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 Freson; Stephen 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

doi:10.1016/j.cell.2016.10.042

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

Bristol Medical School (PHS)

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Abstract

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.

Original language	English
Pages (from-to)	1415-1429.e19
Journal	Cell
Volume	167
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2016.10.042
Publication status	Published - 17 Nov 2016

Keywords

blood
genetics
Hematology
Epigenetics
Hematopoiesis
Mendelian randomisation
COMPLEX DISEASES
cardiovasular diseases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Astle, W. J., Elding, H., Jiang, T., Allen, D., Ruklisa, D., Mann, A. L., Mead, D., Bouman, H., Riveros-Mckay, F., Kostadima, M. A., Lambourne, J. J., Sivapalaratnam, S., Downes, K., Kundu, K., Bomba, L., Berentsen, K., Bradley, J. R., Daugherty, L. C., Delaneau, O., ... Soranzo, N. (2016). The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease. Cell, 167(5), 1415-1429.e19. https://doi.org/10.1016/j.cell.2016.10.042

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title = "The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease",

abstract = "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.",

keywords = "blood, genetics, Hematology, Epigenetics, Hematopoiesis, Mendelian randomisation, COMPLEX DISEASES, cardiovasular diseases",

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doi = "10.1016/j.cell.2016.10.042",

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Astle, WJ, Elding, H, Jiang, T, Allen, D, Ruklisa, D, Mann, AL, Mead, D, Bouman, H, Riveros-Mckay, F, Kostadima, MA, Lambourne, JJ, Sivapalaratnam, S, Downes, K, Kundu, K, Bomba, L, Berentsen, K, Bradley, JR, Daugherty, LC, Delaneau, O, Freson, K, Garner, SF, Grassi, L, Guerrero, J, Haimel, M, Janssen-Megens, EM, Kaan, A, Kamat, M, Kim, B, Mandoli, A, Marchini, J, Martens, JHA, Meacham, S, Megy, K, O'Connell, J, Petersen, R, Sharifi, N, Sheard, SM, Staley, JR, Tuna, S, van der Ent, M, Walter, K, Wang, S-Y, Wheeler, E, Wilder, SP, Iotchkova, V, Moore, C, Sambrook, J, Stunnenberg, HG, Di Angelantonio, E, Kaptoge, S, Kuijpers, TW, Carrillo-de-Santa-Pau, E, Juan, D, Rico, D, Valencia, A, Chen, L, Ge, B, Vasquez, L, Kwan, T, Garrido-Martín, D, Watt, S, Yang, Y, Guigo, R, Beck, S, Paul, DS, Pastinen, T, Bujold, D, Bourque, G, Frontini, M, Danesh, J, Roberts, DJ, Ouwehand, WH, Butterworth, AS & Soranzo, N 2016, 'The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease', Cell, vol. 167, no. 5, pp. 1415-1429.e19. https://doi.org/10.1016/j.cell.2016.10.042

TY - JOUR

T1 - The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

AU - Astle, William J

AU - Elding, Heather

AU - Jiang, Tao

AU - Allen, Dave

AU - Ruklisa, Dace

AU - Mann, Alice L

AU - Mead, Daniel

AU - Bouman, Heleen

AU - Riveros-Mckay, Fernando

AU - Kostadima, Myrto A

AU - Lambourne, John J

AU - Sivapalaratnam, Suthesh

AU - Downes, Kate

AU - Kundu, Kousik

AU - Bomba, Lorenzo

AU - Berentsen, Kim

AU - Bradley, John R

AU - Daugherty, Louise C

AU - Delaneau, Olivier

AU - Freson, Kathleen

AU - Garner, Stephen F

AU - Grassi, Luigi

AU - Guerrero, Jose

AU - Haimel, Matthias

AU - Janssen-Megens, Eva M

AU - Kaan, Anita

AU - Kamat, Mihir

AU - Kim, Bowon

AU - Mandoli, Amit

AU - Marchini, Jonathan

AU - Martens, Joost H A

AU - Meacham, Stuart

AU - Megy, Karyn

AU - O'Connell, Jared

AU - Petersen, Romina

AU - Sharifi, Nilofar

AU - Sheard, Simon M

AU - Staley, James R

AU - Tuna, Salih

AU - van der Ent, Martijn

AU - Walter, Klaudia

AU - Wang, Shuang-Yin

AU - Wheeler, Eleanor

AU - Wilder, Steven P

AU - Iotchkova, Valentina

AU - Moore, Carmel

AU - Sambrook, Jennifer

AU - Stunnenberg, Hendrik G

AU - Di Angelantonio, Emanuele

AU - Kaptoge, Stephen

AU - Kuijpers, Taco W

AU - Carrillo-de-Santa-Pau, Enrique

AU - Juan, David

AU - Rico, Daniel

AU - Valencia, Alfonso

AU - Chen, Lu

AU - Ge, Bing

AU - Vasquez, Louella

AU - Kwan, Tony

AU - Garrido-Martín, Diego

AU - Watt, Stephen

AU - Yang, Ying

AU - Guigo, Roderic

AU - Beck, Stephan

AU - Paul, Dirk S

AU - Pastinen, Tomi

AU - Bujold, David

AU - Bourque, Guillaume

AU - Frontini, Mattia

AU - Danesh, John

AU - Roberts, David J

AU - Ouwehand, Willem H

AU - Butterworth, Adam S

AU - Soranzo, Nicole

PY - 2016/11/17

Y1 - 2016/11/17

N2 - 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.

AB - 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.

KW - blood

KW - genetics

KW - Hematology

KW - Epigenetics

KW - Hematopoiesis

KW - Mendelian randomisation

KW - COMPLEX DISEASES

KW - cardiovasular diseases

U2 - 10.1016/j.cell.2016.10.042

DO - 10.1016/j.cell.2016.10.042

M3 - Article (Academic Journal)

C2 - 27863252

SN - 0092-8674

VL - 167

SP - 1415-1429.e19

JO - Cell

JF - Cell

IS - 5

ER -

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

Abstract

Keywords

UN SDGs

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