Astle William J, Elding Heather, Jiang Tao, Allen Dave, Ruklisa Dace, Mann Alice L, Mead Daniel, Bouman Heleen, Riveros-Mckay Fernando, Kostadima Myrto A, Lambourne John J, Sivapalaratnam Suthesh, Downes Kate, Kundu Kousik, Bomba Lorenzo, Berentsen Kim, Bradley John R, Daugherty Louise C, Delaneau Olivier, Freson Kathleen, Garner Stephen F, Grassi Luigi, Guerrero Jose, Haimel Matthias, Janssen-Megens Eva M, Kaan Anita, Kamat Mihir, Kim Bowon, Mandoli Amit, Marchini Jonathan, Martens Joost H A, Meacham Stuart, Megy Karyn, O'Connell Jared, Petersen Romina, Sharifi Nilofar, Sheard Simon M, Staley James R, Tuna Salih, van der Ent Martijn, Walter Klaudia, Wang Shuang-Yin, Wheeler Eleanor, Wilder Steven P, Iotchkova Valentina, Moore Carmel, Sambrook Jennifer, Stunnenberg Hendrik G, Di Angelantonio Emanuele, Kaptoge Stephen, Kuijpers Taco W, Carrillo-de-Santa-Pau Enrique, Juan David, Rico Daniel, Valencia Alfonso, Chen Lu, Ge Bing, Vasquez Louella, Kwan Tony, Garrido-Martín Diego, Watt Stephen, Yang Ying, Guigo Roderic, Beck Stephan, Paul Dirk S, Pastinen Tomi, Bujold David, Bourque Guillaume, Frontini Mattia, Danesh John, Roberts David J, Ouwehand Willem H, Butterworth Adam S, Soranzo Nicole
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge CB2 0PT, UK; Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Forvie Site, Robinson Way, Cambridge CB2 0SR, UK; MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK.
Department of Human Genetics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, UK; The National Institute for Health Research Blood and Transplant Unit (NIHR BTRU) in Donor Health and Genomics at the University of Cambridge, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge CB1 8RN, UK.
Cell. 2016 Nov 17;167(5):1415-1429.e19. doi: 10.1016/j.cell.2016.10.042.
Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.
许多常见变异已与血液学特征相关联，但确定因果基因和途径已被证明具有挑战性。我们在英国生物银行和INTERVAL研究中进行了全基因组关联分析，在173480名欧洲血统参与者中测试了2950万个基因变异与36种红细胞、白细胞和血小板特性的关联。这项工作产生了数百个对血细胞表型有强烈影响的低频（<5%）和罕见（<1%）变异。我们的数据突出了复杂性状等位基因结构的一般特性，包括不同基因组调控域的多基因信号所解释的每种血液性状遗传成分的比例。最后，通过孟德尔随机化，我们提供了将血细胞指数与复杂病理（包括自身免疫性疾病、精神分裂症和冠心病）联系起来的共享遗传途径的证据，以及表明先前报道的血细胞指数与心血管疾病之间的人群关联可能是非因果关系的证据。
