DETECTING RARE VARIANTS FOR COMPLEX TRAITS USING FAMILY AND UNRELATED DATA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 已经进行了大规模的全基因组关联研究(GWAS)来检测与常见疾病有关的常见遗传变异，但大多数以这种方式发现的变异只占性状变异的一小部分。此外，基于候选基因的重新测序表明，许多罕见的遗传变异导致了常见疾病的性状差异。在这里，我们提出了两个设计，同胞配对设计和无关案例设计，在候选基因或全基因组关联分析中检测罕见的遗传变异。首先，我们证明了我们可以使用相对较小的样本与这些设计中的任何一个一起检测和分类罕见的风险单倍型，然后增加在较大的病例对照样本中测试关联的能力。这种方法也可以应用于数据的重新排序。接下来，我们将该方法应用于惠康信托病例对照联盟(WTCCC)的冠心病(CAD)和高血压(HT)数据，后者是最初的WTCCC研究中唯一没有全基因组关联证据的性状，并在全基因组显著水平上确定了一个与HT相关的有趣基因和四个与CAD相关的基因。这些结果表明，寻找罕见的遗传变异是可行的，并可能在当前的GWAS、候选基因研究或重新测序研究中取得丰硕成果。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Large genome-wide association studies (GWAS) have been performed to detect common genetic variants involved in common diseases, but most of the variants found this way account for only a small portion of the trait variance. Furthermore, candidate gene-based resequencing suggests that many rare genetic variants contribute to the trait variance of common diseases. Here we propose two designs, sibpair and unrelated-case designs, to detect rare genetic variants in either a candidate gene-based or genome-wide association analysis. First we show that we can detect and classify together rare risk haplotypes using a relatively small sample with either of these designs, and then have increased power to test association in a larger case-control sample. This method can also be applied to resequencing data. Next we apply the method to the Wellcome Trust Case Control Consortium (WTCCC) coronary artery disease (CAD) and hypertension (HT) data, the latter being the only trait for which no genome-wide association evidence was reported in the original WTCCC study, and identify one interesting gene associated with HT and four associated with CAD at a genome-wide significance level of 5%. These results suggest that searching for rare genetic variants is feasible and can be fruitful in current GWAS, candidate gene studies or resequencing studies.