Concurrent substance use and psychiatric disorders: a pipeline to investigate shared genomic liability and causal effects

并发物质使用和精神疾病：研究共同基因组责任和因果效应的管道

基本信息

批准号：
10575767
负责人：
Meghan Chenoweth
金额：
$ 14.34万
依托单位：
CENTRE FOR ADDICTION AND MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10575767
关键词：
Address Antipsychotic Agents Big Data Biological Biological Factors Biological Markers Cigarette Cognitive deficits Collaborations Complex Controlled Study Cotinine Data Data Set Disease Drug Addiction Drug abuse Early Intervention Environmental Risk Factor Etiology European ancestry Future Gene Cluster Genes Genetic Genetic Risk Genetic Transcription Genetic study Genomics Genotype Grant Health Care Costs Hereditary Disease Heritability Heterogeneity Individual Intake International Intervention Investigation Maps Measures Mendelian randomization Mental disorders Nicotine Nicotinic Receptors Pathway interactions Patient Self-Report Pharmaceutical Preparations Population Population Heterogeneity Prevention Research Research Design Research Personnel Sample Size Schizophrenia Self Medication Sex Differences Signal Transduction Smoke Smoker Smoking Smoking Behavior Subgroup Substance Use Disorder Testing Tobacco Use Disorder Tobacco use Training Woman Work addiction bioinformatics tool care costs comorbidity diagnostic criteria drug discovery economic cost experience genetic architecture genetic risk factor genetic variant genome wide association study genome-wide genomic data genomic locus hydroxycotinine improved men new therapeutic target nicotine use non-smoker novel pleiotropism programs risk variant schizophrenia risk sex side effect statistics substance use theories trait transcriptome treatment strategy

项目摘要

Project Summary Substance use and other psychiatric disorders result in enormous personal, healthcare, and economic costs. Substance use (e.g., tobacco use disorder) and psychiatric (e.g., schizophrenia) disorders are highly comorbid. Three main theories have been proposed to explain the high comorbidity of tobacco use and schizophrenia: 1) self-medication (e.g., schizophrenia promotes tobacco use due to nicotine’s effect on reducing cognitive deficits and medication side effects), 2) tobacco use causes schizophrenia, and 3) a shared liability, due to shared genetic and environmental factors. Tobacco use and schizophrenia are each highly heritable (~60- 80%) and we and others have shown that they share several common genetic risk factors. Two traits may share genetic risk factors due pleiotropy (i.e., a gene variant influences both traits) or because one disorder causes the other. Furthermore, shared genetic risk may be present in all individuals (i.e., whole-group pleiotropy) or may be restricted to a subset of individuals (i.e., sub-group heterogeneity). Using our expertise in tobacco use, biomarkers, schizophrenia, statistical genetics, and transcriptional analyses, we will develop a comprehensive analytic pipeline to elucidate the shared genomic liability of tobacco use and schizophrenia, and identify potential causal effects. Our study improves upon initial cross-disorder analyses, and involves 1) obtaining data from the largest available genomics datasets of schizophrenia and tobacco use, 2) examining genetic correlation between the traits, 3) identifying shared genetic variants, 4) examining biological (i.e., mechanistic) pathways, 5) exploring functional effects of the shared genetic variants, and 6) testing causal directions and effects of whole-group pleiotropy versus sub-group heterogeneity. In Aim 1, we will become proficient in all 6 steps of the analytic pipeline by analyzing women and men together. In Aim 2, we will conduct genome-wide sex-based analyses of tobacco use to determine the feasibility of using sex-based genomic analyses in future investigations of concurrent psychiatric disorders. To develop the pipeline, we will use nicotine intake biomarkers, which capture tobacco use more accurately than self-reported measures. However, GWAS of self-reported traits or diagnostic criteria could be used when biomarkers are unavailable. This grant will train the young investigator PI for a larger genomics program investigating the shared genomic liability and causality between other pairs of heritable and concurrent psychiatric disorders. We will apply this pipeline to diverse populations as the datasets become available. Through these efforts, we will better understand the biological vulnerability to developing co-occurring substance use and psychiatric disorders. This work may lead to improved prevention and treatment approaches, as well as reveal novel targets for drug discovery.

项目摘要药物使用和其他精神疾病会导致巨大的个人，医疗保健和经济费用。药物使用（例如烟草使用障碍）和精神病（例如精神分裂症）疾病高度高度合并。提出了三种主要理论来解释烟草使用的高合并症和精神分裂症：1）自我药物（例如，由于尼古丁对减少的影响，精神分裂症促进了烟草的使用认知缺陷和药物副作用），2）烟草使用会导致精神分裂症，3）共同的责任，由于共有的遗传和环境因素。烟草使用和精神分裂症都是高度遗传的（约60-- 80％）和我们和其他人表明它们具有几个常见的遗传危险因素。两个特征可能会分享由于多效性的一般危险因素（即基因变异都会影响性状）或因为一种疾病引起另一个。此外，所有个体（即全组多效）中可能存在共同的遗传风险或可能存在仅限于个体的一部分（即亚组异质性）。利用我们在烟草使用，生物标志物，精神分裂症，统计遗传学和转录的专业知识分析，我们将开发全面的分析管道，以阐明烟草的共同基因组责任使用和精神分裂症，并确定潜在的因果作用。我们的研究在初始跨界方面有所改善分析，涉及1）从精神分裂症的最大可用基因组数据集中获取数据和烟草使用，2）检查性状之间的遗传相关性，3）识别共享遗传变异，4）检查生物学（即机械）途径，5）探索共享遗传变异的功能效应， 6）测试全组多效性与亚组异质性的因果方向和影响。在AIM 1中，我们将通过共同分析男女共同分析分析管道的所有6个步骤。在AIM 2中，我们将对烟草使用的基于全基因组的性别分析来确定使用基于性别的可行性基因组分析在对并发精神疾病的未来研究中进行。为了开发管道，我们将使用尼古丁的摄入生物标志物，该生物标志物比自我报告的措施更准确地捕获烟草使用。但是，当生物标志物不可用时，可以使用自我报告的特征或诊断标准的GWA。该赠款将培训年轻的研究者PI进行更大的基因组学计划，以调查共享基因组责任和因果关系和并发精神疾病之间的因果关系。我们将随着数据集的可用，将此管道应用于潜水员人群。通过这些努力，我们会更好了解开发同时发生物质使用和精神疾病的生物脆弱性。这工作可能会改善预防和治疗方法，并揭示药物的新目标发现。