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。它也极有可能显著并立即改善糖尿病患者的生活质量。99%的人类基因组不编码蛋白质，但对于非编码变异对人类疾病的贡献知之甚少。DNA测序的成本和通量限制，以及解释非编码区域变异的功能后果的相对困难，意味着对人类疾病的遗传原因的研究一直集中在基因组的小编码部分。现在，测序技术的进步预示着廉价全基因组测序的到来，这样就可以快速识别患者基因组中的所有300万个变异。与此同时，表观基因组学的巨大进步使得非编码基因组的详细注释和数以千计的功能调控序列得以确定。这些序列就像开关一样，开启和关闭基因，决定细胞类型。这些DNA开关中只有少数变异导致疾病的例子，但我们最近表明，将全基因组测序与表观基因组注释结合起来可以识别这种未被重视的突变类型。我们发现，远离关键胰腺发育基因的短序列变异是导致儿童出生时没有胰腺的最常见原因。我们最近也表明，这些调控序列中的一些变异增加了晚发性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发性糖尿病的调控序列中的突变。我们将对100名青年期成熟型糖尿病（MODY）患者的全基因组进行测序。MODY是一种遗传性糖尿病，通常在25岁之前被诊断出来。我们将从世界上最大的“未解”MODY家庭（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获得的调控序列注释。这些细胞是糖尿病的核心，因为它们分泌胰岛素。然后，我们将测试相同的调控序列是否在多个MODY家族中发生突变。我们将通过测试这些变异是否与更广泛家族的疾病状态相跟踪来跟踪变异，并对我们的其余MODY队列和来自我们全球合作者网络的未解决的MODY家族的假定调控元件进行测序。任何在MODY中有非常强的遗传证据的变异都将被测试，看看是否在体外使用培养的人类细胞和斑马鱼体内有功能影响，斑马鱼已被证明是检查胰腺调节元件的极好模型。这个项目将使我们更好地了解非编码突变在人类疾病中的作用，并使我们能够开发出识别这类突变的方法。如果我们要充分利用廉价和广泛可用的全基因组测序技术，我们的项目就很重要。确定新的糖尿病单基因病因也很重要，因为这可能会给患者带来直接的好处。我们已经证明，最常见形式的新生儿糖尿病和MODY患者可以通过片剂治疗而不是胰岛素注射得到很好的控制。其他有葡萄糖感应基因葡萄糖激酶突变的患者可以完全停止治疗，因为他们的空腹血糖水平轻度升高，稳定，不影响健康，对治疗没有反应或不需要治疗。MODY和2型糖尿病之间的相似之处意味着确定MODY的新病因将为晚发性和更常见的疾病形式的生物学提供重要的新见解。从长远来看，这可能会导致糖尿病新疗法的发展。

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

Genome-wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics.

• DOI: 10.1093/hmg/ddx429
• 发表时间: 2018-02-15
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Beaumont RN;Warrington NM;Cavadino A;Tyrrell J;Nodzenski M;Horikoshi M;Geller F;Myhre R;Richmond RC;Paternoster L;Bradfield JP;Kreiner-Møller E;Huikari V;Metrustry S;Lunetta KL;Painter JN;Hottenga JJ;Allard C;Barton SJ;Espinosa A;Marsh JA;Potter C;Zhang G;Ang W;Berry DJ;Bouchard L;Das S;Early Growth Genetics (EGG) Consortium;Hakonarson H;Heikkinen J;Helgeland Ø;Hocher B;Hofman A;Inskip HM;Jones SE;Kogevinas M;Lind PA;Marullo L;Medland SE;Murray A;Murray JC;Njølstad PR;Nohr EA;Reichetzeder C;Ring SM;Ruth KS;Santa-Marina L;Scholtens DM;Sebert S;Sengpiel V;Tuke MA;Vaudel M;Weedon MN;Willemsen G;Wood AR;Yaghootkar H;Muglia LJ;Bartels M;Relton CL;Pennell CE;Chatzi L;Estivill X;Holloway JW;Boomsma DI;Montgomery GW;Murabito JM;Spector TD;Power C;Järvelin MR;Bisgaard H;Grant SFA;Sørensen TIA;Jaddoe VW;Jacobsson B;Melbye M;McCarthy MI;Hattersley AT;Hayes MG;Frayling TM;Hivert MF;Felix JF;Hyppönen E;Lowe WL Jr;Evans DM;Lawlor DA;Feenstra B;Freathy RM
• 通讯作者: Freathy RM

Genetic evidence that higher central adiposity causes gastro-oesophageal reflux disease: a Mendelian randomization study.

• DOI: 10.1093/ije/dyaa082
• 发表时间: 2020-08-01
• 期刊: International journal of epidemiology
• 影响因子: 7.7
• 作者: Green HD;Beaumont RN;Wood AR;Hamilton B;Jones SE;Goodhand JR;Kennedy NA;Ahmad T;Yaghootkar H;Weedon MN;Frayling TM;Tyrrell J
• 通讯作者: Tyrrell J

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