A Three-Way Interaction among Maternal and Fetal Variants Contributing to Congenital Heart Defects

Details

• Alternative Title:
  Ann Hum Genet
• Personal Author:
  Li, Ming ; Li, Jingyun ; Wei, Changshuai ; Lu, Qing ; Tang, Xinyu ; Erickson, Stephen W. ; Macleod, Stewart L. ; Hobbs, Charlotte A.
• Corporate Authors:
  National Birth Defects Prevention Study
• Description:
  Congenital heart defects (CHDs) develop through a complex interplay between genetic variants, epigenetic modifications, and maternal environmental exposures. Genetic studies of CHDs have commonly tested single genetic variants for association with CHDs. Less attention has been given to complex gene-by-gene and gene-by-environment interactions. In this study, we applied a recently developed likelihood-ratio Mann-Whitney (LRMW) method to detect joint actions among maternal variants, fetal variants, and maternal environmental exposures, allowing for high-order statistical interactions. All subjects are participants from the National Birth Defect Prevention Study, including 623 mother-offspring pairs with CHD-affected pregnancies and 875 mother-offspring pairs with unaffected pregnancies. Each individual has 872 single nucleotide polymorphisms encoding for critical enzymes in the homocysteine, folate, and trans-sulfuration pathways. By using the LRMW method, three variants (fetal rs625879, maternal rs2169650, and maternal rs8177441) were identified with a joint association to CHD risk (nominal P-value = 1.13e-07). These three variants are located within genes BHMT2, GSTP1, and GPX3, respectively. Further examination indicated that maternal SNP rs2169650 may interact with both fetal SNP rs625879 and maternal SNP rs8177441. Our findings suggest that the risk of CHD may be influenced by both the intragenerational interaction within the maternal genome and the intergenerational interaction between maternal and fetal genomes.
• Subjects:
  Adult Betaine-Homocysteine S-Methyltransferase DNA Mutational Analysis Female Fetus Genome, Human Genotype Glutathione Peroxidase Glutathione S-Transferase Pi Heart Defects, Congenital Humans Likelihood Functions Maternal Exposure Polymorphism, Single Nucleotide Young Adult

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• Keywords:
  Congenital Heart Defects Fetal Variants Gene-by-gene Interaction High-order Interactions Likelihood Ratio Maternal Variants U-Statistics
• Source:
  Ann Hum Genet. 80(1):20-31
• Pubmed ID:
  26612412
• Pubmed Central ID:
  PMC4839294
• Document Type:
  Journal Article
• Funding:
  UL1 TR000039/TR/NCATS NIH HHSUnited States/ ; U01 DD000491/DD/NCBDD CDC HHSUnited States/ ; UL1TR000039/TR/NCATS NIH HHSUnited States/ ; R03 DE022379/DE/NIDCR NIH HHSUnited States/ ; 5U01DD000491/DD/NCBDD CDC HHSUnited States/ ; KL2 TR000063/TR/NCATS NIH HHSUnited States/ ; 5R01HD039054/HD/NICHD NIH HHSUnited States/ ; KL2TR000063/TR/NCATS NIH HHSUnited States/ ; UL1 TR001108/TR/NCATS NIH HHSUnited States/ ; K01 DA033346/DA/NIDA NIH HHSUnited States/ ; R01 HD039054/HD/NICHD NIH HHSUnited States/
• Volume:
  80
• Issue:
  1
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:d06854acba457779707213dc888a78c9713cb917955249c035dac9b896d79a4c
• Download URL:
  https://stacks.cdc.gov/view/cdc/39055/cdc_39055_DS1.pdf
• File Type:
  [PDF - 340.59 KB ]