ASSOCIATION OF A SNP UPSTREAM OF INSIG2 WITH BMI

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。 最近，赫伯特和他的同事发现INSIG2基因上游的一个SNP rs7566605与体重指数(BMI)测量的肥胖有关。来自弗雷明翰心脏研究后代队列的923个相关个体的86,604个SNPs的全基因组关联扫描数据首次观察到BMI增加与微小等位基因纯合性之间的关联。这种关联在另外四个队列中重现，但在第五个队列中没有出现。为了进一步评估这种关联的一般重复性，我们在来自多个种族的8个群体(总计n=16,969)的9个大队列中对rs7566605进行了基因分型。我们使用基于家庭、基于人群和病例对照的设计，在隐性模型下，在每个样本中测试该变异与BMI的关联。我们在五个队列中观察到显著的关联(p&lt；0.05)，但在另外三个队列中没有发现关联。在弗雷明翰心脏研究后代队列中来自无关个体的纵向数据中，关联证据的强度在不同的检查周期中存在差异。一项联合分析显示，在无关(p=0.046)和以家庭为基础(p=0.004)的样本中，这种关联都得到了显著的独立验证。该等位基因带来的估计风险很小，很容易被小样本量、人口分层或其他混杂因素所掩盖。这些验证研究表明，原始关联不太可能是虚假的，但未能在每个数据集中观察到关联表明，SNP rs7566605对BMI的影响可能在人群样本中是不同的。

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. A SNP of upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples.