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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：
9975089
负责人：
KENNETH SEEDMAN KENDLER
金额：
$ 65.77万
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/9975089
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 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 sharing data warehouse design disorder risk disorder subtype ethnic diversity genetic analysis genetic testing genome wide association study genome-wide improved innovation insight instrument neuropsychiatry novel therapeutics phenotypic data polygenic risk score population based programs psychiatric genomics recruit response risk variant social socioeconomics support network symptomatology tool treatment strategy

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）是一种具有高度公共卫生影响的遗传性综合征