Genomic analyses implicate noncoding de novo variants in congenital heart disease

被引：0

作者：

Felix Richter

Sarah U. Morton

Seong Won Kim

Alexander Kitaygorodsky

Lauren K. Wasson

Kathleen M. Chen

Jian Zhou

Hongjian Qi

Nihir Patel

Steven R. DePalma

Michael Parfenov

Jason Homsy

Joshua M. Gorham

Kathryn B. Manheimer

Matthew Velinder

Andrew Farrell

Gabor Marth

Eric E. Schadt

Jonathan R. Kaltman

Jane W. Newburger

Alessandro Giardini

Elizabeth Goldmuntz

Martina Brueckner

Richard Kim

George A. Porter

Daniel Bernstein

Wendy K. Chung

Deepak Srivastava

Martin Tristani-Firouzi

Olga G. Troyanskaya

Diane E. Dickel

Yufeng Shen

Jonathan G. Seidman

Christine E. Seidman

Bruce D. Gelb

机构：

[1] Icahn School of Medicine at Mount Sinai,Graduate School of Biomedical Sciences

[2] Harvard Medical School,Department of Pediatrics

[3] Boston Children’s Hospital,Division of Newborn Medicine

[4] Harvard Medical School,Department of Genetics

[5] Columbia University,Departments of Systems Biology and Biomedical Informatics

[6] Simons Foundation,Flatiron Institute

[7] Princeton University,Lewis

[8] University of Texas Southwestern Medical Center,Sigler Institute for Integrative Genomics

[9] Icahn School of Medicine at Mount Sinai,Lyda Hill Department of Bioinformatics

[10] Takeda Pharmaceuticals USA,Department of Genetics and Genomic Sciences

[11] Sema4,Center for External Innovation

[12] University of Utah School of Medicine,Department of Human Genetics, Utah Center for Genetic Discovery

[13] Icahn School of Medicine at Mount Sinai,Icahn Institute for Genomics and Multiscale Biology

[14] Division of Cardiovascular Sciences,Heart Development and Structural Diseases Branch

[15] NHLBI/NIH,Division of Cardiology

[16] Boston Children’s Hospital,Department of Pediatrics, The Perelman School of Medicine

[17] Cardiorespiratory Unit,Departments of Pediatrics and Genetics

[18] Great Ormond Street Hospital,Department of Pediatrics

[19] Children’s Hospital of Philadelphia,Department of Pediatrics

[20] University of Pennsylvania,Departments of Pediatrics and Medicine

[21] Yale University School of Medicine,Division of Pediatric Cardiology

[22] Children’s Hospital Los Angeles,Department of Computer Science

[23] University of Rochester,Environmental Genomics and Systems Biology Division

[24] Stanford University,Department of Cardiology

[25] Columbia University Medical Center,Mindich Child Health and Development Institute

[26] Gladstone Institute of Cardiovascular Disease and University of California San Francisco,Department of Pediatrics

[27] University of Utah School of Medicine,undefined

[28] Princeton University,undefined

[29] Lawrence Berkeley National Lab,undefined

[30] Brigham and Women’s Hospital,undefined

[31] Icahn School of Medicine at Mount Sinai,undefined

[32] Icahn School of Medicine at Mount Sinai,undefined

来源：

Nature Genetics | 2020年 / 52卷

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摘要：

A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.7 × 10−4). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10−5). We observed significant overlap between these transcription-based approaches (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.1–5.0, P = 5.4 × 10−3). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1–1.2, P = 8.8 × 10−5). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs.

引用

页码：769 / 777

页数：8

共 127 条

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