Rare variant contribution to human disease in 281,104 UK Biobank exomes.
Rare variant contribution to human disease in 281,104 UK Biobank exomes.
复制标题
罕见变异对281，104个英国生物库外显子组中人类疾病的贡献
DOI：
10.1038/s41586-021-03855-y
复制
发表时间：
2021-09
期刊：
影响因子：
64.8
通讯作者：
Petrovski S
中科院分区：
文献类型：
--
作者：
Wang Q;Dhindsa RS;Carss K;Harper AR;Nag A;Tachmazidou I;Vitsios D;Deevi SVV;Mackay A;Muthas D;Hühn M;Monkley S;Olsson H;AstraZeneca Genomics Initiative;Wasilewski S;Smith KR;March R;Platt A;Haefliger C;Petrovski S
全基因组关联研究已经发现了数千种与人类疾病相关的常见变异，但罕见变异对常见疾病的贡献仍然相对未被探索。英国生物库包含与大约50万参与者的医疗记录相关的详细表型数据，为评估罕见变异对广泛性状的影响提供了前所未有的机会。在这里，我们使用来自269，171名欧洲血统的英国生物银行参与者的外显子组测序数据研究了罕见蛋白质编码变体与17，361个二元和1，419个定量表型之间的关系。基于基因的崩溃分析揭示了1，703个统计学显著的二元性状基因-表型关联，中位比值比为12.4。此外，83%的这些协会是无法检测到的通过单变量关联测试，强调了基于基因的崩溃分析的力量，在设置高等位基因异质性。基因-表型关联也显著富集了功能丧失介导的性状和批准的药物靶点。最后，我们使用来自11，933名来自非洲，东亚或南亚血统的英国生物银行参与者的外显子组测序数据进行了祖先特异性和泛祖先崩溃分析。我们的研究结果突出了罕见变异对常见疾病的重大贡献。汇总统计数据可通过互动门户网站（http：//azphewas.com/）公开查阅。作者分析了罕见的蛋白质编码遗传变异与英国生物库队列中的18，780个性状的关联。
Genome-wide association studies have uncovered thousands of common variants associated with human disease, but the contribution of rare variants to common disease remains relatively unexplored. The UK Biobank contains detailed phenotypic data linked to medical records for approximately 500,000 participants, offering an unprecedented opportunity to evaluate the effect of rare variation on a broad collection of traits. Here we study the relationships between rare protein-coding variants and 17,361 binary and 1,419 quantitative phenotypes using exome sequencing data from 269,171 UK Biobank participants of European ancestry. Gene-based collapsing analyses revealed 1,703 statistically significant gene–phenotype associations for binary traits, with a median odds ratio of 12.4. Furthermore, 83% of these associations were undetectable via single-variant association tests, emphasizing the power of gene-based collapsing analysis in the setting of high allelic heterogeneity. Gene–phenotype associations were also significantly enriched for loss-of-function-mediated traits and approved drug targets. Finally, we performed ancestry-specific and pan-ancestry collapsing analyses using exome sequencing data from 11,933 UK Biobank participants of African, East Asian or South Asian ancestry. Our results highlight a significant contribution of rare variants to common disease. Summary statistics are publicly available through an interactive portal (http://azphewas.com/). The authors analyse rare protein-coding genetic variants for association with 18,780 traits in the UK Biobank cohort.
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：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.