Genetic association analysis of 77,539 genomes reveals rare disease etiologies.
Genetic association analysis of 77,539 genomes reveals rare disease etiologies.
复制标题
DOI：
10.1038/s41591-023-02211-z
复制
发表时间：
2023-03
期刊：
影响因子：
82.9
通讯作者：
Turro, Ernest
中科院分区：
文献类型：
--
作者：
Greene, Daniel;Pirri, Daniela;Frudd, Karen;Sackey, Ege;Al-Owain, Mohammed;Giese, Arnaud P. J.;Ramzan, Khushnooda;Riaz, Sehar;Yamanaka, Itaru;Boeckx, Nele;Thys, Chantal;Gelb, Bruce D.;Brennan, Paul;Hartill, Verity;Harvengt, Julie;Kosho, Tomoki;Mansour, Sahar;Masuno, Mitsuo;Ohata, Takako;Stewart, Helen;Taibah, Khalid;Turner, Claire L. S.;Imtiaz, Faiqa;Riazuddin, Saima;Morisaki, Takayuki;Ostergaard, Pia;Loeys, Bart L.;Morisaki, Hiroko;Ahmed, Zubair M.;Birdsey, Graeme M.;Freson, Kathleen;Mumford, Andrew;Turro, Ernest
超过一半的罕见疾病的遗传病因尚不清楚。标准化的基因组测序和大规模患者队列的表型分型为发现未知病因提供了机会，但这取决于有效和强大的分析方法。我们建立了一个紧凑的数据库--“RAPENTER”，其中包含了77,539名参与者的罕见变异基因类型和表型，这些基因和表型由100,000个基因组计划测序。然后，我们使用贝叶斯遗传关联方法BeviMed来推断基因与临床医生分配给参与者的269种罕见疾病类别中的每一种之间的关联。我们确定了241个已知的关联和19个以前未确定的关联。我们通过搜索其他队列中的家系，并使用生物信息学和实验方法，验证了与ERG、PMEPA1和GPR156的相关性。我们提供的证据表明：(1)红细胞转化特异性家族转录因子编码基因ERG的功能缺失导致原发性淋巴水肿；(2)转化生长因子-β调节基因PMEPA1的最后一个外显子的截短变异导致Loeys-Dietz综合征；(3)GPR156的功能缺失变异导致隐性先天性听力障碍。RATHACHORGE提供了一个轻便、灵活和便携的系统，用于合成研究有数万名参与者的罕见疾病队列所需的遗传和表型数据。一个灵活而紧凑的数据库，其中包含由100,000基因组计划测序的77,539名参与者的罕见变异基因和表型，从而能够识别新的致病基因。
The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the ‘Rareservoir’, containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG, PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-β regulator PMEPA1 result in Loeys–Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants. A flexible and compact database containing rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project enables the identification of new disease-causing genes.
登录
查看更多内容
影响因子：
14.9
作者：
Howe KL;Achuthan P;Allen J;Allen J;Alvarez-Jarreta J;Amode MR;Armean IM;Azov AG;Bennett R;Bhai J;Billis K;Boddu S;Charkhchi M;Cummins C;Da Rin Fioretto L;Davidson C;Dodiya K;El Houdaigui B;Fatima R;Gall A;Garcia Giron C;Grego T;Guijarro-Clarke C;Haggerty L;Hemrom A;Hourlier T;Izuogu OG;Juettemann T;Kaikala V;Kay M;Lavidas I;Le T;Lemos D;Gonzalez Martinez J;Marugán JC;Maurel T;McMahon AC;Mohanan S;Moore B;Muffato M;Oheh DN;Paraschas D;Parker A;Parton A;Prosovetskaia I;Sakthivel MP;Salam AIA;Schmitt BM;Schuilenburg H;Sheppard D;Steed E;Szpak M;Szuba M;Taylor K;Thormann A;Threadgold G;Walts B;Winterbottom A;Chakiachvili M;Chaubal A;De Silva N;Flint B;Frankish A;Hunt SE;IIsley GR;Langridge N;Loveland JE;Martin FJ;Mudge JM;Morales J;Perry E;Ruffier M;Tate J;Thybert D;Trevanion SJ;Cunningham F;Yates AD;Zerbino DR;Flicek P
通讯作者：
Flicek P
影响因子：
13.8
作者：
Ellaithy A;Gonzalez-Maeso J;Logothetis DA;Levitz J
通讯作者：
Levitz J
影响因子：
4
作者：
Gordon K;Varney R;Keeley V;Riches K;Jeffery S;Van Zanten M;Mortimer P;Ostergaard P;Mansour S
通讯作者：
Mansour S
影响因子：
4.7
作者：
Thalhammer A;Trinidad JC;Burlingame AL;Schoepfer R
通讯作者：
Schoepfer R
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G