Tissue-specific and tissue-agnostic effects of genome sequence variation modulating blood pressure

Genome-wide association studies (GWASs) have identified numerous variants associated with polygenic traits and diseases. However, with few exceptions, a mechanistic understanding of which variants affect which genes in which tissues to modulate trait variation is lacking. Here, we present genomic an...

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Veröffentlicht in:Cell reports (Cambridge) Jg. 42; H. 11; S. 113351
Hauptverfasser: Lee, Dongwon, Han, Seong Kyu, Yaacov, Or, Berk-Rauch, Hanna, Mathiyalagan, Prabhu, Ganesh, Santhi K., Chakravarti, Aravinda
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 28.11.2023
Elsevier
Schlagworte:
blood pressure
Blood Pressure - genetics
complex traits
CP: Genomics
Gene Expression Regulation
Gene Regulatory Networks
Genetic Variation
Genome-Wide Association Study
heritability
Humans
Phenotype
Polymorphism, Single Nucleotide - genetics
Quantitative Trait Loci - genetics
regulatory variants
transcriptional machinery
blood pressure
complex traits
transcriptional machinery
CP: Genomics
regulatory variants
heritability
ISSN:2211-1247, 2211-1247
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Zusammenfassung:Genome-wide association studies (GWASs) have identified numerous variants associated with polygenic traits and diseases. However, with few exceptions, a mechanistic understanding of which variants affect which genes in which tissues to modulate trait variation is lacking. Here, we present genomic analyses to explain trait heritability of blood pressure (BP) through the genetics of transcriptional regulation using GWASs, multiomics data from different tissues, and machine learning approaches. Approximately 500,000 predicted regulatory variants across four tissues explain 33.4% of variant heritability: 2.5%, 5.3%, 7.7%, and 11.8% for kidney-, adrenal-, heart-, and artery-specific variants, respectively. Variation in the enhancers involved shows greater tissue specificity than in the genes they regulate, suggesting that gene regulatory networks perturbed by enhancer variants in a tissue relevant to a phenotype are the major source of interindividual variation in BP. Thus, our study provides an approach to scan human tissue and cell types for their physiological contribution to any trait. [Display omitted] •Variants in enhancers exhibit greater tissue specificity than gene expression•Enhancer variants disentangle tissue-specific dysregulation of genes and CREs•Artery-specific enhancer variants explain the most heritability of blood pressure Investigating tissue-specific effects of sequence variants on complex traits through a gene regulatory network is challenging. Lee et al. demonstrate that the heritability of blood pressure is largely explained by predicted tissue-specific enhancer variants and that artery-specific enhancer variants are the greatest source of interindividual variation in blood pressure regulation.
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D.L. and A.C. conceived and designed the study; S.K.G. collected the adult kidney tissues; O.Y., H.B.-R., and P.M. performed ATAC-seq experiments; D.L. and S.K.H. conducted all computational analyses; and D.L., S.K.H., and A.C. wrote the manuscript. All authors were involved in manuscript editing and revision.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2023.113351