Genomewide Association Study of Conotruncal Heart Disease

描述（由申请人提供）：心脏畸形是最常见、最严重的出生缺陷，也是患者一生中发病和死亡的重要原因。尽管这些情况具有公共卫生意义，但先天性心脏缺陷的原因知之甚少，缺乏初级预防方法。与神经管缺陷和面部裂等其他结构性畸形一样，大多数非综合征性冠心病病例被认为是由多种环境和遗传因素决定的遗传复杂情况。然而，一般来说，对于非综合征性冠心病或像CTDs这样的亚组来说，几乎没有确定的危险因素。这种情况与其他几种常见的复杂疾病没有什么不同，最近的全基因组关联研究（GWAS）为这些疾病提供了强有力的证据，证明存在与疾病相关的常见基因变异。因此，全基因组方法在冠心病研究中的应用是非常有趣的，并且有可能显著提高我们对这些疾病发展过程的理解。我们建议进行必要的统计分析，以完成被称为圆锥状心脏缺陷（CTDs）的冠心病亚组的GWAS。该亚组约占所有冠心病的1/3，并且有大量来自动物和人类研究的数据表明，与其他形式的冠心病相比，属于该亚组的心脏表型彼此之间的关系更为密切。通过本研究小组的持续努力，来自Illumina 550K芯片的800例CTD病例-亲本三联体的SNP基因分型数据已经掌握，并等待分析：(1)确定与CTD相关的母体和遗传（即病例）基因型，以及(2)确定与CTD相关的途径和基因集。

DESCRIPTION (provided by applicant): Malformations of the heart are the most common, serious birth defects, and an important cause of morbidity and mortality throughout the lifespan of affected individuals. Despite the public health significance of these conditions, the causes of congenital heart defects are poorly understood and primary prevention methods are lacking. Like other structural malformations, such as neural tube defects and facial clefts, most non-syndromic cases of CHDs are thought to be genetically complex conditions determined by the effects of multiple environmental and genetic factors. However, there are few established risk factors for non-syndromic CHDs in general, or for subgroups such as the CTDs. This situation is not unlike that for several other common, complex diseases, for which recent genome-wide association studies (GWAS) have provided strong evidence for the existence of common, disease-related, gene variants. Hence, application of genome-wide approaches to the study of CHDs is of extreme interest and has the potential to significantly advance our understanding of the pathways that are involved in the development of these conditions. We propose to perform the statistical analyses required to complete a GWAS of a subgroup of CHDs referred to as conotruncal heart defects (CTDs). This subgroup accounts for approximately 1/3rd of all CHDs, and there is a substantial body of data, derived from both animal and human studies, indicating that the cardiac phenotypes that fall within it are more closely related to each other than to other forms of CHDs. Through the ongoing efforts of this research team, SNP genotyping data from the Illumina 550K chip for 800 CTD case-parent triads are in hand and awaiting analyses to: (1) Identify maternal and inherited (i.e. case) genotypes that are associated with CTDs, and (2) Identify pathways and gene sets that are associated with CTDs. PUBLIC HEALTH RELEVANCE: Conotruncal heart defects are common, serious malformations of the heart that have a significant impact on affected individuals, their families and society. Despite the health significance of these conditions, the causes of conotruncal heart defects are poorly understood and primary prevention methods are lacking. The work proposed in this application will help to indentify genes that are associated with the risk that a child will be born with one of these conditions.