ASSOCIATION OF A SNP UPSTREAM OF INSIG2 WITH BMI

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 赫伯特及其同事最近发现INSIG 2基因上游的一个SNP rs7566605与肥胖相关，该SNP通过体重指数（BMI）进行测量。BMI增加与次要等位基因纯合性之间的关联首次在来自心脏研究后代队列的923名相关个体的86，604个SNP的全基因组关联扫描数据中观察到。这种关联在另外四个队列中重现，但在第五个队列中没有观察到。为了进一步评估这种关联的一般重现性，我们在来自多个种族的8个人群的9个大队列中对rs7566605进行了基因分型（总n = 16，969）。我们使用基于家庭、基于人群和病例对照的设计，在隐性模型下测试了每个样本中该变异与BMI的相关性。我们在5个队列中观察到显著（p < 0.05）相关性，但在其他3个队列中未观察到相关性。在Frachial Heart Study Offspring队列中，来自无关个体的纵向数据在检查周期之间的关联证据强度存在变异性。一项综合分析显示，在无关（p = 0.046）和基于家族（p = 0.004）的样本中，这种相关性得到了显著的独立验证。由该等位基因赋予的估计风险很小，并且很容易被小样本量、人群分层或其他混杂因素掩盖。这些验证研究表明，最初的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异质的。

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.