Sequencing Annotation and Functional Analysis in Risk of Intracerebral Hemorrhage
Sequencing Annotation and Functional Analysis in Risk of Intracerebral Hemorrhage
批准号:
10066375
负责人:
Christopher David Anderson
金额:
$65.29万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-01-15 至 2022-11-30
关键词:
13q341q22AcuteAnimalsArteriesBinding SitesBioinformaticsBiologicalBiological AssayBiologyBrain hemorrhageCaringCatalogsCell modelCellular AssayCerebral hemisphere hemorrhageChromatinClustered Regularly Interspaced Short Palindromic RepeatsCodeCollectionComplexDataDeteriorationDiseaseDistantEpidemiologyExpression LibraryFoundationsFunctional disorderFundingFutureGaitGene Expression RegulationGenesGenetic RiskGenetic TranscriptionGenetic studyGenomeGenomic approachGenomicsGenotypeImpaired cognitionInvestmentsIschemic StrokeKnowledgeLinkMapsMeta-AnalysisMicrovascular DysfunctionMorbidity - disease rateMutagenesisNational Heart, Lung, and Blood InstituteNational Human Genome Research InstituteNational Institute of Neurological Disorders and StrokeNervePathologicPathway interactionsPhenotypePopulationPrevention strategyProcessPromoter RegionsProteinsReporterResolutionResourcesRiskRoleSingle Nucleotide PolymorphismSiteSourceStrokeStructureTestingTherapeuticTissuesTrans-Omics for Precision MedicineUnited States National Institutes of HealthUntranslated RNAVariantbioinformatics pipelinebioinformatics toolcase controlcausal variantcell typecostdesigndisabilityeffective therapygenetic analysisgenetic associationgenetic risk factorgenetic variantgenome sequencinggenome wide association studygeriatric depressionhuman diseasehypertension controlimprovedin silicoinnovationinsertion/deletion mutationinsightmortalitynovelnovel strategiespleiotropismprogramspromoterprotein structurerisk variantscreeningsextargeted sequencingtooltraittranscription factortranslational approachtranslational genomicstreatment strategywhole genome
中文摘要
脑出血(ICH)是中风中最致命的一种形式,那些存活下来的人背负着沉重的负担
英文摘要
Intracerebral hemorrhage (ICH) is the most deadly form of stroke, and those that survive carry a high burden of
long-term disability. ICH is an acute manifestation of progressive small vessel disease (CSVD), a condition that
collectively causes ICH and small vessel (SV) ischemic stroke, cognitive decline, late-life depression, and gait
deterioration. Because we have found shared epidemiologic and genetic risk factors among ICH and other CSVD
manifestations, understanding the biological foundations of ICH offers the opportunity to develop effective
treatment and prevention strategies across CSVD. Through prior genome-wide association studies (GWAS), we
have identified three promising gene-rich loci, 1q22, 13q34, and 16q24, carrying associations with both ICH and
SV stroke. These loci are united by a common theme in which associated variants are located in regions enriched
for non-coding regulatory roles, rather than protein-coding function. Identification of causal functional variants
and their regulatory mechanisms must occur before this knowledge can be applied to improve stroke care. Our
proposal is motivated by (A) well-powered GWAS of ICH and small vessel stroke as well as preliminary targeted
sequencing data suggesting a prominent regulatory role for ICH-associated variants at these loci, (B) the
availability of whole genome sequencing (WGS) data on large populations with ICH and ischemic stroke for well-
powered association testing at these loci, and (C) accumulated expertise in translational genomic approaches
that can link genetic variants to functional biological effects, bridging the gap between disease association results
and biological consequence.
This proposal serves our central hypothesis that exploring the functional impact of genetic associations in ICH
will yield biological insights that will identify novel treatment targets and advance the search for therapeutic
strategies with bedside applications. Our proposal, entitled “Sequencing Annotation and Functional Analysis of
Risk in ICH”, or SAFARI-ICH, will leverage NIH-supported WGS efforts from NHLBI TOPMed and the NHGRI
Centers for Common Disease Genomics to comprehensively determine 1) which particular sequence and
structural variants at 1q22, 13q34, and 16q24 predispose to CSVD, 2) which of these associated variants, using
annotation and cross-phenotype analyses, are most likely to reflect causal biology, and 3) what effect these
putative causal variants have on gene transcription at these and other loci using relevant cellular models. Our
approach leverages NIH investment in WGS at no cost to this proposal, allowing resources to be devoted to
identifying the causal variants and their functional ramifications in ICH and SV stroke. Because our approach is
designed to characterize variants with an impact on gene regulation at the cellular level, this proposal offers a
unique opportunity to deliver insight into ICH pathobiology and highlight potential targets for future treatment of
ICH and other adverse and highly prevalent CSVD manifestations.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Sequencing Annotation and Functional Analysis in Risk of Intracerebral Hemorrhage
-
批准号:10307139
-
项目类别:
-
资助金额:$65.54万
-
财政年份:2018
-
负责人:Christopher David Anderson
-
依托单位:
Genetic Analyses of Lipids in Cerebral Hemorrhage and Small Vessel Disease
-
批准号:8817328
-
项目类别:
-
资助金额:$18.62万
-
财政年份:2014
-
负责人:Christopher David Anderson
-
依托单位:
Genetic Analyses of Lipids in Cerebral Hemorrhage and Small Vessel Disease
-
批准号:9232225
-
项目类别:
-
资助金额:$19.43万
-
财政年份:2014
-
负责人:Christopher David Anderson
-
依托单位:
Genetic Analyses of Lipids in Cerebral Hemorrhage and Small Vessel Disease
-
批准号:8677019
-
项目类别:
-
资助金额:$19.06万
-
财政年份:2014
-
负责人:Christopher David Anderson
-
依托单位:
ERICH-GENE
-
批准号:10250540
-
项目类别:
-
资助金额:$199.06万
-
财政年份:2010
-
负责人:Christopher David Anderson
-
依托单位:
ERICH-GENE
-
批准号:10655629
-
项目类别:
-
资助金额:$199.49万
-
财政年份:2010
-
负责人:Christopher David Anderson
-
依托单位:
ERICH-GENE
-
批准号:10490307
-
项目类别:
-
资助金额:$202.84万
-
财政年份:2010
-
负责人:Christopher David Anderson
-
依托单位:
海外基金