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

William J. Astle, Heather Elding, Tao Jiang, Dave Allen, Dace Ruklisa, Alice L. Mann, Daniel Mead, Heleen Bouman, Fernando Riveros-Mckay, Myrto A. Kostadima, John J. Lambourne, Suthesh Sivapalaratnam, Kate Downes, Kousik Kundu, Lorenzo Bomba, Kim Berentsen, John R. Bradley, Louise C. Daugherty, Olivier Delaneau, Kathleen FresonStephen F. Garner, Luigi Grassi, Jose Guerrero, Matthias Haimel, Eva M. Janssen-Megens, Anita Kaan, Mihir Kamat, Bowon Kim, Amit Mandoli, Jonathan Marchini, Joost H.A. Martens, Stuart Meacham, Karyn Megy, Jared O'Connell, Romina Petersen, Nilofar Sharifi, Simon M. Sheard, James R. Staley, Salih Tuna, Martijn van der Ent, Klaudia Walter, Shuang Yin Wang, Eleanor Wheeler, Steven P. Wilder, Valentina Iotchkova, Carmel Moore, Jennifer Sambrook, Hendrik G. Stunnenberg, Emanuele Di Angelantonio, Stephen Kaptoge, Taco W. Kuijpers, Enrique Carrillo-de-Santa-Pau, David Juan, Daniel Rico, Alfonso Valencia, Lu Chen, Bing Ge, Louella Vasquez, Tony Kwan, Diego Garrido-Martín, Stephen Watt, Ying Yang, Roderic Guigo, Stephan Beck, Dirk S. Paul, Tomi Pastinen, David Bujold, Guillaume Bourque, Mattia Frontini, John Danesh, David J. Roberts, Willem H. Ouwehand, Adam S. Butterworth, Nicole Soranzo

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

750 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)1415-1429.e19
TijdschriftCell
Volume167
Nummer van het tijdschrift5
DOI's
StatusGepubliceerd - 17 nov. 2016
Extern gepubliceerdJa

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