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:
- 金额:$ 64.63万
- 依托单位:
- 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:
- 关键词:3-DimensionalATAC-seqAddressAdultAffectAfrican ancestryAlcohol abuseAlcohol consumptionAlcoholsBehavioralBiologicalBiological ModelsBiological ProcessCRISPR/Cas technologyCandidate Disease GeneCellsCessation of lifeChromatinChromosome MappingClinicalClustered Regularly Interspaced Short Palindromic RepeatsCodeDataData SetDevelopmentDiagnosisDiagnosticDrosophila genusDrosophila melanogasterElectronic Health RecordElementsEnhancersEpigenetic ProcessEuropean ancestryGene ExpressionGenesGeneticGenomicsHeavy DrinkingHeritabilityHi-CHumanIndividualInduced pluripotent stem cell derived neuronsLaboratoriesLatinoLightLinkMapsMeasuresMedicalMeta-AnalysisMethodsModelingMolecular GeneticsNeighborhoodsNeuronsNeurotransmittersOrthologous GenePathway AnalysisPathway interactionsPhenotypePopulationPreventionPublic HealthRegulatory ElementReportingResolutionResourcesSamplingSingle Nucleotide PolymorphismSystemTestingTherapeuticTimeTwin Multiple BirthUntranslated RNAVariantVeteransalcohol behavioralcohol effectalcohol related genealcohol use disorderbinge drinkingbiobankcandidate identificationcausal variantcomorbiditydata integrationdopaminergic neuronexomeflygenetic architecturegenetic manipulationgenetic variantgenome wide association studygenome-wideinduced pluripotent stem cellinnovationknock-downnovelnovel strategiesoverexpressionphenomepleiotropismpreferenceprogramspromoterpsychosocialrare variantrisk varianttraittranscriptome 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Struan F A Grant', 18)}}的其他基金
Discovery of osteoblast and osteoclast bone mass effector genes using advanced genomics
利用先进基因组学发现成骨细胞和破骨细胞骨量效应基因
- 批准号:
10675631 - 财政年份:2022
- 资助金额:
$ 64.63万 - 项目类别:
Discovery of osteoblast and osteoclast bone mass effector genes using advanced genomics
利用先进基因组学发现成骨细胞和破骨细胞骨量效应基因
- 批准号:
10362112 - 财政年份:2022
- 资助金额:
$ 64.63万 - 项目类别:
Genomics of bone and body composition traits in children
儿童骨骼和身体成分特征的基因组学
- 批准号:
10441340 - 财政年份:2020
- 资助金额:
$ 64.63万 - 项目类别:
Functional Interrogation of T2D-associated genes in human stem cell-derived models and mice
人类干细胞衍生模型和小鼠中 T2D 相关基因的功能研究
- 批准号:
10649538 - 财政年份:2020
- 资助金额:
$ 64.63万 - 项目类别:
Functional Interrogation of T2D-associated genes in human stem cell-derived models and mice
人类干细胞衍生模型和小鼠中 T2D 相关基因的功能研究
- 批准号:
10451608 - 财政年份:2020
- 资助金额:
$ 64.63万 - 项目类别:
Functional Interrogation of T2D-associated genes in human stem cell-derived models and mice
人类干细胞衍生模型和小鼠中 T2D 相关基因的功能研究
- 批准号:
10242941 - 财政年份:2020
- 资助金额:
$ 64.63万 - 项目类别:
Genomics of bone and body composition traits in children
儿童骨骼和身体成分特征的基因组学
- 批准号:
10663174 - 财政年份:2020
- 资助金额:
$ 64.63万 - 项目类别:
Functional Interrogation of T2D-associated genes in human stem cell-derived models and mice
人类干细胞衍生模型和小鼠中 T2D 相关基因的功能研究
- 批准号:
10064866 - 财政年份:2020
- 资助金额:
$ 64.63万 - 项目类别:
Functional Mechanisms of T1D Risk Variants and their Target Genes using 3D Epigenomics and Single Cell Approaches
使用 3D 表观基因组学和单细胞方法研究 T1D 风险变异及其靶基因的功能机制
- 批准号:
9987848 - 财政年份:2019
- 资助金额:
$ 64.63万 - 项目类别:
Functional Mechanisms of T1D Risk Variants and their Target Genes using 3D Epigenomics and Single Cell Approaches
使用 3D 表观基因组学和单细胞方法研究 T1D 风险变异及其靶基因的功能机制
- 批准号:
10398021 - 财政年份:2019
- 资助金额:
$ 64.63万 - 项目类别:
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