Identifying non-coding mutations in early-onset diabetes

识别早发性糖尿病的非编码突变

• 批准号: MR/M005070/1
• 负责人: Michael Weedon
• 金额: $ 70.93万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM005070%2F1
• 关键词: Identifying; non; coding; mutations; early

This project will provide new insights into the role of non-coding mutations in disease and the biology of diabetes. It is also highly likely to dramatically and immediately improve the quality of life for patients with diabetes. Ninety-nine percent of the human genome does not code for protein, yet little is known about the contribution of non-coding variation to human disease. Cost and throughput limitations of DNA sequencing, as well as the relative difficultly of interpreting the functional consequences of variants in non-coding regions, has meant that the search for genetic causes of human disease has been focused on the small coding part of the genome. Now, advances in sequencing technology have heralded the arrival of cheap whole genome sequencing so that all 3 million variants in a patient's genome can be rapidly identified. In parallel, enormous advances in epigenomics have allowed detailed annotation of the non-coding genome and many thousands of functional regulatory sequences have been identified. These sequences act as switches, turning genes on and off and determining cell type. There are only a few examples of variants in these DNA switches causing disease, but we have recently shown that bringing together whole genome sequencing with epigenome annotation can identify this underappreciated type of mutation. We showed that variants of a short sequence far from a key pancreas development gene are the commonest cause of children being born without a pancreas. We have also recently shown that variation in some of these regulatory sequences increase risk of late-onset type 2 diabetes. In this project we will use the same approach to identify mutations in regulatory sequences that cause familial early-onset diabetes.We will sequence the entire genomes of >100 patients with Maturity-onset diabetes of the Young (MODY). MODY is an inherited form of diabetes that is typically diagnosed before the age of 25. We will select these patients from the world's largest collection of "unsolved" MODY families (currently 3000 patients). We will use regulatory sequence annotations that we have derived from pancreas cells. These cells are central to diabetes because they secrete insulin. We will then test whether the same regulatory sequences are mutated in multiple MODY families. We will follow-up variants by testing if these variants track with disease status in the wider family as well as sequencing the putative regulatory elements in the rest of our MODY cohort and in unsolved MODY families from our world-wide network of collaborators. Any variants which have very strong genetic evidence for a role in MODY will be tested to see if there is a functional effect both in vitro using cultured human cells and in vivo in zebrafish which has been demonstrated to be an excellent model for examining pancreatic regulatory elements.This project will give us a better understanding of the role of non-coding mutations in human disease and allow us to develop approaches to identifying this type of mutation. Our project is important if we are to get the most out of the advent of cheap and widely available whole genome sequencing. Identifying new single gene causes of diabetes is also important because of the potential for immediate benefits to patients. We have shown that patients with the commonest forms of neonatal diabetes and MODY can be well-controlled on tablet treatment rather than insulin injections. Other patients that have mutations in the glucose sensing gene glucokinase can be taken off treatment entirely because they have mildly elevated, stable fasting glucose levels which does not affect health and does not respond to or require treatment. The similarities between MODY and Type 2 diabetes, means that identifying new causes of MODY will provide important new insights into the biology of later-onset, and more common, forms of the disease. This may in the long term lead to the development of novel therapeutics for diabetes.

该项目将为非编码突变在疾病和糖尿病生物学中的作用提供新的见解。它也很可能会显着并立即改善糖尿病患者的生活质量。人类基因组的百分之九十九不为蛋白质编码，但对非编码变异对人类疾病的贡献知之甚少。 DNA测序的成本和吞吐量局限性以及相对难以解释非编码区域变体的功能后果，这意味着人们对人类疾病的遗传原因的搜索一直集中在基因组的小编码部分上。现在，测序技术的进步预示了廉价的整个基因组测序的到来，因此可以快速识别患者基因组中的所有300万变体。同时，表观基因组学的巨大进步允许对非编码基因组进行详细注释，并且已经确定了数千种功能调节序列。这些序列充当开关，打开和关闭基因并确定细胞类型。这些DNA开关中只有几个示例引起了疾病，但是我们最近表明，将整个基因组测序与表观基因组注释一起结合在一起可以识别出这种不足的突变类型。我们表明，远离关键胰腺发育基因的短序列的变体是儿童出生而没有胰腺的最常见原因。我们最近还表明，其中一些调节序列的变化增加了晚期2型糖尿病的风险。在这个项目中，我们将使用相同的方法来识别导致家族性早期发作糖尿病的调节序列中的突变。我们将对> 100名年轻（Mody）成熟型糖尿病的患者的整个基因组序列。 Mody是一种遗传的糖尿病形式，通常在25岁之前诊断出来。我们将从世界上最大的“未解决” Mody家族（目前有3000名患者）中选择这些患者。我们将使用从胰腺细胞中得出的调节序列注释。这些细胞是糖尿病的中心，因为它们分泌胰岛素。然后，我们将测试是否在多个Mody家族中突变相同的调节序列。我们将通过测试这些变体是否跟踪更广泛的家族中的疾病状况，并在我们的其他Mody队列中的推定监管元素以及来自我们全球合作者网络的未解决的Mody家族中进行测序。任何具有非常强大的遗传证据在Mody中作用的变体都将经过测试，以查看使用培养的人类细胞和斑马鱼中的体外效应是否具有功能效应，这被证明是检查胰腺调节元件的出色模型，可以更好地理解非编码突变的方法，从而使我们能够更好地理解这种类型的突变。如果我们要充分利用廉价且广泛可用的整个基因组测序的出现，我们的项目很重要。确定糖尿病的新单个基因原因也很重要，因为有可能对患者产生立即益处。我们已经表明，具有最常见的新生儿糖尿病和MODY形式的患者可以很好地控制片剂治疗，而不是胰岛素注射。在葡萄糖感应基因葡萄糖酶中具有突变的其他患者完全可以完全脱离治疗，因为他们的稳定，稳定的空腹葡萄糖水平不影响健康，不反应或需要治疗。 Mody和2型糖尿病之间的相似性意味着，确定Mody的新原因将为以后发作的生物学和更常见的疾病形式提供重要的新见解。从长远来看，这可能会导致糖尿病新型治疗剂的发展。

项目成果

A Common Allele in FGF21 Associated with Sugar Intake Is Associated with Body Shape, Lower Total Body-Fat Percentage, and Higher Blood Pressure.

• DOI: 10.1016/j.celrep.2018.03.070
• 发表时间: 2018-04-10
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Frayling TM;Beaumont RN;Jones SE;Yaghootkar H;Tuke MA;Ruth KS;Casanova F;West B;Locke J;Sharp S;Ji Y;Thompson W;Harrison J;Etheridge AS;Gallins PJ;Jima D;Wright F;Zhou Y;Innocenti F;Lindgren CM;Grarup N;Murray A;Freathy RM;Weedon MN;Tyrrell J;Wood AR
• 通讯作者: Wood AR

Genetic determinants of daytime napping and effects on cardiometabolic health.

• DOI: 10.1038/s41467-020-20585-3
• 发表时间: 2021-02-10
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Dashti HS;Daghlas I;Lane JM;Huang Y;Udler MS;Wang H;Ollila HM;Jones SE;Kim J;Wood AR;23andMe Research Team;Weedon MN;Aslibekyan S;Garaulet M;Saxena R
• 通讯作者: Saxena R

Corrigendum to: A genome-wide association study implicates multiple mechanisms influencing raised urinary albumin-creatinine ratio.

勘误：一项全基因组关联研究暗示了影响尿白蛋白肌酐比值升高的多种机制。

• DOI: 10.1093/hmg/ddac022
• 发表时间: 2022
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Casanova F

Is disrupted sleep a risk factor for Alzheimer's disease? Evidence from a two-sample Mendelian randomization analysis.

• DOI: 10.1093/ije/dyaa183
• 发表时间: 2021-07-09
• 期刊: International journal of epidemiology
• 影响因子: 7.7
• 作者: Anderson EL;Richmond RC;Jones SE;Hemani G;Wade KH;Dashti HS;Lane JM;Wang H;Saxena R;Brumpton B;Korologou-Linden R;Nielsen JB;Åsvold BO;Abecasis G;Coulthard E;Kyle SD;Beaumont RN;Tyrrell J;Frayling TM;Munafò MR;Wood AR;Ben-Shlomo Y;Howe LD;Lawlor DA;Weedon MN;Davey Smith G
• 通讯作者: Davey Smith G

A Mendelian Randomization Study Provides Evidence That Adiposity and Dyslipidemia Lead to Lower Urinary Albumin-to-Creatinine Ratio, a Marker of Microvascular Function.

• DOI: 10.2337/db19-0862
• 发表时间: 2020-05
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Casanova F;Wood AR;Yaghootkar H;Beaumont RN;Jones SE;Gooding KM;Aizawa K;Strain WD;Hattersley AT;Khan F;Shore AC;Frayling TM;Tyrrell J
• 通讯作者: Tyrrell J