A genotype first approach to studying diabetes

项目摘要 10%的美国人患有糖尿病，预计在未来20年内， 与疾病相关的医疗和社会成本也随之上升。随着糖尿病患病率的上升， 糖尿病亚型的精确诊断对于疾病的正确治疗和管理至关重要。 年轻人成熟型糖尿病（MODY）是一种罕见的家族性单基因型糖尿病，由以下原因引起： 参与胰腺β细胞的发育和功能的基因突变，并且通常 误诊为其他糖尿病亚型。MODY基因的突变不仅会导致MODY; 已显示，具有不太严重的功能损害的患者与2型糖尿病（T2 D）风险相关。罕见 突变很难在以人群为基础的环境中进行研究，因为它们很少出现在人群中。 人口。从历史上看，MODY一直是在小家庭为基础的设置，可能会偏向非主流 估计和错过了疾病的完整表型图片。大多数MODY基因研究 在欧洲血统的个体中进行，使得非欧洲血统的群体更难 获得基因医学。随着大规模和多样化生物库的出现，例如 Mount Sinai BioMe生物库和英国生物库（UKBB），现在可以研究MODY基因突变， 一个多血统的人口设置，并评估其对MODY，T2 D和相关性状的影响。 为了解决目前的知识差距，我们提出了以下目标：目标1-评估和 询问BioMe不同祖先个体中已知和新的MODY引起突变 生物银行和UKBB。我们将通过研究糖尿病的发病率和表现力来做到这一点， MODY引起的突变，通过应用 全表型关联研究和识别以前未知的MODY引起的突变。我们 假设对已知MODY致病突变的预测比家族预测更准确， 基于这些发现，已知的MODY致病突变的表型相关性的临床谱将是 扩大，我们将发现新的MODY引起的突变。我们的目标是使用基于人口的 生物库研究罕见和常见遗传变异之间的相互作用以及与T2 D的关联， 相关特征。我们提出：目的2-研究多基因风险如何影响个体的T2 D风险 在BioMe和UKBB中，T2 D和MODY基因突变。我们将研究罕见的 在具有低和高多基因风险的个体中，功能损害性MODY基因突变对T2 D的影响 T2 D和血糖特征。我们假设携带破坏性突变会加剧T2 D的风险。 由多基因负担所赋予。这些步骤有助于了解罕见MODY基因突变的影响 这将有助于我们更好地了解糖尿病遗传学的长期目标， 预防、诊断和治疗到糖尿病医学。

PROJECT SUMMARY Ten percent of Americans suffer from diabetes, and in the next twenty years this number is projected to rise alongside disease related medical and societal costs. With the rise in prevalence of diabetes, early and precise diagnosis of diabetes subtypes are crucial for correct treatment and management of the disease. Maturity Onset Diabetes of the Young (MODY) is a rare familial monogenic form of diabetes that is caused by mutations in genes that are involved in the development and function of the pancreatic beta cell, and is often misdiagnosed as other diabetes subtypes. Mutations in the MODY genes not only cause MODY; mutations with less severe functional impairment have been shown to associate with type 2 diabetes (T2D) risk. Rare mutations have been difficult to study in a population-based setting because of how infrequently they present in the population. Historically, MODY has been studied in small family-based settings, likely biasing penetrance estimates and missing the complete phenotypic picture of the disease. The majority of MODY gene research has been done in European ancestry individuals, making it more difficult for non-European ancestry groups to access genetically-informed medicine. With the availability of large-scale and diverse biobanks, such as the Mount Sinai BioMe biobank and the UK Biobank (UKBB), it is now possible to study MODY gene mutations in a multi-ancestry population setting and assess their impact on MODY, T2D and related traits. To address the current knowledge gaps, we propose the following aims: Aim 1- To assess and interrogate known and novel MODY-causing mutations in individuals of diverse ancestry of the BioMe Biobank and UKBB. We will do this by examining the penetrance and expressivity of diabetes in MODY-causing mutations, broadening the clinical spectrum of MODY-causing mutations by applying phenome-wide association studies and identifying previously unknown MODY-causing mutations. We hypothesize that estimates of penetrance of known MODY-causing mutations will be more accurate than family based findings, the clinical spectrum of phenotypic associations for known MODY-causing mutations will be broadened, and we will discover novel MODY-causing mutations. We further aim to use the population-based biobanks to study the interplay between rare and common genetic variation and the association to T2D and related traits. We propose: Aim 2- To examine how individuals’ risk of T2D is influenced by polygenic risk of T2D and mutations in MODY genes in BioMe and the UKBB. We will examine the impact of rare functionally damaging MODY gene mutations on T2D among individuals with low and high polygenic risk of T2D and glycemic traits. We hypothesize that carrying a damaging mutation will exacerbate the risk of T2D conferred by a polygenic burden. These steps toward understanding the impact of rare MODY gene mutations will facilitate our long-term objective to better understand the genetics of diabetes, and implement precision prevention, diagnostics and therapeutics to diabetes medicine.