Iotchkova Valentina, Huang Jie, Morris John A, Jain Deepti, Barbieri Caterina, Walter Klaudia, Min Josine L, Chen Lu, Astle William, Cocca Massimilian, Deelen Patrick, Elding Heather, Farmaki Aliki-Eleni, Franklin Christopher S, Franberg Mattias, Gaunt Tom R, Hofman Albert, Jiang Tao, Kleber Marcus E, Lachance Genevieve, Luan Jian'an, Malerba Giovanni, Matchan Angela, Mead Daniel, Memari Yasin, Ntalla Ioanna, Panoutsopoulou Kalliope, Pazoki Raha, Perry John R B, Rivadeneira Fernando, Sabater-Lleal Maria, Sennblad Bengt, Shin So-Youn, Southam Lorraine, Traglia Michela, van Dijk Freerk, van Leeuwen Elisabeth M, Zaza Gianluigi, Zhang Weihua, Amin Najaf, Butterworth Adam, Chambers John C, Dedoussis George, Dehghan Abbas, Franco Oscar H, Franke Lude, Frontini Mattia, Gambaro Giovanni, Gasparini Paolo, Hamsten Anders, Issacs Aaron, Kooner Jaspal S, Kooperberg Charles, Langenberg Claudia, Marz Winfried, Scott Robert A, Swertz Morris A, Toniolo Daniela, Uitterlinden Andre G, van Duijn Cornelia M, Watkins Hugh, Zeggini Eleftheria, Maurano Mathew T, Timpson Nicholas J, Reiner Alexander P, Auer Paul L, Soranzo Nicole
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
Nat Genet. 2016 Nov;48(11):1303-1312. doi: 10.1038/ng.3668. Epub 2016 Sep 26.
Large-scale whole-genome sequence data sets offer novel opportunities to identify genetic variation underlying human traits. Here we apply genotype imputation based on whole-genome sequence data from the UK10K and 1000 Genomes Project into 35,981 study participants of European ancestry, followed by association analysis with 20 quantitative cardiometabolic and hematological traits. We describe 17 new associations, including 6 rare (minor allele frequency (MAF) < 1%) or low-frequency (1% < MAF < 5%) variants with platelet count (PLT), red blood cell indices (MCH and MCV) and HDL cholesterol. Applying fine-mapping analysis to 233 known and new loci associated with the 20 traits, we resolve the associations of 59 loci to credible sets of 20 or fewer variants and describe trait enrichments within regions of predicted regulatory function. These findings improve understanding of the allelic architecture of risk factors for cardiometabolic and hematological diseases and provide additional functional insights with the identification of potentially novel biological targets.
大规模全基因组序列数据集为识别影响人类性状的遗传变异提供了新机遇。在此，我们将基于英国10K计划和千人基因组计划的全基因组序列数据进行的基因型填充应用于35981名欧洲血统的研究参与者，随后对20种定量心脏代谢和血液学性状进行关联分析。我们描述了17个新的关联，包括6个与血小板计数（PLT）、红细胞指数（MCH和MCV）以及高密度脂蛋白胆固醇相关的罕见（次要等位基因频率（MAF）<1%）或低频（1%<MAF<5%）变异。对与这20个性状相关的233个已知和新位点进行精细定位分析后，我们将59个位点的关联解析为20个或更少变异的可信集，并描述了预测调控功能区域内的性状富集情况。这些发现增进了对心脏代谢和血液学疾病风险因素等位基因结构的理解，并通过识别潜在的新生物靶点提供了更多功能见解。
