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

• 批准号: 10705566
• 负责人: Hae Kyung Im
• 金额: $ 55.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 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/10705566
• 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; Elasticity; Female; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Grant; Heritability; Homologous Gene; 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; improved; loss of function; male; novel; novel strategies; phenotypic data; polygenic risk score; portability; preference; tool; trait; transcriptome; transcriptomics

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) 导致全球二十分之一的人死亡，并给人们带来了巨大的经济损失 社会。双胞胎研究表明，患 AUD 的风险是可遗传的。全基因组关联 研究（GWAS）表明，与大多数精神疾病一样，AUD 具有高度多基因性。虽然 GWAS 人类和啮齿类动物都有强大的技术，具有不同的优点和缺点， 两者的整合尚不发达。 GWAS 识别影响性状的个体 SNP；因为那些 SNP 是物种特异性的多基因风险评分 (PRS)，并且类似的方法不能用于转移 跨物种的信息。为了解决这个限制，我们提出了一个转移多基因的框架 跨物种信号。我们引入了多基因转录组风险评分（PTRS）的概念。然而 PRS 总结了许多 SNP 的影响，PTRS 总结了遗传预测的转录本丰度的影响 跨越许多基因。因为这些效应是在基因水平，而不是 SNP 水平，所以它们可以应用于 其他物种的直系同源基因。在人类中开发的针对 AUD 的 PTRS 的程度可能 预测与 AUD 相关的啮齿动物行为目前尚不清楚。在这笔赠款中，我们将评估 PTRS 是否可用于在人类和啮齿动物之间翻译与 AUD 相关的多基因信号。我们 关注 AUD，因为存在有关 AUD 和相关特征的高质量人类 GWAS 数据 饮酒量。在目标 1 中，我们将对 1,250 只 HS 大鼠进行多种酒精自我给药特征的表型分析。 在目标 2 中，我们将对酒精相关性状进行 GWAS 和转录组广泛关联分析 (TWAS) 在目标 1 的大鼠中。在目标 3 中，我们将为 AUD 和相关性状构建 PTRS，并优化它们的可移植性 跨物种。这些目标解决了一个关键的限制，即无法转移多基因知识 物种之间的差异，这阻碍了对多基因责任如何更深入理解的进展 AUD 改变分子和细胞过程、大脑回路和行为。如果成功，我们的结果将开放 旨在预测、预防和治疗 AUD 的新研究途径。