Genome Wide Association Study for Hypoplastic Left Heart and Related Defects

描述（由申请人提供）：该提案的目标是通过全基因组关联（GWA）研究扩展先天性左心室流出道梗阻（LVOTO）缺陷的遗传学研究。临床胚胎学、流行病学、细胞遗传学数据为 遗传因素在此类心血管畸形（CVM）中的重要性。正式的遗传分析与大多数病例背后的寡基因/复杂遗传机制最为一致。新的流行病学数据提供了对遗传力、一级相对风险以及患病率的性别和种族差异的更精确估计。该提案的第一个和第二个具体目标涉及使用一组> 500,000 个单核苷酸多态性（SNP，Affymetrix 全基因组人类 SNP 阵列 5.0）对病例亲本三重奏进行基因分型。我们建议使用基于家族的关联测试（FBAT）统计数据进行单个标记和单倍型的关联分析。我们的样本将完全由至少 700 个白人父母三人组组成。由于存在显着的性别比率差异，我们在初步分析中将按性别进行分层。我们还将检查母体基因型和亲本效应。我们将使用多维还原 (MDR) 和候选基因方法来检查上位性。我们还将使用杂交强度数据来识别遗传拷贝数变异（CNV）和从头亚显微染色体畸变， 推断 CNV 基因型，并测试 CNV 与疾病的关联。第三个具体目标将对主要 GWA 筛选中确定的有希望的区域进行更彻底的连锁不平衡图谱。我们将使用正错误发现率方法来帮助确定基因座的优先级。我们将使用多点和单倍型方法来验证父三重奏中的关联，并细化潜在因果变异的位置。第四个具体目标将通过对从德克萨斯州获得的 1000 个病例和 2000 个对照样本进行复制来评估潜在正相关的有效性。 卫生部出生缺陷监测计划。鉴定与先天性 LVOTO 缺陷相关的基因应该提供新的机制见解并改善个体患者和家庭的诊断测试。

DESCRIPTION (provided by applicant): 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.