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Seventy-five genetic loci influencing the human red blood cell

Authors :
Teresa Nutile
Anna-Liisa Hartikainen
Stavroula Kanoni
Johannes H. Smit
Harm-Jan Westra
Beben Benyamin
Gonneke Willemsen
Clara S. Tang
Maria Dimitriou
Peter Vollenweider
Olle Melander
Inga Prokopenko
W.H. Wilson Tang
John P. Kemp
Tim D. Spector
Evelin Mihailov
Paul F. O'Reilly
Eleonora Porcu
Marcus E. Kleber
Sheila Ulivi
George Dedoussis
Manuela Uda
Matthias Nauck
Brenda W.J.H. Penninx
Daniela Ruggiero
Xinzhong Li
Dirk S. Paul
Niek Verweij
Bernd Genser
Harold Snieder
Willem H. Ouwehand
Ido P. Kema
Miriam F. Moffatt
Carmel Moore
Hilma Holm
Nicola Pirastu
Adamo Pio D'Adamo
Michael Stumvoll
Rossella Sorice
Kay-Tee Khaw
Heather Lloyd-Jones
Federico Murgia
Stephen F. Garner
Jing Hua Zhao
Laura Portas
Abdel Abdellaoui
Ursula Puc
Andres Metspalu
Marleen H. M. de Moor
Isleifur Olafsson
Ruth J. F. Loos
Andres Salumets
François Bastardot
James Scott
Jian Yang
Braxton D. Mitchell
Debora Parracciani
Maria Novatchkova
Panos Deloukas
William O.C.M. Cookson
Lorna M. Lopez
Andrew A. Hicks
Aude Saint-Pierre
Daniel F. Gudbjartsson
Vinicius Tragante
Mario Pirastu
Jacques S. Beckmann
L. Joost van Pelt
Winfried Maerz
Hooman Allayee
Jouke-Jan Hottenga
Kari Stefansson
Debashish Das
Weihua Zhang
Anke Tönjes
Michela Traglia
Stuart Meacham
Antonio Piga
Cornelis A. Albers
Nicholas G. Martin
John C. Chambers
Christa Meisinger
Leo-Pekka Lyytikäinen
Nicole Soranzo
Mika Kähönen
Katrin Voss
Micha Hersch
Claudia Langenberg
Sian Tsung Tan
Sandosh Padmanabhan
Christian X. Weichenberger
J. Gustav Smith
Antony P. Attwood
Claire E. Hastie
Gunnar Engström
Janina S. Ried
Carsten Oliver Schmidt
Pall T. Onundarson
Kathy Miller
Francisco S. Domingues
Stefania Bandinelli
Ulrich Elling
Augusto Rendon
Paul Elliott
Quince Gibson
Tõnu Esko
Robert Sladek
Marina Ciullo
Gerald Wirnsberger
Franco Anni
Antonietta Robino
Serena Sanna
Hein Schepers
Jonathan Stephens
Joban Sehmi
Beverley Balkau
Jennifer G. Sambrook
Lucia Perseu
Ilja M. Nolte
Herman H W Silljé
John M. Starr
Cinzia Sala
Peter P. Pramstaller
David M. Evans
Renzo Galanello
Uwe Völker
Philippe Froguel
Dorret I. Boomsma
Vasiliki Lagou
Gerjan Navis
Christian Gieger
Susan M. Ring
Alexander Teumer
Angela Döring
Ale Algra
Toshiko Tanaka
Bo Hedblad
Anneli Pouta
Unnur Thorsteinsdottir
Bernhard R. Winkelmann
Liming Liang
John Danesh
Paolo Gasparini
Sarah E. Medland
Ian J. Deary
Martin Gögele
Pim van der Harst
Giorgia Girotto
Josef M. Penninger
Jaspal S. Kooner
Patrick Sulem
Thomas Illig
Yasin Memari
Sarah E. Harris
Wiek H. van Gilst
Francesco Cucca
Dirk J. van Veldhuisen
So-Youn Shin
Giorgio Pistis
Olli T. Raitakari
Lude Franke
Folkert W. Asselbergs
Abtehale Al-Hussani
Stanley L. Hazen
Manuel A. R. Ferreira
Aimo Ruokonen
Christian Dina
Aparna Radhakrishnan
Irene Mateo Leach
Nicholas J. Wareham
George Davey Smith
Eric E. Schadt
Alan R. Shuldiner
John Whitfield
Gudmundur I. Eyjolfsson
Eco J. C. de Geus
Grant W. Montgomery
Afshin Parsa
Terho Lehtimäki
Paolo Fortina
Luigi Ferrucci
Andreas Greinacher
Marjo-Riitta Järvelin
Krista Fischer
Fabrice Danjou
Rudolf A. de Boer
Paul I.W. de Bakker
Peter M. Visscher
Anna F. Dominiczak
Ramiro Ramirez-Solis
Jennifer Jolley
Bruce H. R. Wolffenbuttel
Jaana Hartiala
Daniela Toniolo
Bernhard O. Boehm
van der Harst, P
Zhang, W
Mateo Leach, I
Rendon, A
Verweij, N
Sehmi, J
Paul, D
Elling, U
Allayee, H
Li, X
Radhakrishnan, A
Tan, St
Voss, K
Weichenberger, Cx
Albers, Ca
Al Hussani, A
Asselbergs, Fw
Ciullo, M
Danjou, F
Dina, C
Esko, T
Evans, Dm
Franke, L
Gögele, M
Hartiala, J
Hersch, M
Holm, H
Hottenga, Jj
Kanoni, S
Kleber, Me
Lagou, V
Langenberg, C
Lopez, Lm
Lyytikäinen, Lp
Melander, O
Murgia, F
Nolte, Im
O'Reilly, Pf
Padmanabhan, S
Parsa, A
Pirastu, Nicola
Porcu, E
Portas, L
Prokopenko, I
Ried, J
Shin, Sy
Tang, C
Teumer, A
Traglia, Michela
Ulivi, S
Westra, Hj
Yang, J
Zhao, Jh
Anni, F
Abdellaoui, A
Attwood, A
Balkau, B
Bandinelli, S
Bastardot, F
Benyamin, B
Boehm, Bo
Cookson, Wo
Das, D
de Bakker, Pi
de Boer, Ra
de Geus, Ej
de Moor, Mh
Dimitriou, M
Domingues, F
Döring, A
Engström, G
Eyjolfsson, Gi
Ferrucci, L
Fischer, K
Galanello, R
Garner, Sf
Genser, B
Gibson, Qd
Girotto, Giorgia
Gudbjartsson, Df
Harris, Se
Hartikainen, Al
Hastie, Ce
Hedblad, B
Illig, T
Jolley, J
Kähönen, M
Kema, Ip
Kemp, Jp
Liang, L
Lloyd Jones, H
Loos, Rj
Meacham, S
Medland, Se
Meisinger, C
Memari, Y
Mihailov, E
Miller, K
Moffatt, Mf
Nauck, M
Novatchkova, M
Nutile, T
Olafsson, I
Onundarson, Pt
Parracciani, D
Penninx, Bw
Perseu, L
Piga, A
Pistis, G
Pouta, A
Puc, U
Raitakari, O
Ring, Sm
Robino, Antonietta
Ruggiero, D
Ruokonen, A
Saint Pierre, A
Sala, C
Salumets, A
Sambrook, J
Schepers, H
Schmidt, Co
Silljé, Hh
Sladek, R
Smit, Jh
Starr, Jm
Stephens, J
Sulem, P
Tanaka, T
Thorsteinsdottir, U
Tragante, V
van Gilst, Wh
van Pelt, Lj
van Veldhuisen, Dj
Völker, U
Whitfield, Jb
Willemsen, G
Winkelmann, Br
Wirnsberger, G
Algra, A
Cucca, F
D'Adamo, ADAMO PIO
Danesh, J
Deary, Ij
Dominiczak, Af
Elliott, P
Fortina, P
Froguel, P
Gasparini, Paolo
Greinacher, A
Hazen, Sl
Jarvelin, Mr
Khaw, Kt
Lehtimäki, T
Maerz, W
Martin, Ng
Metspalu, A
Mitchell, Bd
Montgomery, Gw
Moore, C
Navis, G
Pirastu, M
Pramstaller, Pp
Ramirez Solis, R
Schadt, E
Scott, J
Shuldiner, Ar
Smith, Gd
Smith, Jg
Snieder, H
Sorice, R
Spector, Td
Stefansson, K
Stumvoll, M
Tang, Wh
Toniolo, D
Tönjes, A
Visscher, Pm
Vollenweider, P
Wareham, Nj
Wolffenbuttel, Bh
Boomsma, Di
Beckmann, J
Dedoussis, Gv
Deloukas, P
Ferreira, Ma
Sanna, S
Uda, M
Hicks, Aa
Penninger, Jm
Gieger, C
Kooner, J
Ouwehand, Wh
Soranzo, N
Chambers, J. C.
Psychiatry
EMGO - Mental health
NCA - Anxiety & Depression
Biological Psychology
Neuroscience Campus Amsterdam - Anxiety & Depression
EMGO+ - Mental Health
Van Der Harst, Pim
Zhang, Weihua
Mateo Leach, Irene
Rendon, Augusto
Benyamin, Beben
Chambers, John C
Cardiovascular Centre (CVC)
Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)
Life Course Epidemiology (LCE)
Guided Treatment in Optimal Selected Cancer Patients (GUTS)
Lifestyle Medicine (LM)
Stem Cell Aging Leukemia and Lymphoma (SALL)
Groningen Kidney Center (GKC)
Vascular Ageing Programme (VAP)
Center for Liver, Digestive and Metabolic Diseases (CLDM)
Source :
Nature, vol. 492, no. 7429, pp. 369-375, Nature (Lond.) 492 (2012): 369–375. doi:10.1038/nature11677, info:cnr-pdr/source/autori:Pim van der Harst, Weihua Zhang, Irene Mateo Leach, Augusto Rendon, Niek Verweij, Joban Sehmi, Dirk S. Paul, Ulrich Elling, Hooman Allayee, Xinzhong Li, Aparna Radhakrishnan, Sian-Tsung Tan, Katrin Voss, Christian X. Weichenberger, Cornelis A. Albers, Abtehale Al-Hussani, Folkert W. Asselbergs, Marina Ciullo, Fabrice Danjou, Christian Dina, Tõnu Esko, David M. Evans, Lude Franke, Martin Gögele, Jaana Hartiala, Micha Hersch, Hilma Holm, Jouke-Jan Hottenga, Stavroula Kanoni, Marcus E. Kleber, Vasiliki Lagou, Claudia Langenberg, Lorna M. Lopez, Leo-Pekka Lyytikäinen, Olle Melander, Federico Murgia, Ilja M. Nolte, Paul F. O'Reilly, Sandosh Padmanabhan, Afshin Parsa, Nicola Pirastu, Eleonora Porcu, Laura Portas, Inga Prokopenko, Janina S. Ried, So-Youn Shin, Clara S. Tang, Alexander Teumer, Michela Traglia, Sheila Ulivi, Harm-Jan Westra, Jian Yang, Jing Hua Zhao, Franco Anni, Abdel Abdellaoui, Antony Attwood, Beverley Balkau, Stefania Bandinelli, François Bastardot, Beben Benyamin, Bernhard O. Boehm, William O. Cookson, Debashish Das, Paul I. W. de Bakker, Rudolf A. de Boer, Eco J. C. de Geus, Marleen H. de Moor, Maria Dimitriou, Francisco S. Domingues, Angela Döring, Gunnar Engström, Gudmundur Ingi Eyjolfsson, Luigi Ferrucci, Krista Fischer, Renzo Galanello, Stephen F. Garner, Bernd Genser, Quince D. Gibson, Giorgia Girotto, Daniel Fannar Gudbjartsson, Sarah E. Harris, Anna-Liisa Hartikainen, Claire E. Hastie, Bo Hedblad, Thomas Illig, Jennifer Jolley, Mika Kähönen, Ido P. Kema, John P. Kemp, Liming Liang, Heather Lloyd-Jones, Ruth J. F. Loos, Stuart Meacham, Sarah E. Medland, Christa Meisinger, Yasin Memari, Evelin Mihailov, Kathy Miller, Miriam F. Moffatt, Matthias Nauck, Maria Novatchkova, Teresa Nutile, Isleifur Olafsson, Pall T. Onundarson, Debora Parracciani, Brenda W. Penninx, Lucia Perseu, Antonio Piga, Giorgio Pistis, Anneli Pouta, Ursula Puc, Olli Raitakari, Susan M. Ring, Antonietta Robino, Daniela Ruggiero, Aimo Ruokonen, Aude Saint-Pierre, Cinzia Sala, Andres Salumets, Jennifer Sambrook, Hein Schepers, Carsten Oliver Schmidt, Herman H. W. Silljé, Rob Sladek, Johannes H. Smit, John M. Starr, Jonathan Stephens, Patrick Sulem, Toshiko Tanaka, Unnur Thorsteinsdottir, Vinicius Tragante, Wiek H. van Gilst, L. Joost van Pelt, Dirk J. van Veldhuisen, Uwe Völker, John B. Whitfield, Gonneke Willemsen, Bernhard R. Winkelmann, Gerald Wirnsberger, Ale Algra, Francesco Cucca, Adamo Pio d'Adamo, John Danesh, Ian J. Deary, Anna F. Dominiczak, Paul Elliott, Paolo Fortina, Philippe Froguel, Paolo Gasparini, Andreas Greinacher, Stanley L. Hazen, Marjo-Riitta Jarvelin, Kay Tee Khaw, Terho Lehtimäki, Winfried Maerz, Nicholas G. Martin, Andres Metspalu, Braxton D. Mitchell, Grant W. Montgomery, Carmel Moore, Gerjan Navis, Mario Pirastu, Peter P. Pramstaller, Ramiro Ramirez-Solis, Eric Schadt, James Scott, Alan R. Shuldiner, George Davey Smith, J. Gustav Smith, Harold Snieder, Rossella Sorice, Tim D. Spector, Kari Stefansson, Michael Stumvoll, W. H. Wilson Tang, Daniela Toniolo, Anke Tönjes, Peter M. Visscher, Peter Vollenweider, Nicholas J. Wareham, Bruce H. R. Wolffenbuttel, Dorret I. Boomsma, Jacques S. Beckmann, George V. Dedoussis, Panos Deloukas, Manuel A. Ferreira, Serena Sanna, Manuela Uda, Andrew A. Hicks, Josef Martin Penninger, Christian Gieger, Jaspal S. Kooner, Willem H. Ouwehand, Nicole Soranzo & John C. Chambers/titolo:Seventy-five genetic loci influencing the human red blood cell/doi:10.1038%2Fnature11677/rivista:Nature (Lond.)/anno:2012/pagina_da:369/pagina_a:375/intervallo_pagine:369–375/volume:492, Nature; Vol 492, van der Harst, P, Zhang, W, Mateo Leach, I, Rendon, A, Verweij, N, Sehmi, J, Paul, D S, Elling, U, Allayee, H, Li, X, Radhakrishnan, A, Tan, S T, Voss, K, Weichenberger, C X, Albers, C A, Al-Hussani, A, Asselbergs, F W, Ciullo, M, Danjou, F, Dina, C, Esko, T, Evans, D M, Franke, L, Gögele, M, Hartiala, J, Hersch, M, Holm, H, Hottenga, J J, Kanoni, S, Kleber, M E, Lagou, V, Langenberg, C, Lopez, L M, Lyytikäinen, L P, Melander, O, Murgia, F, Nolte, I M, O'Reilly, P F, Padmanabhan, S, Parsa, A, Pirastu, N, Porcu, E, Portas, L, Prokopenko, I, Ried, J S, Shin, S Y, Tang, C S, Teumer, A, Traglia, M, Ulivi, S, Westra, H J, Yang, J, Zhao, J H, Anni, F, Abdellaoui, A, Attwood, A, Balkau, B, Bandinelli, S, Bastardot, F, Benyamin, B, Boehm, B O, Cookson, W O, Das, D, de Bakker, P I, de Boer, R A, de Geus, E J C, de Moor, M H M, Dimitriou, M, Domingues, F S, Döring, A, Engström, G, Eyjolfsson, G I, Ferrucci, L, Fischer, K, Galanello, R, Garner, S F, Genser, B, Gibson, Q D, Girotto, G, Gudbjartsson, D F, Harris, S E, Hartikainen, A L, Hastie, C E, Hedblad, B, Illig, T, Jolley, J, Kähönen, M, Kema, I P, Kemp, J P, Liang, L, Lloyd-Jones, H, Loos, R J, Meacham, S, Medland, S E, Meisinger, C, Memari, Y, Mihailov, E, Miller, K, Moffatt, M F, Nauck, M, Novatchkova, M, Nutile, T, Olafsson, I, Onundarson, P T, Parracciani, D, Penninx, B W J H, Perseu, L, Piga, A, Pisits, G, Pouta, A, Puc, U, Raitakari, O, Ring, S M, Robino, A, Ruggiero, D, Ruokonen, A, Saint-Pierre, A, Sala, C, Salumets, A, Sambrook, J, Schepers, H, Schmidt, C O, Silljé, H H, Sladek, R, Smit, J H, Starr, J M, Stephens, J, Sulem, P, Tanaka, T, Thorsteinsdottir, U, Tragante, V, van Gilst, W H, van Pelt, L J, van Veldhuisen, D J, Völker, U, Whitfield, J B, Willemsen, G, Winkelmann, B R, Wirnsberger, G, Algra, A, Cucca, F, d'Adamo, A P, Danesh, J, Deary, I J, Dominiczak, A F, Elliott, P, Fortina, P, Froguel, P, Gasparini, P, Greinacher, A, Hazen, S L, Jarvelin, M-R, Khaw, K T, Lehtimäki, T, Maerz, W, Martin, N G, Metspalu, A, Mitchell, B D, Montgomery, G W, Moore, C, Navis, G, Pirastu, M, Pramstaller, P P, Ramirez-Solis, R, Schadt, E, Scott, J, Shuldiner, A R, Smith, G D, Smith, J G, Snieder, H, Sorice, R, Spector, T D, Stefansson, K, Stumvoll, M, Tang, W H, Toniolo, D, Tönjes, A, Visscher, P M, Vollenweider, P, Wareham, N J, Wolffenbuttel, B H R, Boomsma, D I, Beckmann, J S, Dedoussis, G V, Deloukas, P, Ferreira, M A, Sanna, S, Uda, M, Hicks, A A, Penninger, J M, Gieger, C, Kooner, J S, Ouwehand, W H, Soranzo, N & Chambers, J C 2012, ' Seventy-five genetic loci influencing the human red blood cell ', Nature, vol. 492, no. 7429, pp. 369-375 . https://doi.org/10.1038/nature11677, Nature, 492(7429), 369, Nature, 492(7429), 369-375. Nature Publishing Group, Nature, Nature, 492, 369-75, Nature, 492, 7429, pp. 369-75
Publication Year :
2012

Abstract

Item does not contain fulltext Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.

Details

Language :
English
ISSN :
00280836
Database :
OpenAIRE
Journal :
Nature, vol. 492, no. 7429, pp. 369-375, Nature (Lond.) 492 (2012): 369–375. doi:10.1038/nature11677, info:cnr-pdr/source/autori:Pim van der Harst, Weihua Zhang, Irene Mateo Leach, Augusto Rendon, Niek Verweij, Joban Sehmi, Dirk S. Paul, Ulrich Elling, Hooman Allayee, Xinzhong Li, Aparna Radhakrishnan, Sian-Tsung Tan, Katrin Voss, Christian X. Weichenberger, Cornelis A. Albers, Abtehale Al-Hussani, Folkert W. Asselbergs, Marina Ciullo, Fabrice Danjou, Christian Dina, Tõnu Esko, David M. Evans, Lude Franke, Martin Gögele, Jaana Hartiala, Micha Hersch, Hilma Holm, Jouke-Jan Hottenga, Stavroula Kanoni, Marcus E. Kleber, Vasiliki Lagou, Claudia Langenberg, Lorna M. Lopez, Leo-Pekka Lyytikäinen, Olle Melander, Federico Murgia, Ilja M. Nolte, Paul F. O'Reilly, Sandosh Padmanabhan, Afshin Parsa, Nicola Pirastu, Eleonora Porcu, Laura Portas, Inga Prokopenko, Janina S. Ried, So-Youn Shin, Clara S. Tang, Alexander Teumer, Michela Traglia, Sheila Ulivi, Harm-Jan Westra, Jian Yang, Jing Hua Zhao, Franco Anni, Abdel Abdellaoui, Antony Attwood, Beverley Balkau, Stefania Bandinelli, François Bastardot, Beben Benyamin, Bernhard O. Boehm, William O. Cookson, Debashish Das, Paul I. W. de Bakker, Rudolf A. de Boer, Eco J. C. de Geus, Marleen H. de Moor, Maria Dimitriou, Francisco S. Domingues, Angela Döring, Gunnar Engström, Gudmundur Ingi Eyjolfsson, Luigi Ferrucci, Krista Fischer, Renzo Galanello, Stephen F. Garner, Bernd Genser, Quince D. Gibson, Giorgia Girotto, Daniel Fannar Gudbjartsson, Sarah E. Harris, Anna-Liisa Hartikainen, Claire E. Hastie, Bo Hedblad, Thomas Illig, Jennifer Jolley, Mika Kähönen, Ido P. Kema, John P. Kemp, Liming Liang, Heather Lloyd-Jones, Ruth J. F. Loos, Stuart Meacham, Sarah E. Medland, Christa Meisinger, Yasin Memari, Evelin Mihailov, Kathy Miller, Miriam F. Moffatt, Matthias Nauck, Maria Novatchkova, Teresa Nutile, Isleifur Olafsson, Pall T. Onundarson, Debora Parracciani, Brenda W. Penninx, Lucia Perseu, Antonio Piga, Giorgio Pistis, Anneli Pouta, Ursula Puc, Olli Raitakari, Susan M. Ring, Antonietta Robino, Daniela Ruggiero, Aimo Ruokonen, Aude Saint-Pierre, Cinzia Sala, Andres Salumets, Jennifer Sambrook, Hein Schepers, Carsten Oliver Schmidt, Herman H. W. Silljé, Rob Sladek, Johannes H. Smit, John M. Starr, Jonathan Stephens, Patrick Sulem, Toshiko Tanaka, Unnur Thorsteinsdottir, Vinicius Tragante, Wiek H. van Gilst, L. Joost van Pelt, Dirk J. van Veldhuisen, Uwe Völker, John B. Whitfield, Gonneke Willemsen, Bernhard R. Winkelmann, Gerald Wirnsberger, Ale Algra, Francesco Cucca, Adamo Pio d'Adamo, John Danesh, Ian J. Deary, Anna F. Dominiczak, Paul Elliott, Paolo Fortina, Philippe Froguel, Paolo Gasparini, Andreas Greinacher, Stanley L. Hazen, Marjo-Riitta Jarvelin, Kay Tee Khaw, Terho Lehtimäki, Winfried Maerz, Nicholas G. Martin, Andres Metspalu, Braxton D. Mitchell, Grant W. Montgomery, Carmel Moore, Gerjan Navis, Mario Pirastu, Peter P. Pramstaller, Ramiro Ramirez-Solis, Eric Schadt, James Scott, Alan R. Shuldiner, George Davey Smith, J. Gustav Smith, Harold Snieder, Rossella Sorice, Tim D. Spector, Kari Stefansson, Michael Stumvoll, W. H. Wilson Tang, Daniela Toniolo, Anke Tönjes, Peter M. Visscher, Peter Vollenweider, Nicholas J. Wareham, Bruce H. R. Wolffenbuttel, Dorret I. Boomsma, Jacques S. Beckmann, George V. Dedoussis, Panos Deloukas, Manuel A. Ferreira, Serena Sanna, Manuela Uda, Andrew A. Hicks, Josef Martin Penninger, Christian Gieger, Jaspal S. Kooner, Willem H. Ouwehand, Nicole Soranzo & John C. 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Nature Publishing Group, Nature, Nature, 492, 369-75, Nature, 492, 7429, pp. 369-75
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