title: Application of gene network analysis techniques identifies AXIN1/PDIA2 and endoglin haplotypes associated with bicuspid aortic valve.
abstract: Bicuspid Aortic Valve (BAV) is a highly heritable congenital heart defect. The low frequency of BAV (1% of general population) limits our ability to perform genome-wide association studies. We present the application of four a priori SNP selection techniques, reducing the multiple-testing penalty by restricting analysis to SNPs relevant to BAV in a genome-wide SNP dataset from a cohort of 68 BAV probands and 830 control subjects. Two knowledge-based approaches, CANDID and STRING, were used to systematically identify BAV genes, and their SNPs, from the published literature, microarray expression studies and a genome scan. We additionally tested Functionally Interpolating SNPs (fitSNPs) present on the array; the fourth consisted of SNPs selected by Random Forests, a machine learning approach. These approaches reduced the multiple testing penalty by lowering the fraction of the genome probed to 0.19% of the total, while increasing the likelihood of studying SNPs within relevant BAV genes and pathways. Three loci were identified by CANDID, STRING, and fitSNPS. A haplotype within the AXIN1-PDIA2 locus (p-value of 2.926x10(-06)) and a haplotype within the Endoglin gene (p-value of 5.881x10(-04)) were found to be strongly associated with BAV. The Random Forests approach identified a SNP on chromosome 3 in association with BAV (p-value 5.061x10(-06)). The results presented here support an important role for genetic variants in BAV and provide support for additional studies in well-powered cohorts. Further, these studies demonstrate that leveraging existing expression and genomic data in the context of GWAS studies can identify biologically relevant genes and pathways associated with a congenital heart defect.
authors.affiliation: MCRI Center for Translational Genomics, Molecular Cardiology Research Institute, Boston, Massachusetts, United States of America.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Wooten
authors.forename: Lakshmanan K
authors.initials: LK
authors.lastname: Iyer
authors.forename: Maria Claudia
authors.initials: MC
authors.lastname: Montefusco
authors.forename: Alyson Kelley
authors.initials: AK
authors.lastname: Hedgepeth
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Payne
authors.forename: Navin K
authors.initials: NK
authors.lastname: Kapur
authors.forename: David E
authors.initials: DE
authors.lastname: Housman
authors.forename: Michael E
authors.initials: ME
authors.lastname: Mendelsohn
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Huggins
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D001021:Aortic Valve / Q000002:abnormalities*; D060466:Axin Protein; D016022:Case-Control Studies; D000071063:Endoglin; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006330:Heart Defects, Congenital / Q000235:genetics*; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D019704:Protein Disulfide-Isomerases / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: C555451:AXIN1 protein, human; D015703:Antigens, CD; D060466:Axin Protein; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C526504:PDIA2 protein, human; D019704:Protein Disulfide-Isomerases