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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.

项目摘要物质使用和其他精神障碍导致巨大的个人、医疗保健和经济成本。物质使用障碍(如烟草使用障碍)和精神障碍(如精神分裂症)的发生率很高同病相怜。已经提出了三种主要理论来解释烟草使用和吸烟的高共患率精神分裂症：1)自我用药(例如，精神分裂症由于尼古丁的减少作用而促进烟草的使用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。吸烟和精神分裂症都是高度可遗传的(~60- 80%)，我们和其他人已经证明，他们有几个共同的遗传风险因素。两个可能共有的特征遗传风险因素是由于多效性(即，一个基因变异影响两个性状)或因为一个疾病引起的另一个。此外，共同的遗传风险可能存在于所有个人中(即，整个群体多效性)，或者可以仅限于个体的子集(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共同的基因组风险使用和精神分裂症，并确定潜在的因果影响。我们的研究改进了最初的交叉障碍分析，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)识别共同的遗传变异，4) 检查生物(即，机械的)途径，5)探索共享的遗传变体的功能效应， 6)检验整群多效性与亚群异质性的因果方向和效应。在目标1中，通过一起分析女性和男性，我们将精通分析管道的所有6个步骤。在目标2中，我们将对烟草使用进行基于性别的全基因组分析，以确定基于性别的使用的可行性基因组分析在未来并发精神障碍研究中的应用。为了开发这条管道，我们将使用尼古丁摄入量生物标记物，它比自我报告的指标更准确地捕捉烟草使用情况。然而，当生物标记物不可用时，可以使用自我报告特征或诊断标准的GWA。这笔赠款将为一个更大的基因组计划培训年轻的研究员Pi，该计划将调查共享的其他遗传性和并发精神障碍之间的基因组责任和因果关系。我们会当数据集可用时，将这条管道应用于不同的人群。通过这些努力，我们将会更好地了解生物易患共患药物使用和精神疾病的风险。这这项工作可能导致改进预防和治疗方法，并揭示药物的新靶点发现号。