MULTIPLE SEVERE OBESITY RISK GENES IN UTAH PEDIGREES

描述（由申请人提供）：犹他州谱系中的多重严重肥胖风险基因严重肥胖（BMIS35 kg/m2）包括肥胖的一个特殊子集，其疾病，残疾和死亡率的风险极高。严重肥胖具有重要的遗传成分，目前的假设表明，导致严重肥胖的潜在基因比导致轻度或中度肥胖的基因具有更大的影响（或更大的外显率）。统计模型的改进已经导致越来越多的关于遗传上位性和性别特异性影响的公开证据，支持了长期以来的观点，即肥胖是一种涉及多种基因以复杂方式相互作用的复杂疾病。我们发现了一种新的严重肥胖易感基因TBC1D1，该基因在严重肥胖的女性家庭成员中明显分离，并解释了bbb90lod评分的大部分原因。独特的大型犹他血统与许多非常严重的肥胖受试者导致了如此戏剧性的联系证据，其次是显著的关联和生物学证据。此外，有证据表明，染色体4q上的另一个非连锁位点显示出与TBC1D1的统计相互作用的强有力证据，因此，仅分析分离TBC1D1的家族对TBC1D1的调节使4q LOD评分从1.7增加到5.0。由于TBC1D1的存在并不会导致所有携带者都出现严重的肥胖，因此上述结果提示，肥胖的完全表达还需要其他基因。我们还发表了证据表明，20号染色体上的一个位点似乎包含两个紧密相连的基因，一个对严重肥胖有显性影响，另一个有隐性影响（LOD=4.9）。这个基因座被放置在一个同源小鼠系中，该系也显示出多种肥胖表型的证据。此外，当检测来自分离TBC1D1和4q位点的家族的20号染色体LOD评分时，发现一些家系存在额外的重叠。这进一步表明，这些谱系中包含多个基因以未知的方式共同作用，导致这些谱系中严重肥胖的密集聚集。本应用程序拟通过精细定位和测序，鉴定4q区基因和20号染色体基因，以检验这些基因的非加性和性别特异性效应。由于已经确定了TBC1D1，因此这项研究的优势在于，它可以对已知的、常见的易感基因进行调节，从而找到其他基因，并对它们如何导致严重肥胖进行建模。这组信息丰富的家谱将被用来进一步揭示严重肥胖的遗传基础的复杂性，这可能有助于理解不那么严重的肥胖。验证将在大型病例/对照系列、波利尼西亚家族和20号染色体的先天性小鼠模型中进行测试。

DESCRIPTION (provided by applicant): Multiple Severe Obesity Risk Genes in Utah Pedigrees Severe obesity (BMIS35 kg/m2) comprises a special subset of obesity for which the risk of disease, disability, and mortality is extremely high. Severe obesity has a significant genetic component and current hypotheses suggest underlying genes for severe obesity have larger effects (or greater penetrance) than genes contributing to mild or moderate obesity. Improvements in statistical modeling have led to increased published evidence of genetic epistasis and gender-specific effects, supporting the long-held view that obesity is a complex disease involving multiple genes that interact in complex ways. Evidence is presented herein of a new susceptibility gene we have identified for severe obesity, TBC1D1, that clearly segregates in female family members with severe obesity and explains most of the >9 LOD score. The unique set of large Utah pedigrees with many very severely obese subjects led to such dramatic linkage evidence, followed by significant association and biological evidence. Furthermore, evidence is presented that another unlinked locus on chromosome 4q shows strong evidence of statistical interaction with TBC1D1, such that conditioning on TBC1D1 by analyzing only families segregating TBC1D1 increases the 4q LOD score from 1.7 to 5.0. Since the presence of TBC1D1 does not lead to severe obesity in all carriers, the above result suggests that other gene(s) are also necessary for full expression of obesity. We have also published evidence that a locus on chromosome 20 appears to contain two closely linked genes, one with a dominant and one with a recessive effect on severe obesity (LOD=4.9). This locus was placed in a congenic mouse line which also showed evidence for multiple obesity phenotypes. Further, when the chromosome 20 LOD scores from families segregating for TBC1D1 and the 4q locus were examined, there was additional overlap of some pedigrees. This further suggests that these pedigrees contain multiple genes acting together in unknown fashion resulting in the dense aggregation of severe obesity in these pedigrees. This application proposes to identify, through fine mapping and sequencing, the region 4q gene and chromosome 20 gene(s) to examine nonadditive and gender-specific effects of these genes. Because TBC1D1 has already been identified, this study has the advantage of conditioning on a known, common, susceptibility gene in order to find additional genes and model how they might lead to severe obesity. This highly informative set of pedigrees will be used to further unravel the complexity of the genetic underpinnings of severe obesity that may contribute to the understanding of less severe obesity. Validation will be tested in a large case/control series, Polynesian families, and, for chromosome 20, in the congenic mouse model.