A parent-of-origin analysis of paternal genetic variants and increased risk of conotruncal heart defects

Am J Med Genet A. 2018 Mar;176(3):609-617. doi: 10.1002/ajmg.a.38611. Epub 2018 Feb 5.


The association between conotruncal heart defects (CTHDs) and maternal genetic and environmental exposures is well studied. However, little is known about paternal genetic or environmental exposures and risk of CTHDs. We assessed the effect of paternal genetic variants in the folate, homocysteine, and transsulfuration pathways on risk of CTHDs in offspring. We utilized National Birth Defects Prevention Study data to conduct a family-based case only study using 616 live-born infants with CTHDs, born October 1997-August 2008. Maternal, paternal and infant DNA was genotyped using an Illumina® Golden Gate custom single nucleotide polymorphism (SNP) panel. Relative risks (RR) and 95% confidence intervals (CI) from log-linear models determined parent of origin effects for 921 SNPs in 60 candidate genes involved in the folate, homocysteine, and transsulfuration pathways on risk of CTHDs. The risk of CTHD among children who inherited a paternally derived copy of the A allele on GLRX (rs17085159) or the T allele of GLRX (rs12109442) was 0.23 (95%CI: 0.12, 0.42; p = 1.09 × 10-6 ) and 0.27 (95%CI: 0.14, 0.50; p = 2.06 × 10-5 ) times the risk among children who inherited a maternal copy of the same allele. The paternally inherited copy of the GSR (rs7818511) A allele had a 0.31 (95%CI: 0.18, 0.53; p = 9.94 × 10-6 ] risk of CTHD compared to children with the maternal copy of the same allele. The risk of CTHD is less influenced by variants in paternal genes involved in the folate, homocysteine, or transsulfuration pathways than variants in maternal genes in those pathways.

Keywords: congenital heart defect; conotruncal heart defects; genetic variants; parent-of-origin; paternal genetic variants.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Alleles
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Genetic Variation*
  • Genotype
  • Heart Defects, Congenital / epidemiology*
  • Heart Defects, Congenital / genetics*
  • Humans
  • Male
  • Maternal Inheritance*
  • Middle Aged
  • Paternal Inheritance*
  • Polymorphism, Single Nucleotide
  • Population Surveillance
  • Risk Assessment
  • Risk Factors
  • Young Adult