A promoter interaction map for cardiovascular disease genetics

Abstract
Data availability
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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.

Data availability

Raw and processed sequencing data are provided at ArrayExpress through accession numbers E-MTAB-6014 (Hi-C) and E-MTAB-6013 (RNA-seq).

The following data sets were generated

1. Montefiori LE
2. Sobreira DR
3. Sakabe NJ
4. Aneas I
5. Joslin AC
6. Hansen GT
7. Bozek G
8. Moskowitz IP
9. McNally EM
10. Nóbrega MA
(2018) Capture Hi-C in iPSC and CM
E-MTAB-6014.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-6014/
1. Montefiori LE
2. Sobreira DR
3. Sakabe NJ
4. Aneas I
5. Joslin AC
6. Hansen GT
7. Bozek G
8. Moskowitz IP
9. McNally EM
10. Nóbrega MA
(2018) RNA-seq in iPSC and CM
E-MTAB-6013.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-6013/

The following previously published data sets were used

1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project - H1-H3K4me1
E003-H3K4me1.narrowPeak.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-H1-H3K27ac
E003-H3K27ac.narrowPeak.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-H1-H3K27me3
E003-H3K27me3.narrowPeak.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-H9-H3K4me1
E008-H3K4me1.narrowPeak.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-H9-H3K27ac
E008-H3K27ac.narrowPeak.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-H9-H3K27me3
E008-H3K27me3.narrowPeak.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-LV-H3K4me1
E095-H3K4me1.narrowPeak.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-LV-H3K27ac
E095-H3K27ac.narrowPeak.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-LV-H3K27me3
E095-H3K27me3.narrowPeak.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-RV-H3K4me1
E105-H3K4me1.narrowPeak.gz.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-RV-H3K27ac
E105-H3K27ac.narrowPeak.gz.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-RV-H3K27me3
E105-H3K27me3.narrowPeak.gz.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-RA-H3K4me1
E104-H3K4me1.narrowPeak.gz.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-RA-H3K27ac
E104-H3K27ac.narrowPeak.gz.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. Roadmap Epigenomics Consortium
2. Kundaje A et al
(2015) Roadmap Epigenome Project-RA-H3K27me3
E104-H3K27me3.narrowPeak.gz.

http://egg2.wustl.edu/roadmap/data/byFileType/peaks/consolidated/narrowPeak/
1. ENCODE Project Consortium
(2012) H1-CTCF
GSE29611.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE29611
1. ENCODE Project Consortium
(2012) Human CM - CTCF
GSE35583.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi
(2010) ENCODE_RNA-seq-fetal heart 1
GSM1059494.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM1059494
(2010) ENCODE_RNA-seq-fetal heart 2
GSM1059495.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi
(2010) ENCODE_RNA-seq-H1-1
GSM438361.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi
(2010) ENCODE_RNA-seq-H1-2
GSM958737.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi
(2010) ENCODE_RNA-seq-H1-3
GSM958737.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi
(2010) ENCODE_RNA-seq-H1-4
GSM1817053.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi
(2010) ENCODE_RNA-seq-LV-1
GSM1010938.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi
(2010) ENCODE_RNA-seq-LV-2
GSM1010964.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi
1. Kilpinen H
2. Waszak SM
3. Gschwind AR
4. Raghav SK
5. Witwicki RM
6. Orioli A
7. Migliavacca E
8. Wiederkehr M
9. Gutierrez-Arcelus M
10. Panousis N
11. Yurovsky A
12. Lappalainen T
13. Romano-Palumbo L
14. Planchon A
15. Bielser D
16. Bryois J
17. Padioleau I
18. Udin G
19. Thurnheer S
20. Hacker D
21. Core LJ
22. Lis JT
23. Hernandez N
24. Reymond A
25. Deplancke B
26. Dermitzakis ET
(2013) 1000G_RNA-seq-LCL_1883_GM11830_1
ERR356375.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-1883/
1. Kilpinen H
2. Waszak SM
3. Gschwind AR
4. Raghav SK
5. Witwicki RM
6. Orioli A
7. Migliavacca E
8. Wiederkehr M
9. Gutierrez-Arcelus M
10. Panousis N
11. Yurovsky A
12. Lappalainen T
13. Romano-Palumbo L
14. Planchon A
15. Bielser D
16. Bryois J
17. Padioleau I
18. Udin G
19. Thurnheer S
20. Hacker D
21. Core LJ
22. Lis JT
23. Hernandez N
24. Reymond A
25. Deplancke B
26. Dermitzakis ET
(2013) 1000G_RNA-seq-LCL_1883_GM11894_1
ERR356368.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-1883/
1. Kilpinen H
2. Waszak SM
3. Gschwind AR
4. Raghav SK
5. Witwicki RM
6. Orioli A
7. Migliavacca E
8. Wiederkehr M
9. Gutierrez-Arcelus M
10. Panousis N
11. Yurovsky A
12. Lappalainen T
13. Romano-Palumbo L
14. Planchon A
15. Bielser D
16. Bryois J
17. Padioleau I
18. Udin G
19. Thurnheer S
20. Hacker D
21. Core LJ
22. Lis JT
23. Hernandez N
24. Reymond A
25. Deplancke B
26. Dermitzakis ET
(2013) 1000G_RNA-seq-LCL_1883_GM12043_1
ERR356365.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-1883/
1. Kilpinen H
2. Waszak SM
3. Gschwind AR
4. Raghav SK
5. Witwicki RM
6. Orioli A
7. Migliavacca E
8. Wiederkehr M
9. Gutierrez-Arcelus M
10. Panousis N
11. Yurovsky A
12. Lappalainen T
13. Romano-Palumbo L
14. Planchon A
15. Bielser D
16. Bryois J
17. Padioleau I
18. Udin G
19. Thurnheer S
20. Hacker D
21. Core LJ
22. Lis JT
23. Hernandez N
24. Reymond A
25. Deplancke B
26. Dermitzakis ET
(2013) 1000G_RNA-seq-LCL_1883_GM12878_1
ERR356372.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-1883/
(2012) ENCODE_RNA-seq-LCL_encode_1
ENCFF000CXI.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM958730
(2012) ENCODE_RNA-seq-LCL_encode_2
ENCFF770NYA.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE33480
(2013) GEUVADIS_RNA-seq-LCL_geuvadis_1
ERR187488.

https://www.ebi.ac.uk/arrayexpress/experiments/E-GEUV-3/
(2013) GEUVADIS_RNA-seq-LCL_geuvadis_2
ERR187490.

https://www.ebi.ac.uk/arrayexpress/experiments/E-GEUV-3/

Article and author information

Author details

Lindsey E Montefiori

Department of Human Genetics, University of Chicago, Chicago, United States

For correspondence
lem@uchicago.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2342-6349
Debora R Sobreira

Department of Human Genetics, University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Noboru J Sakabe

Department of Human Genetics, University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Ivy Aneas

Department of Human Genetics, University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Amelia C Joslin

Department of Human Genetics, University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Grace T Hansen

Department of Human Genetics, University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Grazyna Bozek

Department of Human Genetics, University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Ivan P Moskowitz

Department of Human Genetics, University of Chicago, Chicago, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0014-4963
Elizabeth M McNally

Center for Genetic Medicine, Northwestern University, Chicago, United States

Competing interests
The authors declare that no competing interests exist.
Marcelo A Nóbrega

Department of Human Genetics, University of Chicago, Chicago, United States

For correspondence
nobrega@uchicago.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0451-7846

Funding

National Institutes of Health (HL123857)

Marcelo A Nóbrega

National Institutes of Health (HL119967)

Marcelo A Nóbrega

National Institutes of Health (HL118758)

Marcelo A Nóbrega

National Institutes of Health (HL128075)

Elizabeth M McNally
Marcelo A Nóbrega

National Institutes of Health (T32GMOO7197)

Lindsey E Montefiori

American Heart Association (17PRE33410726)

Lindsey E Montefiori

National Institutes of Health (HL137307-01)

Lindsey E Montefiori

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.