质之间遗传风险的共同点。与此和平行的类似项目，将确定足够的AUD案例和相关对照的样本量要识别风险SNP，请将其追溯到其相关风险基因并使用这些汇总发现提供洞悉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AUD的关键但不良综合征的预防策略。