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Leveraging GWAS Findings to Map Variants and Identify Novel Effector Genes for Alcohol-Related Traits

利用 GWAS 研究结果绘制变异图谱并识别酒精相关特征的新效应基因

基本信息

批准号：
10657933
负责人：
Struan F A Grant
金额：
$ 64.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2023-05-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657933
关键词：
3-Dimensional ATAC-seq Address Adult Affect African ancestry Alcohol abuse Alcohol consumption Alcohols Behavioral Biological Biological Models Biological Process CRISPR/Cas technology Candidate Disease Gene Cells Cessation of life Chromatin Chromosome Mapping Clinical Clustered Regularly Interspaced Short Palindromic Repeats Code Data Data Set Development Diagnosis Diagnostic Drosophila genus Drosophila melanogaster Electronic Health Record Elements Enhancers Epigenetic Process European ancestry Gene Expression Genes Genetic Genomics Heavy Drinking Heritability Hi-C Human Individual Induced pluripotent stem cell derived neurons Laboratories Latino Light Link Maps Measures Medical Meta-Analysis Methods Modeling Molecular Genetics Neighborhoods Neurons Neurotransmitters Orthologous Gene Pathway Analysis Pathway interactions Phenotype Population Prevention Public Health Regulatory Element Reporting Resolution Resources Sampling Single Nucleotide Polymorphism System Testing Therapeutic Time Twin Multiple Birth Untranslated RNA Variant Veterans alcohol behavior alcohol effect alcohol related gene alcohol use disorder binge drinking biobank candidate identification causal variant comorbidity data integration dopaminergic neuron exome fly genetic architecture genetic manipulation genetic variant genome wide association study genome-wide induced pluripotent stem cell innovation knock-down novel novel strategies overexpression phenome pleiotropism preference programs promoter psychosocial rare variant risk variant trait transcriptome sequencing

项目摘要

More than one-quarter of U.S. adults report past-year binge drinking and 5.6% meet criteria for a past-year alcohol use disorder (AUD). These traits are associated with psychosocial disruption, medical co-morbidities, and nearly 10% of all U.S. deaths annually. Alcohol consumption and AUD have an estimated twin heritability of 43% and 49%, respectively. Genome-wide association studies (GWAS) of these traits have identified 380 genome-wide significant SNPs in 155 loci. In this revised application, we propose to use a “variant to gene mapping to clinical impact” approach, intersecting GWAS data with ATAC-seq and high-resolution promoter- focused Capture C neuronal datasets derived from human induced pluripotent stem cells (iPSCs) to identify potential effector genes. To prioritize SNPs, we will focus on those residing in open chromatin and with enhancer epigenetic marks; we will also use eQTL resources, as needed. We will validate these and newly identified candidates in three ways: 1) in established Drosophila models of alcohol behavioral effects, 2) initially with human iPSC-derived cortical and dopaminergic neurons and subsequently with neurons of other neurotransmitter systems, as indicated, to delete the genomic neighborhood harboring a putative causal variant to determine its effects on the gene's expression, and 3) with data from 4 biobanks to corroborate the association of the functionally validated genes with alcohol-related phenotypes. In Aim 1, we will expand our preliminary set of 43 loci from iPSC-derived cortical neurons, initially by applying similar methods to iPSC- derived dopaminergic neurons and other neuronal types, as indicated. In Aim 2a, we will screen candidate genes identified in preliminary findings and those identified in Aim 1 by knocking down or over-expressing their orthologs in fly models of alcohol consumption, preference, sensitivity, and tolerance. In Aim 2b, we will use SNP-CRISPR in human iPSC-derived neurons to test whether deleting the genomic neighborhood of putative causal variants from preliminary data or those identified in Aim 1 affects expression of their target gene(s). In Aim 3, we will use array and exome sequence data from both European- and African-ancestry individuals to validate all putative effector genes by examining their association with alcohol-related traits, conducting downstream analyses, testing rare variant effects, and examining pleiotropy in phenome-wide association studies. This project will identify novel genetic variants and the corresponding effector genes that contribute to alcohol-related traits, thereby shedding light on the biological pathways that influence the development of the traits. Study results will have fundamental implications for novel approaches to the diagnosis, prevention, and treatment of heavy drinking and AUD.

超过四分之一的美国成年人报告过去一年酗酒，5.6%的人符合过去一年的标准