The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

被引：841

作者：

Astle, William J. ^{[1
,2
,3
,4
]}

Elding, Heather ^{[5
,6
]}

Jiang, Tao ^{[4
]}

Allen, Dave ^{[7
]}

Ruklisa, Dace ^{[1
,2
,3
]}

Mann, Alice L. ^{[5
]}

Mead, Daniel ^{[5
]}

Bouman, Heleen ^{[5
]}

Riveros-Mckay, Fernando ^{[5
]}

Kostadima, Myrto A. ^{[1
,2
,8
]}

Lambourne, John J. ^{[1
,2
]}

Sivapalaratnam, Suthesh ^{[1
,9
]}

Downes, Kate ^{[1
,2
]}

Kundu, Kousik ^{[1
,5
]}

Bomba, Lorenzo ^{[5
]}

Berentsen, Kim ^{[10
]}

Bradley, John R. ^{[11
,12
]}

Daugherty, Louise C. ^{[1
,2
,13
]}

Delaneau, Olivier ^{[14
]}

Freson, Kathleen ^{[15
]}

Garner, Stephen F. ^{[1
,2
]}

Grassi, Luigi ^{[1
,2
]}

Guerrero, Jose ^{[1
,2
]}

Haimel, Matthias ^{[11
,13
]}

Janssen-Megens, Eva M. ^{[10
]}

Kaan, Anita ^{[10
]}

Kamat, Mihir ^{[4
]}

Kim, Bowon ^{[10
]}

Mandoli, Amit ^{[10
]}

Marchini, Jonathan ^{[16
,17
]}

Martens, Joost H. A. ^{[10
]}

Meacham, Stuart ^{[1
,2
,13
]}

Megy, Karyn ^{[1
,2
,13
]}

O'Connell, Jared ^{[16
,17
]}

Petersen, Romina ^{[1
,2
]}

Sharifi, Nilofar ^{[10
]}

Sheard, Simon M. ^{[18
]}

Staley, James R. ^{[4
]}

Tuna, Salih ^{[1
,13
]}

van der Ent, Martijn ^{[10
]}

Walter, Klaudia ^{[5
]}

Wang, Shuang-Yin ^{[10
]}

Wheeler, Eleanor ^{[5
]}

Wilder, Steven P. ^{[8
]}

Iotchkova, Valentina ^{[5
,8
]}

Moore, Carmel ^{[4
]}

Sambrook, Jennifer ^{[1
,2
,4
]}

Stunnenberg, Hendrik G. ^{[10
]}

Di Angelantonio, Emanuele ^{[4
,6
,19
]}

Kaptoge, Stephen ^{[4
,6
]}

机构：

[1] Univ Cambridge, Dept Haematol, Cambridge Biomed Campus,Long Rd, Cambridge CB2 0PT, England

[2] Natl Hlth Serv NHS Blood & Transplant, Cambridge Biomed Campus,Long Rd, Cambridge CB2 0PT, England

[3] MRC, Biostat Unit, Cambridge Inst Publ Hlth, Cambridge Biomed Campus,Forvie Site,Robinson Way, Cambridge CB2 0SR, England

[4] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, MRC BHF Cardiovasc Epidemiol Unit, Worts Causeway, Cambridge CB1 8RN, England

[5] Wellcome Trust Sanger Inst, Dept Human Genet, Wellcome Trust Genome Campus, Cambridge CB10 1HH, England

[6] Univ Cambridge, Strangeways Res Lab, Natl Inst Hlth Res Blood & Transplant Unit NIHR B, Worts Causeway, Cambridge CB1 8RN, England

[7] John Radcliffe Hosp, NHS Blood & Transplant, Blood Res Grp, Headley Way, Oxford OX3 9BQ, England

[8] European Bioinformat Inst, European Mol Biol Lab, Wellcome Trust Genome Campus, Cambridge CB10 1SD, England

[9] Barts Hlth NHS Trust, Royal London Hosp, Dept Haematol, Whitechapel Rd, London E1 1BB, England

[10] Radboud Univ Nijmegen, Fac Sci, Dept Mol Biol, NL-6525 GA Nijmegen, Netherlands

[11] Univ Cambridge, Dept Med, Cambridge Biomed Campus,Long Rd, Cambridge CB2 0QQ, England

[12] Cambridge Univ Hosp, Natl Inst Hlth Res, Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England

[13] Univ Cambridge, NIHR BioResource Rare Dis, Cambridge Biomed Campus,Long Rd, Cambridge CB2 0PT, England

[14] Univ Geneva, Dept Genet & Dev GEDEV, CH-1211 Geneva 4, Switzerland

[15] Univ Leuven, Ctr Mol & Vasc Biol, Dept Cardiovasc Sci, B-3000 Leuven, Belgium

[16] Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England

[17] Univ Oxford, Dept Stat, 1 South Parks Rd, Oxford OX1 3TG, England

[18] UK Biobank Ltd, 1-4 Spectrum Way, Stockport SK3 0SA, Lancs, England

[19] Addenbrookes Hosp, Div Cardiovasc Med, British Heart Fdn Ctr Excellence, Hills Rd, Cambridge CB2 0QQ, England

[20] Univ Amsterdam, Acad Med Ctr, Emma Childrens Hosp, Locat H7-230,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands

[21] Sanquin Res & Landsteiner Lab, Blood Cell Res, Plesmanlaan 125, NL-1066 CX Amsterdam, Netherlands

[22] Spanish Natl Canc Res Ctr CNIO, Struct Biol & BioComp Programme, Melchor Fernandez Almagro 3, Madrid 28029, Spain

[23] Newcastle Univ, Inst Cellular Med, Framlington Pl, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[24] McGill Univ, Human Genet, 740 Dr Penfield, Montreal, PQ H3A 0G1, Canada

[25] Barcelona Inst Sci & Technol, CRG, Bioinformat & Genom, Carrer Dr Aiguader 88, Barcelona 8003, Spain

[26] Univ Pompeu Fabra, Dept Expt & Hlth Sci, Placa de la Merce 10-12, Barcelona 8002, Spain

[27] Inst Hosp Mar Invest Med IMIM, Computat Genom, Carrer Dr Aiguader 88, Barcelona 8003, Spain

[28] UCL, Inst Canc, 72 Huntley St, London WC1E 6BT, England

[29] Univ Oxford, John Radcliffe Hosp, Radcliffe Dept Med, Headley Way, Oxford OX3 9DU, England

[30] Churchill Hosp, Dept Haematol, Oxford OX3 7LE, England

来源：

CELL | 2016年 / 167卷 / 05期

基金：

欧洲研究理事会; 英国医学研究理事会; 英国惠康基金;

关键词：

GENOME-WIDE ASSOCIATION; MENDELIAN RANDOMIZATION; IDENTIFIES LOCI; WHOLE-EXOME; RISK; PHENOTYPE; VARIANTS; COUNT; GENE; METAANALYSIS;

D O I：

10.1016/j.cell.2016.10.042

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1415 / +

页数：33

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