Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants

Lu Qiao; Carrie L. Welch; Rebecca Hernan; Julia Wynn; Usha S. Krishnan; Jill M. Zalieckas; Terry Buchmiller; Julie Khlevner; Aliva De; Christiana Farkouh-Karoleski; Amy J. Wagner; Andreas Heydweiller; Andreas C. Mueller; Annelies de Klein; Brad W. Warner; Carlo Maj; Dai Chung; David J. McCulley; David Schindel; Douglas Potoka; Elizabeth Fialkowski; Felicitas Schulz; Florian Kipfmuller; Foong Yen Lim; Frank Magielsen; George B. Mychaliska; Gudrun Aspelund; Heiko Martin Reutter; Howard Needelman; J. Marco Schnater; Jason C. Fisher; Kenneth Azarow; Mahmoud Elfiky; Markus M. Nöthen; Melissa E. Danko; Mindy Li; Przemyslaw Kosiński; Rene M.H. Wijnen; Robert A. Cusick; Samuel Z. Soffer; Suzan C.M. Cochius-Den Otter; Thomas Schaible; Timothy Crombleholme; Vincent P. Duron; Patricia K. Donahoe; Xin Sun; Frances A. High; Charlotte Bendixen; Erwin Brosens; Yufeng Shen; Wendy K. Chung

doi:10.1016/j.ajhg.2024.08.024

Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants

Lu Qiao, Carrie L. Welch, Rebecca Hernan, Julia Wynn, Usha S. Krishnan, Jill M. Zalieckas, Terry Buchmiller, Julie Khlevner, Aliva De, Christiana Farkouh-Karoleski, Amy J. Wagner, Andreas Heydweiller, Andreas C. Mueller, Annelies de Klein, Brad W. Warner, Carlo Maj, Dai Chung, David J. McCulley, David Schindel, Douglas PotokaElizabeth Fialkowski, Felicitas Schulz, Florian Kipfmuller, Foong Yen Lim, Frank Magielsen, George B. Mychaliska, Gudrun Aspelund, Heiko Martin Reutter, Howard Needelman, J. Marco Schnater, Jason C. Fisher, Kenneth Azarow, Mahmoud Elfiky, Markus M. Nöthen, Melissa E. Danko, Mindy Li, Przemyslaw Kosiński, Rene M.H. Wijnen, Robert A. Cusick, Samuel Z. Soffer, Suzan C.M. Cochius-Den Otter, Thomas Schaible, Timothy Crombleholme, Vincent P. Duron, Patricia K. Donahoe, Xin Sun, Frances A. High, Charlotte Bendixen, Erwin Brosens, Yufeng Shen^*, Wendy K. Chung^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.

Original language	English
Pages (from-to)	2362-2381
Number of pages	20
Journal	American Journal of Human Genetics
Volume	111
Issue number	11
DOIs	https://doi.org/10.1016/j.ajhg.2024.08.024
Publication status	Published - 7 Nov 2024

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Publisher Copyright:
© 2024 American Society of Human Genetics

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10.1016/j.ajhg.2024.08.024

1-s2.0-S0002929724003343-mainFinal published version, 30.7 MBLicence: Article 25fa Dutch Copyright Act

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Qiao, L., Welch, C. L., Hernan, R., Wynn, J., Krishnan, U. S., Zalieckas, J. M., Buchmiller, T., Khlevner, J., De, A., Farkouh-Karoleski, C., Wagner, A. J., Heydweiller, A., Mueller, A. C., de Klein, A., Warner, B. W., Maj, C., Chung, D., McCulley, D. J., Schindel, D., ... Chung, W. K. (2024). Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants. American Journal of Human Genetics, 111(11), 2362-2381. https://doi.org/10.1016/j.ajhg.2024.08.024

@article{d4e8a56e05114feeb1ce819ad3d42d68,

title = "Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants",

abstract = "Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.",

author = "Lu Qiao and Welch, {Carrie L.} and Rebecca Hernan and Julia Wynn and Krishnan, {Usha S.} and Zalieckas, {Jill M.} and Terry Buchmiller and Julie Khlevner and Aliva De and Christiana Farkouh-Karoleski and Wagner, {Amy J.} and Andreas Heydweiller and Mueller, {Andreas C.} and {de Klein}, Annelies and Warner, {Brad W.} and Carlo Maj and Dai Chung and McCulley, {David J.} and David Schindel and Douglas Potoka and Elizabeth Fialkowski and Felicitas Schulz and Florian Kipfmuller and Lim, {Foong Yen} and Frank Magielsen and Mychaliska, {George B.} and Gudrun Aspelund and Reutter, {Heiko Martin} and Howard Needelman and Schnater, {J. Marco} and Fisher, {Jason C.} and Kenneth Azarow and Mahmoud Elfiky and N{\"o}then, {Markus M.} and Danko, {Melissa E.} and Mindy Li and Przemyslaw Kosi{\'n}ski and Wijnen, {Rene M.H.} and Cusick, {Robert A.} and Soffer, {Samuel Z.} and {Cochius-Den Otter}, {Suzan C.M.} and Thomas Schaible and Timothy Crombleholme and Duron, {Vincent P.} and Donahoe, {Patricia K.} and Xin Sun and High, {Frances A.} and Charlotte Bendixen and Erwin Brosens and Yufeng Shen and Chung, {Wendy K.}",

note = "Publisher Copyright: {\textcopyright} 2024 American Society of Human Genetics",

year = "2024",

month = nov,

day = "7",

doi = "10.1016/j.ajhg.2024.08.024",

language = "English",

volume = "111",

pages = "2362--2381",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "11",

}

Qiao, L, Welch, CL, Hernan, R, Wynn, J, Krishnan, US, Zalieckas, JM, Buchmiller, T, Khlevner, J, De, A, Farkouh-Karoleski, C, Wagner, AJ, Heydweiller, A, Mueller, AC, de Klein, A, Warner, BW, Maj, C, Chung, D, McCulley, DJ, Schindel, D, Potoka, D, Fialkowski, E, Schulz, F, Kipfmuller, F, Lim, FY, Magielsen, F, Mychaliska, GB, Aspelund, G, Reutter, HM, Needelman, H, Schnater, JM, Fisher, JC, Azarow, K, Elfiky, M, Nöthen, MM, Danko, ME, Li, M, Kosiński, P, Wijnen, RMH, Cusick, RA, Soffer, SZ, Cochius-Den Otter, SCM, Schaible, T, Crombleholme, T, Duron, VP, Donahoe, PK, Sun, X, High, FA, Bendixen, C, Brosens, E, Shen, Y & Chung, WK 2024, 'Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants', American Journal of Human Genetics, vol. 111, no. 11, pp. 2362-2381. https://doi.org/10.1016/j.ajhg.2024.08.024

TY - JOUR

T1 - Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants

AU - Qiao, Lu

AU - Welch, Carrie L.

AU - Hernan, Rebecca

AU - Wynn, Julia

AU - Krishnan, Usha S.

AU - Zalieckas, Jill M.

AU - Buchmiller, Terry

AU - Khlevner, Julie

AU - De, Aliva

AU - Farkouh-Karoleski, Christiana

AU - Wagner, Amy J.

AU - Heydweiller, Andreas

AU - Mueller, Andreas C.

AU - de Klein, Annelies

AU - Warner, Brad W.

AU - Maj, Carlo

AU - Chung, Dai

AU - McCulley, David J.

AU - Schindel, David

AU - Potoka, Douglas

AU - Fialkowski, Elizabeth

AU - Schulz, Felicitas

AU - Kipfmuller, Florian

AU - Lim, Foong Yen

AU - Magielsen, Frank

AU - Mychaliska, George B.

AU - Aspelund, Gudrun

AU - Reutter, Heiko Martin

AU - Needelman, Howard

AU - Schnater, J. Marco

AU - Fisher, Jason C.

AU - Azarow, Kenneth

AU - Elfiky, Mahmoud

AU - Nöthen, Markus M.

AU - Danko, Melissa E.

AU - Li, Mindy

AU - Kosiński, Przemyslaw

AU - Wijnen, Rene M.H.

AU - Cusick, Robert A.

AU - Soffer, Samuel Z.

AU - Cochius-Den Otter, Suzan C.M.

AU - Schaible, Thomas

AU - Crombleholme, Timothy

AU - Duron, Vincent P.

AU - Donahoe, Patricia K.

AU - Sun, Xin

AU - High, Frances A.

AU - Bendixen, Charlotte

AU - Brosens, Erwin

AU - Shen, Yufeng

AU - Chung, Wendy K.

PY - 2024/11/7

Y1 - 2024/11/7

N2 - Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.

AB - Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.

UR - http://www.scopus.com/inward/record.url?scp=85207783790&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2024.08.024

DO - 10.1016/j.ajhg.2024.08.024

M3 - Article

C2 - 39332409

AN - SCOPUS:85207783790

SN - 0002-9297

VL - 111

SP - 2362

EP - 2381

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 11

ER -

Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants

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