Characterizing the phenotypic spectrum associated with genetic liability for alcohol use disorder

表征与酒精使用障碍遗传倾向相关的表型谱

基本信息

批准号：
10347325
负责人：
Rachel Lorraine Kember
金额：
$ 12.87万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-10 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10347325
关键词：
Adverse effects Affect African Age Alcohol consumption Alcoholism Alcohols Anxiety Disorders Biological Biological Process Cardiovascular Diseases Clinical Complex Consumption Data Data Set Development Diabetes Mellitus Diagnosis Diagnostic Disease Drug Addiction Early identification Effectiveness Environment Environmental Exposure Environmental Risk Factor Epidemiologic Methods Etiology European Exhibits Exposure to Foundations Funding Future Gastrointestinal Diseases Genetic Genetic Heterogeneity Genetic Models Genetic Risk Genomics Goals Gout Height Heterogeneity Individual Intervention Interview K-Series Research Career Programs Knowledge Lipids Lung diseases Measures Medical Medical Genetics Mental disorders Methods Mood Disorders Pathway interactions Phenotype Population Prevention strategy Records Reporting Research Research Activity Research Personnel Resources Risk Risk Marker Role Sampling Schedule Schizophrenia Severities Social Behavior Stratification Structure Subgroup Substance Use Disorder Testing Tissues Training Training Activity Training Programs Translations United States accurate diagnosis addiction alcohol abuse therapy alcohol exposure alcohol use disorder base career childhood adversity comorbidity design disorder risk drinking ethnic diversity gene environment interaction genetic analysis genetic epidemiology genetic variant genome wide association study genome-wide innovation insight personalized medicine phenome phenomenological models pleiotropism polygenic risk score predictive test prevent psychiatric comorbidity risk prediction model risk variant skills social trait trauma exposure treatment program

项目摘要

PROJECT SUMMARY Individuals with alcohol use disorder (AUD) are at increased risk of comorbid psychiatric and medical disorders. Comorbidity of disease poses a challenge to both the diagnosis and treatment of AUD, but the etiologic factors underlying comorbidity are not well understood. Recent large-scale genome-wide association studies (GWAS) have identified common risk markers for AUD and several other traits. Genetic correlations between AUD and psychiatric disorders have identified genetic overlap across multiple loci. These findings suggest that there are common loci or biological pathways that increase risk for multiple disorders. Identifying these loci will provide insight into the etiologic pathways for comorbid disorders, and could advance efforts to accurately diagnose, categorize, prevent, and treat AUD and co-occurring medical and psychiatric conditions. Research to date has been limited by the lack of resources with well characterized phenotypic information alongside genetic data for large numbers of individuals. The project proposed in this K-award application uses information collected with a comprehensive psychiatric interview schedule in a sample of >15,000 individuals enriched for substance use disorders to create a multi-phenotype dataset for phenome-wide association analysis. Polygenic risk scores for the same set of individuals will be used to characterize the genetic liability for disease. We will: 1) identify phenotypes associated with genetic liability for AUD; 2) identify whether genetic liability for other traits is associated with AUD; 3) incorporate biological information to identify pathways that underlie comorbid risk; and 4) include environmental factors to test for gene-environment interactions. Our ethnically diverse sample (nearly equal numbers of African and European ancestry) will allow us to establish the genetic liability for comorbidities in both ancestral populations. In the context of conducting this research, this career development award will enable the applicant to obtain fundamental training in the phenomenology and assessment of psychiatric phenotypes to allow the accurate translation of the phenotypic records into a dataset for high-throughput genetic analysis. Additionally, the applicant will acquire the necessary skills in genetic epidemiology to develop models for genetic liability and comorbid disease. The proposed project will provide a foundation for future studies that would allow stratification of individuals into personalized treatment programs based on their disease etiology, along with the promise of early identification of at-risk individuals to target with intervention strategies.

项目概要患有酒精使用障碍 (AUD) 的个体罹患精神和医学共病的风险增加失调。疾病的合并症给AUD的诊断和治疗带来了挑战，但合并症的病因尚不清楚。最近大规模的全基因组关联研究 (GWAS) 已经确定了 AUD 和其他几个特征的常见风险标记。遗传相关性 AUD 和精神疾病之间的多个基因座之间存在遗传重叠。这些发现表明存在共同的位点或生物途径会增加多种疾病的风险。识别这些位点将提供对共病疾病病因途径的深入了解，并可能推动努力准确诊断、分类、预防和治疗 AUD 以及同时发生的医疗和精神疾病。迄今为止的研究因缺乏具有明确表型信息的资源而受到限制以及大量个体的遗传数据。本次 K 奖申请中提出的项目使用通过全面的精神病学访谈计划在超过 15,000 人的样本中收集的信息丰富了物质使用障碍，为全表型关联创建多表型数据集分析。同一组个体的多基因风险评分将用于表征遗传责任为了疾病。我们将：1）确定与 AUD 遗传倾向相关的表型； 2）鉴别是否遗传其他特征的责任与 AUD 相关； 3）整合生物信息来识别途径存在共病风险； 4) 纳入环境因素来测试基因与环境的相互作用。我们的种族多样化的样本（非洲和欧洲血统的数量几乎相等）将使我们能够建立两个祖先群体中合并症的遗传倾向。在进行这项研究的背景下，该职业发展奖将使申请人能够获得现象学方面的基础培训和精神表型评估，以便将表型记录准确转化为用于高通量遗传分析的数据集。此外，申请人将获得必要的技能遗传流行病学开发遗传倾向和共病疾病模型。拟议的项目将为未来的研究奠定基础，使个体能够进行个性化治疗分层基于疾病病因学的计划，以及早期识别高危个体的承诺目标与干预策略。