TY - JOUR
T1 - Allele-specific NKX2-5 binding underlies multiple genetic associations with human electrocardiographic traits
AU - Benaglio, Paola
AU - D’Antonio-Chronowska, Agnieszka
AU - Ma, Wubin
AU - Yang, Feng
AU - Young Greenwald, William W.
AU - Donovan, Margaret K.R.
AU - DeBoever, Christopher
AU - Li, He
AU - Drees, Frauke
AU - Singhal, Sanghamitra
AU - Matsui, Hiroko
AU - van Setten, Jessica
AU - Sotoodehnia, Nona
AU - Gaulton, Kyle J.
AU - Smith, Erin N.
AU - D’Antonio, Matteo
AU - Rosenfeld, Michael G.
AU - Frazer, Kelly A.
N1 - Funding Information:
This work was supported in part by California Institute for Regenerative Medicine grant (CIRM) GC1R-06673-B, NIH grants HG008118 and HL107442, and National Science Foundation grant 1728497. P.B. was supported by the Swiss National Science Foundation Postdoc Mobility fellowships P2LAP3-155105 and P300PA-167612. W.W.Y.G. was supported by the NHLBI under award number HL142151. C.D. was supported in part by the UCSD Genetics Training Program through an institutional training grant from the NIGMS under award number GM008666 and the CIRM Interdisciplinary Stem Cell Training Program at UCSD II (TG2-01154). Library preparation and sequencing services were conducted by K. Jepsen and M. Khosroheidari at the UCSD IGM Genomics Center, supported by NIH grant CA023100. N.S. was supported by NIH grants HL116747 and HL141989. K.J.G. was supported by NIH grant DK114650 and ADA grant 1-17-JDF-027. W.M., F.Y. and M.G.R. were supported by NIH grants DK018477 and DK039949. M.G.R. is a HHMI investigator. We are thankful to C.-A. Yen and N. Spann for assistance with the ChIP-Seq experiments, and to A. Schmitt for the Hi-C data. We thank A. Aguirre for performing immunofluorescence. We thank E. Farley and K. Olson for help with reporter assays. We thank many colleagues for helpful comments.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - The cardiac transcription factor (TF) gene NKX2-5 has been associated with electrocardiographic (EKG) traits through genome-wide association studies (GWASs), but the extent to which differential binding of NKX2-5 at common regulatory variants contributes to these traits has not yet been studied. We analyzed transcriptomic and epigenomic data from induced pluripotent stem cell-derived cardiomyocytes from seven related individuals, and identified ~2,000 single-nucleotide variants associated with allele-specific effects (ASE-SNVs) on NKX2-5 binding. NKX2-5 ASE-SNVs were enriched for altered TF motifs, for heart-specific expression quantitative trait loci and for EKG GWAS signals. Using fine-mapping combined with epigenomic data from induced pluripotent stem cell–derived cardiomyocytes, we prioritized candidate causal variants for EKG traits, many of which were NKX2-5 ASE-SNVs. Experimentally characterizing two NKX2-5 ASE-SNVs (rs3807989 and rs590041) showed that they modulate the expression of target genes via differential protein binding in cardiac cells, indicating that they are functional variants underlying EKG GWAS signals. Our results show that differential NKX2-5 binding at numerous regulatory variants across the genome contributes to EKG phenotypes.
AB - The cardiac transcription factor (TF) gene NKX2-5 has been associated with electrocardiographic (EKG) traits through genome-wide association studies (GWASs), but the extent to which differential binding of NKX2-5 at common regulatory variants contributes to these traits has not yet been studied. We analyzed transcriptomic and epigenomic data from induced pluripotent stem cell-derived cardiomyocytes from seven related individuals, and identified ~2,000 single-nucleotide variants associated with allele-specific effects (ASE-SNVs) on NKX2-5 binding. NKX2-5 ASE-SNVs were enriched for altered TF motifs, for heart-specific expression quantitative trait loci and for EKG GWAS signals. Using fine-mapping combined with epigenomic data from induced pluripotent stem cell–derived cardiomyocytes, we prioritized candidate causal variants for EKG traits, many of which were NKX2-5 ASE-SNVs. Experimentally characterizing two NKX2-5 ASE-SNVs (rs3807989 and rs590041) showed that they modulate the expression of target genes via differential protein binding in cardiac cells, indicating that they are functional variants underlying EKG GWAS signals. Our results show that differential NKX2-5 binding at numerous regulatory variants across the genome contributes to EKG phenotypes.
UR - http://www.scopus.com/inward/record.url?scp=85074188621&partnerID=8YFLogxK
U2 - 10.1038/s41588-019-0499-3
DO - 10.1038/s41588-019-0499-3
M3 - Article
C2 - 31570892
AN - SCOPUS:85074188621
SN - 1061-4036
VL - 51
SP - 1506
EP - 1517
JO - Nature Genetics
JF - Nature Genetics
IS - 10
ER -