Genome Wide Association Study for Hypoplastic Left Heart and Related Defects

描述（由申请人提供）：本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、流行病学和细胞遗传学数据为 遗传因素在这类心血管畸形（CVM）中的重要性。正式的遗传分析是最一致的寡基因/复杂的遗传机制，大多数情况下。新的流行病学数据提供了更精确的估计遗传力，一级相对风险，以及性别和种族的患病率差异。该提案的第一个和第二个特定目标涉及对具有> 500，000个单核苷酸多态性的病例-亲本三重基因组进行基因分型（SNP，Affytechnology全基因组人类SNP阵列5.0）。我们建议使用基于家族的关联检验（FBAT）统计的关联分析的单标记和单倍型。我们的样本将由至少700名白人病例父母三人组组成。由于存在显著的性别比率差异，我们将在主要分析中按性别分层。我们还将研究母体基因型和亲本来源的影响。我们将使用多维简化（MDR）和候选基因的方法来检查上位性。我们还将使用杂交强度数据来鉴定遗传拷贝数变异（CNV）和从头亚显微染色体畸变， 推断CNV基因型，并检测CNV-疾病相关性。第三个具体目标将进行更彻底的连锁不平衡映射的有希望的地区确定的主要GWA屏幕。我们将使用阳性假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母三重奏情况下的关联性，并细化潜在因果变异的位置。第四个具体目标将通过在得克萨斯州获得的1000例病例和2000例对照样本中进行重复，评估潜在正相关的有效性。 卫生部出生缺陷监测计划。对先天性LVOTO缺陷相关基因的鉴定应提供新的机制见解，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.