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.

项目概要药物滥用和其他精神疾病导致巨大的个人、医疗保健和经济损失药物使用（例如烟草使用障碍）和精神疾病（例如精神分裂症）的成本很高。已经提出了三种主要理论来解释烟草使用和吸烟的高合并症。精神分裂症：1）自我药疗（例如，精神分裂症由于尼古丁的作用而促进吸烟）认知缺陷和药物副作用），2）吸烟导致精神分裂症，以及 3）共同责任，由于共同的遗传和环境因素，烟草使用和精神分裂症都具有高度遗传性（~60-）。 80%），我们和其他人已经表明，他们有几个共同的遗传风险因素，有两个特征可能相同。由于多效性（即基因变异影响两种性状）或由于一种疾病导致的遗传风险因素此外，共享的遗传风险可能存在于所有个体中（即全群体多效性），或者可能存在于所有个体中。仅限于个体的子集（即子组异质性）。利用我们在烟草使用、生物标志物、精神分裂症、统计遗传学和转录方面的专业知识分析，我们将开发一个全面的分析管道来阐明烟草的共同基因组责任我们的研究在最初的交叉障碍的基础上进行了改进。分析，并涉及 1) 从最大的可用精神分裂症基因组数据集中获取数据烟草使用，2) 检查性状之间的遗传相关性，3) 识别共有的遗传变异，4) 检查生物（即机械）途径，5）探索共享遗传变异的功能影响， 6) 测试全组多效性与亚组异质性的因果方向和影响。在目标 2 中，我们将通过一起分析女性和男性来精通分析流程的所有 6 个步骤。我们将对烟草使用进行全基因组性别分析，以确定使用基于性别的可行性为了开发管道，我们将在未来并发精神疾病的研究中进行基因组分析。使用尼古丁摄入量生物标志物，比自我报告的措施更准确地捕捉烟草使用情况。然而，当生物标志物不可用时，可以使用自我报告特征或诊断标准的 GWAS。这笔赠款将培训年轻的研究者 PI，以开展更大的基因组学项目，调查共享的基因组学项目。我们将研究其他对遗传性和并发精神疾病之间的基因组责任和因果关系。当数据集可用时，将此管道应用于不同的人群，通过这些努力，我们将做得更好。了解同时发生的物质使用和精神疾病的生物学脆弱性。这项工作可能会改进预防和治疗方法，并揭示药物的新靶点发现。