title: A genetic association study detects haplotypes associated with obstructive heart defects.
abstract: The development of congenital heart defects (CHDs) involves a complex interplay between genetic variants, epigenetic variants, and environmental exposures. Previous studies have suggested that susceptibility to CHDs is associated with maternal genotypes, fetal genotypes, and maternal-fetal genotype (MFG) interactions. We conducted a haplotype-based genetic association study of obstructive heart defects (OHDs), aiming to detect the genetic effects of 877 SNPs involved in the homocysteine, folate, and transsulfuration pathways. Genotypes were available for 285 mother-offspring pairs with OHD-affected pregnancies and 868 mother-offspring pairs with unaffected pregnancies. A penalized logistic regression model was applied with an adaptive least absolute shrinkage and selection operator (lasso), which dissects the maternal effect, fetal effect, and MFG interaction effects associated with OHDs. By examining the association between 140 haplotype blocks, we identified 9 blocks that are potentially associated with OHD occurrence. Four haplotype blocks, located in genes MGMT, MTHFS, CBS, and DNMT3L, were statistically significant using a Bayesian false-discovery probability threshold of 0.8. Two blocks in MGMT and MTHFS appear to have significant fetal effects, while the CBS and DNMT3L genes may have significant MFG interaction effects.
authors.affiliation: Department of Pediatrics, College of Medicine, University of Arkansas for Medical Sciences, 13 Children's Way Mail Slot 512-40, Little Rock, AR, 72202, USA, mli@uams.edu.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Mario A
authors.initials: MA
authors.lastname: Cleves
authors.forename: Himel
authors.initials: H
authors.lastname: Mallick
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Erickson
authors.forename: Xinyu
authors.initials: X
authors.lastname: Tang
authors.forename: Todd G
authors.initials: TG
authors.lastname: Nick
authors.forename: Stewart L
authors.initials: SL
authors.lastname: Macleod
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Hobbs
mesh_terms: D000328:Adult; D019731:Carbon-Nitrogen Ligases / Q000235:genetics*; D016022:Case-Control Studies; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D005333:Fetus; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014481:United States
chemical_list: D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C412484:DNMT3L protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; C515491:MGMT protein, human; D019731:Carbon-Nitrogen Ligases; C021557:5,10-methenyltetrahydrofolate synthetase; D045643:DNA Repair Enzymes