Evidence map›Paper›PMID 39606363›Full record

ArticlemedRxiv : the preprint server for health sciences2024

Molecular convergence of risk variants for congenital heart defects leveraging a regulatory map of the human fetal heart.

X Rosa Ma, Stephanie D Conley, Michael Kosicki, Danila Bredikhin, Ran Cui, Steven Tran, Maya U Sheth, Wei-Lin Qiu, Sijie Chen, Soumya Kundu and 27 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in medRxiv : the preprint server for health sciences, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

37 authors.

X Rosa MaBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.ORCID 0000-0001-8297-4279
Stephanie D ConleyBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
Michael KosickiEnvironmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.ORCID 0000-0001-7173-8852
Danila BredikhinBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
Ran CuiAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
Steven TranDepartment of Pediatrics, Stanford University, Stanford, CA, USA.
Maya U ShethBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
Wei-Lin QiuThe Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Sijie ChenBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
Soumya KunduDepartment of Genetics, Stanford University, Stanford, CA, USA.
Helen Y KangBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
Dulguun AmgalanBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
Chad J MungerBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
Lauren DuanDepartment of Pediatrics, Stanford University, Stanford, CA, USA.
Katherine DangDepartment of Pediatrics, Stanford University, Stanford, CA, USA.
Oriane Matthys RubioBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
Shinwan KanyCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Siavash ZamirpourSchool of Medicine, University of California San Francisco, San Francisco, CA, USA.
John DePaoloDepartment of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0002-6829-2594
Arun PadmanabhanGladstone Institutes, San Francisco, CA, USA.
Birth Defects Research Laboratory
Jeffrey OlginDivision of Cardiology, Department of Medicine and Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
Scott DamrauerDivision of Vascular Surgery and Endovascular Therapy, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Robin AnderssonThe Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0003-1516-879X
Mingxia GuCenter for Stem Cell and Organoid Medicine, Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
James R PriestDepartment of Pediatrics, Stanford University, Stanford, CA, USA.ORCID 0000-0002-8349-4784
Thomas QuertermousDepartment of Genetics, Stanford University, Stanford, CA, USA.ORCID 0000-0002-7645-9067
Xiaojie QiuBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
Marlene RabinovitchBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
Axel ViselEnvironmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Len PennacchioEnvironmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Anshul KundajeDepartment of Genetics, Stanford University, Stanford, CA, USA.
Ian A GlassMaternal and Child Health Research Institute, Stanford University, Stanford, CA, USA.
Casey A GiffordBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
James P PirruccelloCardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0001-6088-4037
William R GoodyerDepartment of Pediatrics, Stanford University, Stanford, CA, USA.
Jesse M EngreitzBasic Science and Engineering (BASE) Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.ORCID 0000-0002-5754-1719

Funding

INSTITUTIONAL TRAINING GRANT IN GENOME SCIENCET32HG000044 · NHGRI · STANFORD UNIVERSITY · PI MICHAEL P. SNYDER · 1995 to 2026
$32.2M
Generation of an In Vivo Human Genome Transcriptional Enhancer DatasetR01HG003988 · NHGRI · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI Len Alexander Pennacchio · 2006 to 2026
$24.1M
LABORATORY OF DEVELOPMENTAL BIOLOGYR24HD000836 · NICHD · UNIVERSITY OF WASHINGTON · PI Ian Amos Glass · 1995 to 2026
$16.9M
Stanford Center for Connecting DNA Variants to Function and PhenotypeUM1HG011972 · NHGRI · STANFORD UNIVERSITY · PI JESSE M ENGREITZ, THOMAS QUERTERMOUS · 2021 to 2026
$10.5M
Causal variant association mechanisms in TCF21 binding coronary disease lociR01HL134817 · NHLBI · STANFORD UNIVERSITY · PI THOMAS QUERTERMOUS · 2017 to 2026
$6.2M
Graduate Training in Computational and Systems BiologyT32GM087237 · NIGMS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI BURGE, CHRISTOPHER B · 2009 to 2023
$4.6M
A Single-Cell Resolution Enhancer Atlas of Craniofacial DevelopmentR01DE028599 · NIDCR · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI VISEL, AXEL · 2019 to 2023
$4.2M
Predicting context-specific molecular and phenotypic effects of genetic variation through the lens of the cis-regulatory codeU01HG012069 · NHGRI · STANFORD UNIVERSITY · PI Anshul Kundaje · 2021 to 2026
$3.9M
The SMAD3 signaling network in coronary artery disease riskR01HL139478 · NHLBI · STANFORD UNIVERSITY · PI THOMAS QUERTERMOUS · 2018 to 2026
$3.7M
Evaluating the Impact of Mutations in Distant-Acting Enhancers in Structural Birth DefectsR01HD114353 · NICHD · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI Len Alexander Pennacchio, Axel Visel · 2023 to 2026
$3.3M
In vivo Characterization of Regulatory Variant Pathogenicity in Congenital Heart DiseaseR01HL162304 · NHLBI · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI PENNACCHIO, LEN ALEXANDER, VISEL, AXEL · 2022 to 2025
$3.0M
High Shear Stress Alters Gene Regulation in Pulmonary Arterial HypertensionR01HL152134 · NHLBI · STANFORD UNIVERSITY · PI RABINOVITCH, MARLENE · 2021 to 2024
$2.9M
NHGRI NIH HHS DP2 HG014282NHGRI NIH HHS K22 HG000044NHGRI NIH HHS R00 HG012887NHGRI NIH HHS R01 HG003988NHGRI NIH HHS T32 HG000044NHGRI NIH HHS U01 HG012069NHGRI NIH HHS UM1 HG011972NHLBI NIH HHS K08 HL157700NHLBI NIH HHS K08 HL159346NHLBI NIH HHS R01 HL134817NHLBI NIH HHS R01 HL139478NHLBI NIH HHS R01 HL151535NHLBI NIH HHS R01 HL152134NHLBI NIH HHS R01 HL156846NHLBI NIH HHS R01 HL158525NHLBI NIH HHS R01 HL159176NHLBI NIH HHS R01 HL162304NHLBI NIH HHS R01 HL166283NHLBI NIH HHS R01 HL171045NICHD NIH HHS R01 HD114353NICHD NIH HHS R24 HD000836NIDCR NIH HHS R01 DE028599NIGMS NIH HHS R35 GM141861NIGMS NIH HHS T32 GM087237
6 · The paper itself

Abstract

Congenital heart defects (CHD) arise in part due to inherited genetic variants that alter genes and noncoding regulatory elements in the human genome. These variants are thought to act during fetal development to influence the formation of different heart structures. However, identifying the genes, pathways, and cell types that mediate these effects has been challenging due to the immense diversity of cell types involved in heart development as well as the superimposed complexities of interpreting noncoding sequences. As such, understanding the molecular functions of both noncoding and coding variants remains paramount to our fundamental understanding of cardiac development and CHD. Here, we created a gene regulation map of the healthy human fetal heart across developmental time, and applied it to interpret the functions of variants associated with CHD and quantitative cardiac traits. We collected single-cell multiomic data from 734,000 single cells sampled from 41 fetal hearts spanning post-conception weeks 6 to 22, enabling the construction of gene regulation maps in 90 cardiac cell types and states, including rare populations of cardiac conduction cells. Through an unbiased analysis of all 90 cell types, we find that both rare coding variants associated with CHD and common noncoding variants associated with valve traits converge to affect valvular interstitial cells (VICs). VICs are enriched for high expression of known CHD genes previously identified through mapping of rare coding variants. Eight CHD genes, as well as other genes in similar molecular pathways, are linked to common noncoding variants associated with other valve diseases or traits via enhancers in VICs. In addition, certain common noncoding variants impact enhancers with activities highly specific to particular subanatomic structures in the heart, illuminating how such variants can impact specific aspects of heart structure and function. Together, these results implicate new enhancers, genes, and cell types in the genetic etiology of CHD, identify molecular convergence of common noncoding and rare coding variants on VICs, and suggest a more expansive view of the cell types instrumental in genetic risk for CHD, beyond the working cardiomyocyte. This regulatory map of the human fetal heart will provide a foundational resource for understanding cardiac development, interpreting genetic variants associated with heart disease, and discovering targets for cell-type specific therapies.

Identifiers

PMID39606363
PMCPMC11601760

What Socratic holds

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.