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:
  • 金额:
    $ 56.95万
  • 依托单位:
  • 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

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.
摘要 酒精使用障碍(AUD)导致全球每20人中就有1人死亡,并给 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 研究表明,像大多数精神病学疾病一样,AUD是高度多基因的。尽管GWAS 在人类和啮齿动物身上都有强大的技术,具有不同的优势和劣势,技术来 两者合二为一是欠发达的。GWA识别影响某一性状的单个SNP;因为那些 SNP是物种特有的,多基因风险分数(PR)和类似的方法不能用于转移 跨物种的信息。为了解决这一限制,我们提出了一个多基因转移的框架 不同物种之间的信号。我们引入了多基因转录风险分数(PTRS)的概念。鉴于 PTRS汇总了许多SNPs的影响,PTRS汇总了基因预测的转录丰度的影响 跨越了许多基因。因为这些影响是在基因水平上的,而不是SNP水平,所以它们可以应用于 其他物种中的同源基因。在人类中发展的AUD PTRS的程度可能 预测被认为与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能否用于在人和啮齿动物之间翻译与AUD相关的多基因信号。我们 关注AUD,因为存在关于AUD和相关特征的高质量人类Gwas数据,如 饮酒。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性状的表型研究。 在目标2中,我们将对酒精相关性状进行广义关联分析和转录组广谱关联分析 在目标1的大鼠身上。在目标3中,我们将建立AUD和相关性状的PTR,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,即无法传递多基因知识 在物种之间,这阻碍了对多基因责任如何产生更深层次理解的进展 AUD改变了分子和细胞过程、大脑回路和行为。如果成功,我们的结果将打开 旨在预测、预防和治疗AUD的研究的新途径。

项目成果

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Hae Kyung Im其他文献

Hae Kyung Im的其他文献

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{{ truncateString('Hae Kyung Im', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 56.95万
  • 项目类别:
Predicted Gene Expression: High Power, Mechanism, and Direction of Effect
预测基因表达:高功效、机制和作用方向
  • 批准号:
    9130902
  • 财政年份:
    2015
  • 资助金额:
    $ 56.95万
  • 项目类别:

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