The goal of this proposal is to extend genetic studies of congenital left ventricular outflow tract obstruction (LVOTO) defects through a genome wide association (GWA) study. Clinical embryology, epidemiology, and cytogenetic data provide strong support for the importance of genetic factors in this class of cardiovascular malformations (CVM). Formal inheritance analyses are most consistent with an oligogenic/complex genetic mechanism underlying most cases. New epidemiologic data has provided more precise estimates of heritability, first degree relative risk, as well as sex and ethnic differences in prevalence rate. The first and second Specific Aims of this proposal involve genotyping case-parent trios with a panel of >500,000 single nucleotide polymorphisms (SNPs, Affymetrix Genome-Wide Human SNP Array 5.0). We propose to use Family Based Association Tests (FBAT) statistics for association analyses of single markers and haplotypes. Our sample will be composed exclusively of at least 700 Caucasian caseparent trios. Because there is significant sex rate difference, we will stratify by sex in the primary analysis. We will also examine for maternal genotype and parent of origin effects. We will use Multidimensional Reduction (MDR) and candidate gene methods to examine for epistasis. We will also use hybridization intensity data to identify inherited copy number variants (CNVs) and de novo submicroscopic chromosomal aberrations, infer the CNV genotypes, and test for CNV-disease associations. The third Specific Aim will carry out more thorough linkage disequilibrium mapping on promising regions identified in the primary GWA screen. We will use positive false discovery rate methods to help prioritize loci. We will use multipoint and haplotype methods to verify association in case parent trios and to refine the location of the potentially causal variants. The fourth Specific Aim will assess the validity of potential positive associations through replication in a sample of 1000 cases and 2000 controls obtained from the Texas Department of Health Birth Defects Surveillance program. Identification of genes involved in congenital LVOTO defects should provide both new mechanistic insights and improve diagnostic testing in individual patients and families.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090506-03
Application #
7821234
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Schramm, Charlene A
Project Start
2008-05-15
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
3
Fiscal Year
2010
Total Cost
$739,677
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Hanchard, Neil A; Umana, Luis A; D'Alessandro, Lisa et al. (2017) Assessment of large copy number variants in patients with apparently isolated congenital left-sided cardiac lesions reveals clinically relevant genomic events. Am J Med Genet A 173:2176-2188
Li, Alexander H; Hanchard, Neil A; Furthner, Dieter et al. (2017) Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns. Genome Med 9:95
Delaney, Susan K; Hultner, Michael L; Jacob, Howard J et al. (2016) Toward clinical genomics in everyday medicine: perspectives and recommendations. Expert Rev Mol Diagn 16:521-32
Fitzgerald-Butt, S M; Bodine, A; Fry, K M et al. (2016) Measuring genetic knowledge: a brief survey instrument for adolescents and adults. Clin Genet 89:235-43
Prakash, Siddharth K; Bondy, Carolyn A; Maslen, Cheryl L et al. (2016) Autosomal and X chromosome structural variants are associated with congenital heart defects in Turner syndrome: The NHLBI GenTAC registry. Am J Med Genet A 170:3157-3164
Fitzgerald-Butt, Sara M; Klima, Jennifer; Kelleher, Kelly et al. (2014) Genetic knowledge and attitudes of parents of children with congenital heart defects. Am J Med Genet A 164A:3069-75
Klima, Jennifer; Fitzgerald-Butt, Sara M; Kelleher, Kelly J et al. (2014) Understanding of informed consent by parents of children enrolled in a genetic biobank. Genet Med 16:141-8
Bonachea, Elizabeth M; Chang, Sheng-Wei; Zender, Gloria et al. (2014) Rare GATA5 sequence variants identified in individuals with bicuspid aortic valve. Pediatr Res 76:211-6
McBride, Kim L; Garg, Vidu (2011) Heredity of bicuspid aortic valve: is family screening indicated? Heart 97:1193-5
Marian, A J; Belmont, John (2011) Strategic approaches to unraveling genetic causes of cardiovascular diseases. Circ Res 108:1252-69

Showing the most recent 10 out of 13 publications