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.

总结