Family Based Analysis for the Rapid Identification of Rare Variants

描述（由申请人提供）：糖尿病是目前影响美国超过2400万人的主要公共卫生问题。2型糖尿病（T2D）是罪魁祸首，占所有糖尿病病例的90-95%。作为一种复杂的疾病，疾病风险来自生活方式、环境和遗传因素的综合。以前的遗传研究主要集中在寻找导致风险的常见遗传变异，然而，这些只能解释约10%的遗传风险。“缺失的遗传性”可能是由于其他因素，如罕见的变异。该研究旨在通过基于家族的方法识别罕见变异，探索罕见变异在复杂疾病中的作用，特别是胰岛素抵抗和T2D。胰岛素抵抗是T2D的主要特征，但在遗传水平上却知之甚少。该项目建立在一个非常成功的初步研究的基础上，并使用序列分析和基因分型方法来识别和确认具有极端表型的目标家族的变异。最初，该方法将使用两种互补的方法进行测试，检查候选基因磷酸酪氨酸磷酸酶1B (PTPN1)，并评估先前确定的5号染色体上与胰岛素敏感性相关的区域。随后将对与胰岛素敏感性相关的其他区域进行更广泛的基因组调查。此外，外显子组测序将被评价为一种更有效的寻找变异的方法。最后，将在多个研究人群中评估确定的变异对胰岛素敏感性和T2D疾病风险的影响。该方案将实现一种罕见变异的新发现方法，并评估罕见变异在复杂疾病中的贡献。以前，罕见变异在复杂疾病中没有得到很好的研究，因为它们在人群中的频率很低，这使得它们很难被发现。该项目旨在开发一种成本和时间效率高的方法来识别罕见变异，这对复杂疾病风险（如糖尿病易感性）具有潜在的重大影响。

DESCRIPTION (provided by applicant): Diabetes is a major public health problem currently affecting over 24 million individuals in the United States. Type 2 diabetes (T2D) is the main culprit, making up 90-95% of all diabetes cases. As a complex disease, disease risk comes from a combination of lifestyle, environmental, and genetic factors. Previous genetic research has mainly focused on searching for common genetic variants which contribute risk, however, these have only managed to explain ~10% of genetic risk. The "missing heritability" may be due to other factors such as rare variants. The proposed study seeks to explore the role of rare variants in complex diseases, specifically insulin resistance and T2D by using a family based approach to identify rare variants. Insulin resistance is a primary feature of T2D, yet is poorly understood at the genetic level. This project builds upon a highly successful initial study and uses sequence analysis and genotyping methods to identify and confirm variants in target families with extreme phenotypes. Initially this method will be tested using two complementary approaches, examination of a candidate gene phosphotyrosine phosphatase 1B (PTPN1), and evaluation of a previously identified region on chromosome 5 with evidence of linkage to insulin sensitivity. This will be followed by a more generalized survey of the genome for other regions linked to insulin sensitivity. In addition, exome sequencing will be evaluated as a way of searching for variants in a more efficient manner. Finally, variants identified will be assessed for their contribution to insulin sensitivity and T2D disease risk in multiple study populations. This proposal will implement a novel discovery method for rare variants and evaluate the contribution of rare variants in complex diseases. Previously, rare variants have not been well studied in complex diseases due to their low frequency in populations which have made them difficult to detect. This project seeks to develop a cost and time efficient means for the identification of rare variants, which has potentially major implications in complex disease risk, such as diabetes susceptibility. PUBLIC HEALTH RELEVANCE: The goal of this project is to explore a new discovery method for rare genetic variants that contribute to type 2 diabetes disease susceptibility. This knowledge will identify novel variants which will elucidate undiscovered disease mechanisms, allow for early intervention for individuals at risk, and aid in the development of novel therapeutics for prevention and treatment of this disease.