Am J Hum Genet
. 2024 Sep 24:S0002-9297(24)00334-3.
doi: 10.1016/j.ajhg.2024.08.024. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/39332409/
Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants
Lu Qiao 1, Carrie L Welch 2, Rebecca Hernan 3, Julia Wynn 2, Usha S Krishnan 2, Jill M Zalieckas 4, Terry Buchmiller 5, Julie Khlevner 2, Aliva De 2, Christiana Farkouh-Karoleski 2, Amy J Wagner 6, Andreas Heydweiller 7, Andreas C Mueller 8, Annelies de Klein 9, Brad W Warner 10, Carlo Maj 11, Dai Chung 12, David J McCulley 13, David Schindel 14, Douglas Potoka 15, Elizabeth Fialkowski 16, Felicitas Schulz 17, Florian Kipfmuller 8, Foong-Yen Lim 18, Frank Magielsen 9, George B Mychaliska 19, Gudrun Aspelund 2, Heiko Martin Reutter 20, Howard Needelman 21, J Marco Schnater 22, Jason C Fisher 23, Kenneth Azarow 16, Mahmoud Elfiky 24, Markus M Nöthen 25, Melissa E Danko 12, Mindy Li 26, Przemyslaw Kosiński 27, Rene M H Wijnen 22, Robert A Cusick 21, Samuel Z Soffer 28, Suzan C M Cochius-Den Otter 29, Thomas Schaible 30, Timothy Crombleholme 14, Vincent P Duron 31, Patricia K Donahoe 32, Xin Sun 13, Frances A High 33, Charlotte Bendixen 7, Erwin Brosens 9, Yufeng Shen 34, Wendy K Chung 35
Affiliations Expand
- PMID: 39332409
- DOI: 10.1016/j.ajhg.2024.08.024
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.
Keywords: WNT5A; common variants; congenital diaphragmatic hernia; de novo variants; genome-wide association study; single-nucleotide polymorphism.
Copyright © 2024 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
