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

Lu Qiao1, Carrie L Welch2, Rebecca Hernan3

  • 1Department of Pediatrics, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.

American Journal of Human Genetics
|September 27, 2024
PubMed

Insights

This study identifies new genetic factors for congenital diaphragmatic hernia (CDH), a severe birth defect. Genetic analysis reveals both rare and common variants contribute to CDH risk, supporting a polygenic model.

Area of Science:

  • Genetics
  • Developmental Biology
  • Pediatric Medicine

Background:

  • Congenital diaphragmatic hernia (CDH) is a serious birth defect with known genetic links, but most cases remain genetically unexplained.
  • Existing research points to rare de novo variants and copy-number variations as contributors to CDH.
  • A significant portion of CDH cases lack a clear genetic diagnosis, highlighting the need for further investigation.

Purpose of the Study:

  • To identify novel genetic variants and loci associated with congenital diaphragmatic hernia (CDH) through integrated de novo and common-variant analyses.
  • To investigate the genetic architecture of CDH, including the contributions of rare and common genetic variations.
  • To explore the relationship between genetic risk scores and CDH subtypes or the presence of de novo variants.

Main Methods:

  • Genome-wide association study (GWAS) and de novo variant analysis were performed on 1,469 individuals with CDH (1,064 trios) and 6,133 controls.
  • Analysis focused on identifying rare, deleterious de novo variants and common variants associated with CDH risk.
  • Polygenic risk scores were calculated and compared between different CDH groups.

Main Results:

  • Fifteen candidate CDH genes were identified, including eight novel genes, through the analysis of de novo variants.
  • Two genomic loci associated with CDH risk were discovered via common variants, impacting developmental patterning genes.
  • Common variants contribute an estimated 19% to CDH heritability, and polygenic risk scores did not differ significantly between isolated and complex CDH or by de novo variant status.

Conclusions:

  • The genetic basis of CDH is complex, involving both rare de novo mutations and common variants.
  • The identified genetic loci are located in regulatory regions of developmental genes, suggesting a role in early development.
  • A polygenic model is supported for the genetic architecture of congenital diaphragmatic hernia.

Keywords:
WNT5Acommon variantscongenital diaphragmatic herniade novo variantsgenome-wide association studysingle-nucleotide polymorphism

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