A genotype first approach to studying diabetes

项目总结 10%的美国人患有糖尿病，预计在未来20年这一数字将 与疾病相关的医疗和社会成本一起上升。随着糖尿病患病率的上升，早期和 糖尿病亚型的准确诊断是正确治疗和管理疾病的关键。 青年成熟型糖尿病(MODY)是一种罕见的家族性单基因糖尿病，由 与胰腺β细胞的发育和功能有关的基因突变，通常是 误诊为其他糖尿病亚型。MODY基因的突变不仅导致MODY；突变 功能受损程度较轻的患者与2型糖尿病(T2D)风险相关。1~2成熟 突变很难在基于人群的环境中研究，因为它们在人群中出现的频率很低 人口数量。从历史上看，MODY一直是在以家庭为基础的小环境中进行研究的，可能会有偏向外显 估计和遗漏了疾病的完整表型图。大部分MODY基因研究 已经在欧洲血统的个人身上完成了，这使得非欧洲血统的群体更难 获取遗传信息医学。随着大规模和多样化的生物库的可用，例如 西奈山生物库和英国生物库(UKBB)，现在可以研究MODY基因突变在 一个多祖先的人口环境，并评估他们对MODY、T2D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 询问生物群不同祖先个体中已知和新的引起MODY的突变 Biobank和UKBB。我们将通过检测糖尿病的外显性和表现性来实现这一点 导致MODY的突变，通过应用 全基因组关联研究和识别以前未知的导致MODY的突变。我们 假设对已知的引起MODY的突变的外显率的估计将比家族更准确 根据研究结果，已知的引起MODY突变的临床表型关联谱将是 扩大，我们将发现新的导致MODY的突变。我们的进一步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及其与T2D和 相关特征。我们建议：目标2-检查个体的T2D风险如何受到多基因风险的影响 生物群和UKBB中的T2D和MODY基因突变。我们将研究罕见的影响 低、高遗传风险人群T2D功能损伤性MODY基因突变的研究 T2D和血糖性状。我们假设携带破坏性突变会加剧T2D的风险 由多基因负担赋予的。这些步骤有助于了解罕见的MODY基因突变的影响 将有助于我们的长期目标，更好地了解糖尿病的遗传学，并实施精确度 糖尿病医学的预防、诊断和治疗。

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.