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Title: Genomic analyses implicate noncoding de novo variants in congenital heart disease

Abstract

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). Overall, 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.

Authors:
ORCiD logo [1]; ORCiD logo [2];  [3];  [4]; ORCiD logo [3]; ORCiD logo [5]; ORCiD logo [6];  [4]; ORCiD logo [1]; ORCiD logo [3];  [3];  [7];  [3];  [8];  [9];  [9]; ORCiD logo [9]; ORCiD logo [10];  [11];  [12] more »;  [13]; ORCiD logo [14]; ORCiD logo [15];  [16]; ORCiD logo [17]; ORCiD logo [18];  [19];  [20]; ORCiD logo [21];  [22]; ORCiD logo [23]; ORCiD logo [4];  [3]; ORCiD logo [24]; ORCiD logo [25] « less
+ Show Author Affiliations
  1. Icahn School of Medicine at Mount Sinai, New York, NY (United States)
  2. Harvard Medical School, Boston, MA (United States); Boston Children's Hospital, MA (United States)
  3. Harvard Medical School, Boston, MA (United States)
  4. Columbia Univ., New York, NY (United States)
  5. Flatiron Inst., New York, NY (United States). Simons Foundation
  6. Flatiron Inst., New York, NY (United States). Simons Foundation; Princeton Univ., NJ (United States). Lewis-Sigler Inst. for Integrative Genomics; Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
  7. Harvard Medical School, Boston, MA (United States); Takeda Pharmaceuticals USA, Cambridge, MA (United States). Center for External Innovation
  8. Icahn School of Medicine at Mount Sinai, New York, NY (United States); Sema4, Stamford, CT (United States)
  9. Univ. of Utah, Salt Lake City, UT (United States). Utah Center for Genetic Discovery
  10. Icahn School of Medicine at Mount Sinai, New York, NY (United States); Sema4, Stamford, CT (United States); Icahn School of Medicine at Mount Sinai, New York, NY (United States). Icahn Inst. for Genomics and Multiscale Biology
  11. National Institutes of Health (NIH), Bethesda, MD (United States). National Heart, Lung, and Blood Inst. (NHLBI)
  12. Boston Children's Hospital, MA (United States)
  13. Great Ormond Street Hospital, London (United Kingdom)
  14. Children's Hospital of Philadelphia, PA (United States); Univ. of Pennsylvania, Philadelphia, PA (United States)
  15. Yale Univ., New Haven, CT (United States)
  16. Children's Hospital Los Angeles, CA (United States)
  17. Univ. of Rochester, NY (United States)
  18. Stanford Univ., CA (United States)
  19. Columbia Univ. Medical Center, New York, NY (United States)
  20. Univ. of California, San Francisco, CA (United States). Gladstone Inst. of Cardiovascular Disease
  21. Univ. of Utah, Salt Lake City, UT (United States)
  22. Flatiron Inst., New York, NY (United States). Simons Foundation; Princeton Univ., NJ (United States). Lewis-Sigler Inst. for Integrative Genomics
  23. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Computational Cosmology Center
  24. Harvard Medical School, Boston, MA (United States); Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States)
  25. Icahn School of Medicine at Mount Sinai, New York, NY (United States); Icahn School of Medicine at Mount Sinai, New York, NY (United States). Mindich Child Health and Development Inst.
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); US Dept. of Health and Human Services
OSTI Identifier:
1782152
Grant/Contract Number:  
AC02-05CH11231; UM1HL098166; R24HL123879; R01GM071966; UM1HL128711; UM1HL098162; UM1HL098147; UM1HL098123; UM1HL128761; U01HL131003
Resource Type:
Accepted Manuscript
Journal Name:
Nature Genetics
Additional Journal Information:
Journal Volume: 52; Journal Issue: 8; Journal ID: ISSN 1061-4036
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Congenital heart defects; genetics

Citation Formats

Richter, Felix, Morton, Sarah U., Kim, Seong Won, Kitaygorodsky, Alexander, Wasson, Lauren K., Chen, Kathleen M., Zhou, Jian, Qi, Hongjian, Patel, Nihir, DePalma, Steven R., Parfenov, Michael, Homsy, Jason, Gorham, Joshua M., Manheimer, Kathryn B., Velinder, Matthew, Farrell, Andrew, Marth, Gabor, Schadt, Eric E., Kaltman, Jonathan R., Newburger, Jane W., Giardini, Alessandro, Goldmuntz, Elizabeth, Brueckner, Martina, Kim, Richard, Porter, George A., Bernstein, Daniel, Chung, Wendy K., Srivastava, Deepak, Tristani-Firouzi, Martin, Troyanskaya, Olga G., Dickel, Diane E., Shen, Yufeng, Seidman, Jonathan G., Seidman, Christine E., and Gelb, Bruce D. Genomic analyses implicate noncoding de novo variants in congenital heart disease. United States: N. p., 2020. Web. doi:10.1038/s41588-020-0652-z.
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Richter, Felix, Morton, Sarah U., Kim, Seong Won, Kitaygorodsky, Alexander, Wasson, Lauren K., Chen, Kathleen M., Zhou, Jian, Qi, Hongjian, Patel, Nihir, DePalma, Steven R., Parfenov, Michael, Homsy, Jason, Gorham, Joshua M., Manheimer, Kathryn B., Velinder, Matthew, Farrell, Andrew, Marth, Gabor, Schadt, Eric E., Kaltman, Jonathan R., Newburger, Jane W., Giardini, Alessandro, Goldmuntz, Elizabeth, Brueckner, Martina, Kim, Richard, Porter, George A., Bernstein, Daniel, Chung, Wendy K., Srivastava, Deepak, Tristani-Firouzi, Martin, Troyanskaya, Olga G., Dickel, Diane E., Shen, Yufeng, Seidman, Jonathan G., Seidman, Christine E., & Gelb, Bruce D. Genomic analyses implicate noncoding de novo variants in congenital heart disease. United States. https://doi.org/10.1038/s41588-020-0652-z
Copy to clipboard
Richter, Felix, Morton, Sarah U., Kim, Seong Won, Kitaygorodsky, Alexander, Wasson, Lauren K., Chen, Kathleen M., Zhou, Jian, Qi, Hongjian, Patel, Nihir, DePalma, Steven R., Parfenov, Michael, Homsy, Jason, Gorham, Joshua M., Manheimer, Kathryn B., Velinder, Matthew, Farrell, Andrew, Marth, Gabor, Schadt, Eric E., Kaltman, Jonathan R., Newburger, Jane W., Giardini, Alessandro, Goldmuntz, Elizabeth, Brueckner, Martina, Kim, Richard, Porter, George A., Bernstein, Daniel, Chung, Wendy K., Srivastava, Deepak, Tristani-Firouzi, Martin, Troyanskaya, Olga G., Dickel, Diane E., Shen, Yufeng, Seidman, Jonathan G., Seidman, Christine E., and Gelb, Bruce D. Mon . "Genomic analyses implicate noncoding de novo variants in congenital heart disease". United States. https://doi.org/10.1038/s41588-020-0652-z. https://www.osti.gov/servlets/purl/1782152.
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@article{osti_1782152,
title = {Genomic analyses implicate noncoding de novo variants in congenital heart disease},
author = {Richter, Felix and Morton, Sarah U. and Kim, Seong Won and Kitaygorodsky, Alexander and Wasson, Lauren K. and Chen, Kathleen M. and Zhou, Jian and Qi, Hongjian and Patel, Nihir and DePalma, Steven R. and Parfenov, Michael and Homsy, Jason and Gorham, Joshua M. and Manheimer, Kathryn B. and Velinder, Matthew and Farrell, Andrew and Marth, Gabor and Schadt, Eric E. and Kaltman, Jonathan R. and Newburger, Jane W. and Giardini, Alessandro and Goldmuntz, Elizabeth and Brueckner, Martina and Kim, Richard and Porter, George A. and Bernstein, Daniel and Chung, Wendy K. and Srivastava, Deepak and Tristani-Firouzi, Martin and Troyanskaya, Olga G. and Dickel, Diane E. and Shen, Yufeng and Seidman, Jonathan G. and Seidman, Christine E. and Gelb, Bruce D.},
abstractNote = {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). Overall, 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.},
doi = {10.1038/s41588-020-0652-z},
journal = {Nature Genetics},
number = 8,
volume = 52,
place = {United States},
year = {Mon Jun 29 00:00:00 EDT 2020},
month = {Mon Jun 29 00:00:00 EDT 2020}
}
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