UK Infrastructure for Large-scale Clinical Genomics Research

英国大规模临床基因组学研究基础设施

• 批准号: MC_EX_MR/M009203/1
• 负责人: Mark Caulfield
• 金额: $ 2292.42万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_EX_MR%2FM009203%2F1
• 关键词: UK; Infrastructure; Large; scale; Clinical

Background The UK 100,000 Genomes Project will accelerate the application of whole genome sequencing (WGS) into routine care for the National Health Service. The genome is the genetic material of an organism (either in DNA or, for many types of viruses, in RNA). WGS provides the most comprehensive inventory of an individual's genetic variation. By incorporating this into routine care it will transform the health services people receive, changing the processes of diagnosis and management. The UK 100,000 Genomes Project seeks to drive this change by sequencing 100,000 genomes of individuals affected by rare diseases and cancer (and their families) and infectious disease pathogens. Vision The UK Infrastructure for Large-scale Clinical Genomics Research will provide the infrastructure which, using the information from the 100,000 Genomes project, will develop the UK as an international centre of excellences for the analysis of very large and complex biomedical datasets. As a national resource for the development of new knowledge it will provide transformative advances in the speed and range of research into the causes and consequences, prevention and treatment of disease. This proposal presents a unique opportunity for UK clinical research that will enable the discovery of new diagnostics, test complex approaches to stratified medicine, and drive therapeutic innovation. Rare diseases There are between 6,000 and 8,000 rare diseases and while each one only affects a small number of people, overall they affect the lives of 3 million people in England. Only 50% of rare diseases have an existing molecular (genetic) diagnosis. Through the scale of the 100,000 Genomes Project and by having a focus on unmet need, this infrastructure will create significant opportunities for scientific innovation, helping to assist in the interpretation of genetic findings whose clinical significance is currently unknown or uncertain. CancerCancer is, fundamentally, a genetic disorder where mutations lead to uncontrolled cell growth. The clinical impact of sequencing technologies has already enabled precise definitions of disease, uncovered insights into how cancer develops and has helped identify therapeutic targets from which to develop treatments. The importance of around 200 key genes across cancer types is known but focusing only on these alone in clinical care will not be enough to significantly impact upon the majority of individuals with cancer. Due to the scale of the 100,000 Genomes Project it offers the best opportunity to drive forward our understanding. Pathogens and Infectious Disease. WGS for pathogens - both viruses and bacteria is being adopted for routine management of infectious diseases, providing information on transmission and antibiotic resistance and creating tremendous opportunities for clinical research. Output This proposal is to fund the core hardware and software components of a data and computing infrastructure for genomics and clinical genomics research, this includes adapting existing software developed by UK partners who are international leaders in this field. The proposed infrastructure will be innovative in terms of content, technology, and scientific collaboration. It will contain clinical, health, and WGS data on large numbers of patients and pathogens in a range of key therapeutic areas. The data will be collected prospectively and will be extended with regular updates from clinical care. Available to clinicians, patients, industry and academia it will: encourage and enable engagement and collaboration in research, provide a platform for trials recruitment, and increase the depth and quality of the data obtained.

背景英国100,000基因组计划将加速将全基因组测序(WGS)应用到国家卫生服务的常规保健中。基因组是生物体的遗传物质(在DNA中，或者对于许多类型的病毒，在RNA中)。WGS提供了关于个体遗传变异的最全面的清单。通过将其纳入常规护理，它将改变人们接受的卫生服务，改变诊断和管理的过程。英国100,000基因组计划试图通过对受到罕见疾病和癌症(及其家人)和传染病病原体影响的个人的100,000个基因组进行测序来推动这一变化。VISION英国大型临床基因组研究基础设施将提供基础设施，利用来自100,000基因组计划的信息，将英国发展成为分析非常大型和复杂的生物医学数据集的国际卓越中心。作为发展新知识的国家资源，它将在研究疾病的原因和后果、预防和治疗的速度和范围方面取得变革性的进展。这项提议为英国的临床研究提供了一个独特的机会，这将使发现新的诊断方法、测试分层医学的复杂方法并推动治疗创新成为可能。罕见疾病有6000到8000种罕见疾病，虽然每种疾病只影响一小部分人，但总的来说，它们影响着英国300万人的生活。只有50%的罕见疾病有现有的分子(遗传)诊断。通过100,000基因组计划的规模和对未得到满足的需求的关注，这一基础设施将为科学创新创造重大机会，帮助解释目前临床意义未知或不确定的基因发现。从根本上说，癌症是一种遗传性疾病，突变会导致细胞生长失控。测序技术的临床影响已经使人们能够准确定义疾病，揭示了癌症是如何发展的，并帮助确定了用于开发治疗方法的治疗靶点。大约200个关键基因在癌症类型中的重要性是已知的，但在临床护理中仅关注这些基因将不足以对大多数癌症患者产生重大影响。由于100,000基因组计划的规模，它提供了推动我们理解的最好机会。病原体与传染病。病原体的WGS-病毒和细菌正被用于传染病的常规管理，提供有关传播和抗生素耐药性的信息，并为临床研究创造巨大的机会。产出这项提议是为基因组学和临床基因组学研究的数据和计算基础设施的核心硬件和软件组件提供资金，这包括调整由在该领域处于国际领先地位的英国合作伙伴开发的现有软件。拟议的基础设施将在内容、技术和科学协作方面具有创新性。它将包含一系列关键治疗领域中大量患者和病原体的临床、健康和WGS数据。这些数据将被前瞻性地收集，并将随着临床护理的定期更新而扩展。它将提供给临床医生、患者、行业和学术界：鼓励和促进研究中的参与和合作，为试验招募提供一个平台，并提高获得的数据的深度和质量。

项目成果

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.

• DOI: 10.1056/nejmoa2035790
• 发表时间: 2021-11-11
• 期刊: The New England journal of medicine
• 作者: 100,000 Genomes Project Pilot Investigators;Smedley D;Smith KR;Martin A;Thomas EA;McDonagh EM;Cipriani V;Ellingford JM;Arno G;Tucci A;Vandrovcova J;Chan G;Williams HJ;Ratnaike T;Wei W;Stirrups K;Ibanez K;Moutsianas L;Wielscher M;Need A;Barnes MR;Vestito L;Buchanan J;Wordsworth S;Ashford S;Rehmström K;Li E;Fuller G;Twiss P;Spasic-Boskovic O;Halsall S;Floto RA;Poole K;Wagner A;Mehta SG;Gurnell M;Burrows N;James R;Penkett C;Dewhurst E;Gräf S;Mapeta R;Kasanicki M;Haworth A;Savage H;Babcock M;Reese MG;Bale M;Baple E;Boustred C;Brittain H;de Burca A;Bleda M;Devereau A;Halai D;Haraldsdottir E;Hyder Z;Kasperaviciute D;Patch C;Polychronopoulos D;Matchan A;Sultana R;Ryten M;Tavares ALT;Tregidgo C;Turnbull C;Welland M;Wood S;Snow C;Williams E;Leigh S;Foulger RE;Daugherty LC;Niblock O;Leong IUS;Wright CF;Davies J;Crichton C;Welch J;Woods K;Abulhoul L;Aurora P;Bockenhauer D;Broomfield A;Cleary MA;Lam T;Dattani M;Footitt E;Ganesan V;Grunewald S;Compeyrot-Lacassagne S;Muntoni F;Pilkington C;Quinlivan R;Thapar N;Wallis C;Wedderburn LR;Worth A;Bueser T;Compton C;Deshpande C;Fassihi H;Haque E;Izatt L;Josifova D;Mohammed S;Robert L;Rose S;Ruddy D;Sarkany R;Say G;Shaw AC;Wolejko A;Habib B;Burns G;Hunter S;Grocock RJ;Humphray SJ;Robinson PN;Haendel M;Simpson MA;Banka S;Clayton-Smith J;Douzgou S;Hall G;Thomas HB;O'Keefe RT;Michaelides M;Moore AT;Malka S;Pontikos N;Browning AC;Straub V;Gorman GS;Horvath R;Quinton R;Schaefer AM;Yu-Wai-Man P;Turnbull DM;McFarland R;Taylor RW;O'Connor E;Yip J;Newland K;Morris HR;Polke J;Wood NW;Campbell C;Camps C;Gibson K;Koelling N;Lester T;Németh AH;Palles C;Patel S;Roy NBA;Sen A;Taylor J;Cacheiro P;Jacobsen JO;Seaby EG;Davison V;Chitty L;Douglas A;Naresh K;McMullan D;Ellard S;Temple IK;Mumford AD;Wilson G;Beales P;Bitner-Glindzicz M;Black G;Bradley JR;Brennan P;Burn J;Chinnery PF;Elliott P;Flinter F;Houlden H;Irving M;Newman W;Rahman S;Sayer JA;Taylor JC;Webster AR;Wilkie AOM;Ouwehand WH;Raymond FL;Chisholm J;Hill S;Bentley D;Scott RH;Fowler T;Rendon A;Caulfield M
• 通讯作者: Caulfield M

Identification and validation of a novel pathogenic variant in GDF2 (BMP9) responsible for hereditary hemorrhagic telangiectasia and pulmonary arteriovenous malformations.

• DOI: 10.1002/ajmg.a.62584
• 发表时间: 2022-03
• 期刊: AMERICAN JOURNAL OF MEDICAL GENETICS PART A
• 影响因子: 2
• 作者: Balachandar, Srimmitha;Graves, Tamara J.;Shimonty, Anika;Kerr, Katie;Kilner, Jill;Xiao, Sihao;Slade, Richard;Sroya, Manveer;Alikian, Mary;Curetean, Emanuel;Thomas, Ellen;McConnell, Vivienne P. M.;McKee, Shane;Boardman-Pretty, Freya;Devereau, Andrew;Fowler, Tom A.;Caulfield, Mark J.;Alton, Eric W.;Ferguson, Teena;Redhead, Julian;McKnight, Amy J.;Thomas, Geraldine A.;Aldred, Micheala A.;Shovlin, Claire L.
• 通讯作者: Shovlin, Claire L.

SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile.

• DOI: 10.1016/j.gim.2022.02.013
• 发表时间: 2022-06
• 期刊: GENETICS IN MEDICINE
• 影响因子: 8.8
• 作者: Al-Jawahiri, Reem;Foroutan, Aidin;Kerkhof, Jennifer;McConkey, Haley;Levy, Michael;Haghshenas, Sadegheh;Rooney, Kathleen;Turner, Jasmin;Shears, Debbie;Holder, Muriel;Lefroy, Henrietta;Castle, Bruce;Reis, Linda M.;Semina, V. Elena;Lachlan, Katherine;Chandler, Kate;Wright, Thomas;Clayton-Smith, Jill;Hug, Franziska Phan;Pitteloud, Nelly;Bartoloni, Lucia;Hoffjan, Sabine;Park, Soo-Mi;Thankamony, Ajay;Lees, Melissa;Wakeling, Emma;Naik, Swati;Hanker, Britta;Girisha, Katta M.;Agolini, Emanuele;Giuseppe, Zampino;Alban, Ziegler;Tessarech, Marine;Keren, Ziegler Boris;Afenjar, Alexandra;Zweier, Christiane;Reis, Andre;Smol, Thomas;Tsurusaki, Yoshinori;Nobuhiko, Okamoto;Sekiguchi, Futoshi;Tsuchida, Naomi;Matsumoto, Naomichi;Kou, Ikuyo;Yonezawa, Yoshiro;Ikegawa, Shiro;Callewaert, Bert;Freeth, Megan;Kleinendorst, Lotte;Donaldson, Alan;Alders, Marielle;De Paepe, Anne;Sadikovic, Bekim;McNeill, Alisdair
• 通讯作者: McNeill, Alisdair

Diverse ancestry whole-genome sequencing association study identifies TBX5 and PTK7 as susceptibility genes for posterior urethral valves.

• DOI: 10.7554/elife.74777
• 发表时间: 2022-09-20
• 期刊: eLife
• 影响因子: 7.7
• 作者: Chan MMY;Sadeghi-Alavijeh O;Lopes FM;Hilger AC;Stanescu HC;Voinescu CD;Beaman GM;Newman WG;Zaniew M;Weber S;Ho YM;Connolly JO;Wood D;Maj C;Stuckey A;Kousathanas A;Genomics England Research Consortium;Kleta R;Woolf AS;Bockenhauer D;Levine AP;Gale DP
• 通讯作者: Gale DP

An online compendium of treatable genetic disorders.

• DOI: 10.1002/ajmg.c.31874
• 发表时间: 2021-03
• 期刊: American journal of medical genetics. Part C, Seminars in medical genetics
• 作者: Bick D;Bick SL;Dimmock DP;Fowler TA;Caulfield MJ;Scott RH
• 通讯作者: Scott RH