A promoter interaction map for cardiovascular disease genetics

Montefiori, L. E.; Sobreira, D. R.; Sakabe, N. J.; Aneas, I.; Joslin, A. C.; Hansen, G. T.; Bozek, G.; Moskowitz, I. P.; McNally, E. M.; Nobrega, M. A.

doi:10.1101/340869

bioRxiv · 10.1101/340869

A promoter interaction map for cardiovascular disease genetics

Montefiori, L. E.·Sobreira, D. R.·Sakabe, N. J.·Aneas, I.·Joslin, A. C.·Hansen, G. T.·Bozek, G.·Moskowitz, I. P.·McNally, E. M.·Nobrega, M. A.

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Abstract

Over 500 genetic loci have been associated with risk of cardiovascular diseases (CVDs), however most loci are located in gene-distal non-coding regions and their target genes are not known. Here, we generated high-resolution promoter capture Hi-C (PCHi-C) maps in human induced pluripotent stem cells (iPSCs) and iPSC-derived cardiomyocytes (CMs) to provide a resource for identifying and prioritizing the functional targets of CVD associations. We validate these maps by demonstrating that promoters preferentially contact distal sequences enriched for tissue-specific transcription factor motifs and are enriched for chromatin marks that correlate with dynamic changes in gene expression. Using the CM PCHi-C map, we linked 1,999 CVD-associated SNPs to 347 target genes. Remarkably, more than 90% of SNP-target gene interactions did not involve the nearest gene, while 40% of SNPs interacted with at least two genes, demonstrating the importance of considering long-range chromatin interactions when interpreting functional targets of disease loci.

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Montefiori, L. E., Sobreira, D. R., Sakabe, N. J., Aneas, I., Joslin, A. C., Hansen, G. T., Bozek, G., Moskowitz, I. P., McNally, E. M., Nobrega, M. A.. 2018-06-08. A promoter interaction map for cardiovascular disease genetics. https://doi.org/10.1101/340869

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