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

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 RM, Cusick RA, Soffer SZ, Cochius-Den Otter SC, Schaible T, Crombleholme T, Duron VP, Donahoe PK, Sun X, High FA, Bendixen C, Brosens E, Shen Y, Chung WK (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Book Volume: 111

Pages Range: 2362-2381

Journal Issue: 11

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.

Authors with CRIS profile

Involved external institutions

Columbia University Irving Medical Center (CUIMC) United States (USA) (US) University of Nebraska Medical Center (UNMC) United States (USA) (US) Northwell Health United States (USA) (US) New York University (NYU) United States (USA) (US) Massachusetts General Hospital United States (USA) (US) Erasmus MC - Sophia Children’s Hospital Netherlands (NL) Oregon Health and Science University (OSHU) United States (USA) (US) Cairo University Egypt (EG) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Monroe Carell Jr. Children's Hospital / Vanderbilt Children's Hospital United States (USA) (US) Rush University United States (USA) (US) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu Poland (PL) Harvard University United States (USA) (US) children's Wisconsin United States (USA) (US) Universitätsklinikum Bonn Germany (DE) Universitätsklinikum Düsseldorf Germany (DE) Cincinnati Children's Hospital Medical Center United States (USA) (US) University of Michigan United States (USA) (US) Medical City Children's Hospital United States (USA) (US) University of Pittsburgh United States (USA) (US) Washington University in St. Louis United States (USA) (US) Universitätsklinikum Mannheim Germany (DE)

How to cite

APA:

Qiao, L., Welch, C.L., Hernan, R., Wynn, J., Krishnan, U.S., Zalieckas, J.M.,... 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

MLA:

Qiao, Lu, et al. "Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants." American Journal of Human Genetics 111.11 (2024): 2362-2381.

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