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High-resolution regulatory maps connect cardiovascular risk variants to disease related pathways

By Örjan Åkerborg, Rapolas Spalinskas, Sailendra Pradhananga, Anandashankar Anil, Pontus Höjer, Flore-Anne Poujade, Lasse Folkersen, Per Eriksson, Pelin Sahlén

Posted 24 Jul 2018
bioRxiv DOI: 10.1101/376699

Genetic variant landscape of cardiovascular disease (CVD) is dominated by non-coding variants among which many occur within putative enhancers regulating the expression levels of relevant genes. It is crucial to assign the genetic variants to their correct gene both to gain insights into perturbed functions and better assess the risk of disease. In this study, we generated high-resolution genomic interaction maps (~750 bases) in aortic endothelial, smooth muscle and THP-1 macrophages using Hi-C coupled with sequence capture targeting 25,429 features including variants associated with CVD. We detected interactions for 761 CVD risk variants obtained by genome-wide association studies (GWAS) and identified novel as well as established functions associated with CVD. We were able to fine-map 331 GWAS variants using interaction networks, thereby identifying additional genes and functions. We also discovered a subset of risk variants interacting with multiple promoters and the expression levels of such genes were correlated. The presented resource enables functional studies of cardiovascular disease providing novel approaches for its diagnosis and treatment.

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