Genome-wide association studies of structural birth defects: A review and commentary

Birth Defects Res. 2019 Nov 1;111(18):1329-1342. doi: 10.1002/bdr2.1606. Epub 2019 Oct 25.


Background: While there is strong evidence that genetic risk factors play an important role in the etiologies of structural birth defects, compared to other diseases, there have been relatively few genome-wide association studies (GWAS) of these conditions. We reviewed the current landscape of GWAS conducted for birth defects, noting novel insights, and future directions.

Methods: This article reviews the literature with regard to GWAS of structural birth defects. Key defects included in this review include oral clefts, congenital heart defects (CHDs), biliary atresia, pyloric stenosis, hypospadias, craniosynostosis, and clubfoot. Additionally, other issues related to GWAS are considered, including the assessment of polygenic risk scores and issues related to genetic ancestry, as well as utilizing genome-wide single nucleotide polymorphism array data to evaluate gene-environment interactions and Mendelian randomization.

Results: For some birth defects, including oral clefts and CHDs, several novel susceptibility loci have been identified and replicated through GWAS, including 8q24 for oral clefts, DGKK for hypospadias, and 4p16 for CHDs. Relatively common birth defects for which there are currently no published GWAS include neural tube defects, anotia/microtia, anophthalmia/microphthalmia, gastroschisis, and omphalocele.

Conclusions: Overall, GWAS have been successful in identifying several novel susceptibility genes and genomic regions for structural birth defects. These findings have provided new insights into the etiologies of these phenotypes. However, GWAS have been underutilized for understanding the genetic etiologies of several birth defects.

Keywords: GWAS; birth defects; epidemiology; genetics.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Cardiovascular Abnormalities / genetics
  • Congenital Abnormalities / etiology*
  • Congenital Abnormalities / genetics*
  • Eye Abnormalities / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Musculoskeletal Abnormalities / genetics
  • Nervous System Malformations / genetics
  • Otorhinolaryngologic Diseases / genetics