A Framework for Translating Polygenic Findings Related to Alcohol Use Disorder Across Species

跨物种转化与酒精使用障碍相关的多基因发现的框架

基本信息

批准号：
10340683
负责人：
Hae Kyung Im
金额：
$ 56.95万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10340683
关键词：
Address Alcohol abuse Alcohol consumption Alcoholism Alcohols Alleles Architecture Behavior Behavioral Biological Biological Models Biological Testing Brain Brain Diseases Cell physiology Cessation of life Chronic Data Data Set Development Disease Female Gene Expression Genes Genetic Genetic Polymorphism Genetic Variation Genotype Grant Heritability Human Human Genome Individual Knowledge Methods Modeling Molecular Motivation Mus Orthologous Gene Pathway interactions Phenotype Physiological Population Prevention Procedures Psychiatry Public Health Rattus Research Risk Rodent Rodent Model SNP genotyping Self Administration Signal Transduction Single Nucleotide Polymorphism Societies Sum Techniques Testing Tissues Training Transcript Translating Translations Twin Multiple Birth Twin Studies Variant Weight Work alcohol abuse therapy alcohol risk alcohol use disorder comparative consumption measures economic cost genetic architecture genome wide association study loss of function male novel novel strategies phenotypic data polygenic risk score portability preference tool trait transcriptome transcriptomics

Address Alcohol abuse Alcohol consumption Alcoholism Alcohols Alleles Architecture Behavior Behavioral Biological Biological Models Biological Testing Brain Brain Diseases Cell physiology Cessation of life Chronic Data Data Set Development Disease Female Gene Expression Genes Genetic Genetic Polymorphism Genetic Variation Genotype Grant Heritability Human Human Genome Individual Knowledge Methods Modeling Molecular Motivation Mus Orthologous Gene Pathway interactions Phenotype Physiological Population Prevention Procedures Psychiatry Public Health Rattus Research Risk Rodent Rodent Model SNP genotyping Self Administration Signal Transduction Single Nucleotide Polymorphism Societies Sum Techniques Testing Tissues Training Transcript Translating Translations Twin Multiple Birth Twin Studies Variant Weight Work alcohol abuse therapy alcohol risk alcohol use disorder comparative consumption measures economic cost genetic architecture genome wide association study loss of function male novel novel strategies phenotypic data polygenic risk score portability preference tool trait transcriptome transcriptomics

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项目摘要

Summary Alcohol use disorder (AUD) causes 1 in 20 deaths worldwide and imposes huge economic costs on society. Twin studies have shown that the risk for developing AUD is heritable. Genome wide association studies (GWAS) have indicated that, like most psychiatry diseases, AUD is highly polygenic. Although GWAS in both humans and rodents are powerful techniques, with different strengths and weaknesses, techniques to integrate the two are poorly developed. GWAS identify individual SNPs that influence a trait; because those SNPs are species specific, polygenic risk scores (PRS) and similar approaches cannot be used to transfer information across species. To address this limitation, we are proposing a framework for transferring polygenic signals across species. We introduce the concept of polygenic transcriptomic risk scores (PTRS). Whereas PRS sum the effects of many SNPs, a PTRS sums the effects of genetically predicted transcript abundance across many genes. Because these effects are at the gene, rather than SNP level, they can be applied to orthologous genes in other species. The extent to which a PTRS for AUD that was developed in humans might predict rodent behaviors believed to be relevant to AUD is currently unknown. In this grant we will assess whether PTRS can be used to translate polygenic signals related to AUD between humans and rodents. We focus on AUD because of the existence of high quality human GWAS data about AUD and related traits like alcohol consumption. In Aim 1, we will phenotype 1,250 HS rats for multiple alcohol self-administration traits. In Aim 2, we will perform GWAS and transcriptome wide association analysis (TWAS) for alcohol-related traits in the rats from Aim 1. In Aim 3, we will build PTRS for AUD and related traits and optimize them for portability across species. These aims address a critical limitation, namely the inability to transfer polygenic knowledge between species, which is inhibiting progress towards a deeper understanding of how polygenic liability for AUD alters molecular and cellular processes, brain circuits and behaviors. If successful, our results will open new avenues for research aimed at prediction, prevention, and treatment of AUD.

概括酒精使用障碍（AUD）在全球20例中造成1个死亡，并对社会。双胞胎研究表明，发展AUD的风险是可遗传的。基因组广泛的关联研究（GWAS）表明，像大多数精神病学疾病一样，AUD是高度多基因的。虽然GWAS 在人类和啮齿动物中，这都是强大的技术，具有不同的优势和劣势，技术的技术整合两者的发展不佳。 GWAS识别影响特征的个体SNP；因为那些 SNP是特定物种的，多基因风险评分（PR），类似方法不能用于转移跨物种的信息。为了解决这一限制，我们提出了一个转移多基因的框架跨物种的信号。我们介绍了多基因转录组风险评分（PTR）的概念。然而 PRS总和许多SNP的影响，A PTR总结了遗传预测的转录本丰度的影响跨许多基因。因为这些效果是在基因而不是SNP水平的基因上，所以它们可以应用于其他物种中的直系基因。人类开发的ptrs for aud的程度可能在多大程度上可能当前未知的预测被认为与AUD相关的啮齿动物行为。在这笔赠款中，我们将评估是否可以使用PTR来翻译与人与啮齿动物之间的AUD相关的多基因信号。我们由于存在有关AUD和相关特征的高质量人类GWAS数据，因此专注于AUD 饮酒。在AIM 1中，我们将表型为1,250 HS大鼠，以获得多种酒精自助性特征。在AIM 2中，我们将针对酒精相关的性状执行GWAS和转录组广泛的关联分析（TWA）在AIM 1的大鼠中。在AIM 3中，我们将为AUD和相关特征构建PTR，并优化它们以便便携性跨物种。这些目的解决了一个关键限制，即无法传递多基因知识在物种之间，这阻碍了对多基因责任如何对多基因责任的进步 AUD改变了分子和细胞过程，脑回路和行为。如果成功，我们的结果将开放研究的新途径旨在预测，预防和治疗AUD。