Expression-Based Empirical Candidate Genes Influencing Body Mass Index

描述（由申请人提供）：不断升级的肥胖流行病现在是21世纪对人类健康最重大的威胁之一。在这个项目中，我们将采用一种新的方法来实证鉴定影响身体质量指数（BMI）的新的候选基因，这是一项基于大型家庭的研究。利用从1240名圣安东尼奥家庭心脏研究参与者的淋巴细胞样本中获得的全基因组转录谱，我们从定量连锁分析中发现了1400多个转录本，显示出高度显著的顺式调控证据。研究人员研究了这些顺式调控转录物与BMI的关系，其中247个转录物显示出定量基因表达水平与BMI（肥胖的主要危险因素）之间存在显著相关性。该项目将利用这种基于全基因组表达的信息，快速识别影响这些新候选基因转录水平的调控序列变异，并评估它们对BMI和腰围的影响，作为肥胖风险预测因子。利用这一独特的基于家族的全基因组定量转录谱资源，我们将根据经验提名和检验100个新的候选基因，这些基因既能显示出表达水平的顺式调控，又能显示出表达水平与BMI之间的显著相关性。我们先前关于顺式作用序列变异的基于链接的证据可以作为一个概率因果锚来利用，它应该最大限度地提高我们在近端启动子中发现功能变异的机会。对于这些客观选择的基因，我们将：1)在182个创始人个体中对大约2千碱基的推定启动子（转录开始的上游）进行重测序，以确定启动子变体；2)基因型在1,240个SAFHS样本中检测到100个候选基因的启动子变异，我们对其进行了转录谱分析；3)检测启动子序列变异是否与相应候选基因的基因表达水平相关；4)启动子序列变异、BMI和腰围的相关性检验；5)在两个独立的样本群体中证实观察到的与BMI和/或腰围的关联；6)对影响BMI和/或腰围的启动子变异进行初步的功能分析。肥胖在美国和全世界已成为一种流行病，仅在美国每年就造成约930亿美元的经济负担。这个项目的结果应该会加快发现人类BMI变异的新基因的步伐；迄今为止，这项任务进展缓慢且不成功。通过关注那些转录物显示出顺式调节变异和与BMI有密切关系的基因，我们应该最大限度地提高发现影响肥胖风险的因果遗传变异的可能性。

DESCRIPTION (provided by applicant): The escalating obesity epidemic is now one of the most significant threats to human health in the 21st century. In this project, we will employ a novel approach to the empirical identification of novel candidate genes influencing body mass index (BMI), in a large family based study. Using genome-wide transcriptional profiles obtained from lymphocyte samples from 1,240 San Antonio Family Heart Study participants, we identified over 1,400 transcripts that exhibit highly significant evidence for cis-regulation as inferred from quantitative linkage analysis. Each of these cis-regulated transcripts has been examined for association with BMI, with 247 transcripts showing evidence for significant correlations of quantitative gene expression levels and BMI, a major risk factor for obesity. This project will exploit this genome-wide expression-based information to rapidly identify regulatory sequence variants that influence transcriptional levels of these novel candidate genes and to assess their influence on BMI and waist circumference, as obesity risk predictors. Using this unique family-based resource of quantitative genome-wide transcriptional profiles, we will empirically nominate and examine 100 novel candidate genes that exhibit both strong evidence for cis-regulation of expression levels and significant correlations between expression levels and BMI. Our prior linkage-based evidence for cis-acting sequence variation can be exploited as a probabilistic causal anchor that should maximize our chance for finding functional variation within proximal promoters. For each of these objectively chosen genes, we will: 1) resequence approximately two kilobases of putative promoter, upstream of transcription start, in 182 founder individuals to identify promoter variants; 2) genotype all detected promoter variation in each of the 100 candidate genes in the 1,240 SAFHS samples for whom we have transcriptional profiles; 3) test whether promoter sequence variants are associated with gene expression levels of the appropriate candidate gene; 4) test for associations between promoter sequence variants, BMI and waist circumference; 5) confirm observed associations with BMI and/or waist circumference in two independent sample populations and 6) perform preliminary functional analyses of promoter variants influencing BMI and/or waist circumference. Obesity has reached pandemic proportions in the United States and throughout the world, with an estimated economic burden of approximately $93 billion per year in the United States alone. The results of this project should increase the pace of discovery of novel genes underlying human variation in BMI; a task that has been somewhat slow and unsuccessful to date. By focusing on genes whose transcripts show evidence for both cis- regulatory variation and a strong relationship with BMI, we should maximize our probability for finding causal genetic variants influencing obesity risk. PUBLIC HEALTH RELEVANCE: The estimated economic burden of overweight and obesity in the United States alone is approximately $93 billion per year, making this disease one of major public health importance. In this project, we will employ a novel strategy that should increase the pace of discovery of genes that influence body mass index and waist circumference, major indicators of obesity. The knowledge gained will help contribute to the understanding of the genetics of obesity through the identification of novel and potentially functional candidate genes, assisting in the development of new preventative measures and/or therapies.