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Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma
Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.

Went, Molly
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Sud, Amit
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Försti, Asta
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Halvarsson, Britt Marie
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Weinhold, Niels
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Kimber, Scott
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van Duin, Mark
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Thorleifsson, Gudmar
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Holroyd, Amy
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Johnson, David C.
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Li, Ni
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Orlando, Giulia
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Law, Philip J.
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Ali, Mina
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Chen, Bowang
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Broderick, Peter
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Campo, Chiara
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Einsele, Hermann
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Jackson, Graham H.
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Jöckel, Karl Heinz
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Johnsson, Ellinor
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Kristinsson, Sigurður Y.
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Mellqvist, Ulf Henrik
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Nahi, Hareth
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Easton, Douglas
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Pharoah, Paul
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Dunning, Alison
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Peto, Julian
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Canzian, Federico
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Swerdlow, Anthony
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Eeles, Rosalind A.
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Kote-Jarai, ZSofia S.
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Muir, Kenneth
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Pashayan, Nora
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Nickel, Jolanta
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Nöthen, Markus M.
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Rafnar, Thorunn
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Ross, Fiona M.
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da Silva Filho, Miguel Inacio
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Townsend, Paul A.
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The PRACTICAL consortium
Went, Molly
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Sud, Amit
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Försti, Asta
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Halvarsson, Britt Marie
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Weinhold, Niels
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Kimber, Scott
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van Duin, Mark
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Thorleifsson, Gudmar
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Holroyd, Amy
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Johnson, David C.
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Li, Ni
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Orlando, Giulia
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Law, Philip J.
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Ali, Mina
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Chen, Bowang
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Mitchell, Jonathan S.
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Gudbjartsson, Daniel F.
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Kuiper, Rowan
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Stephens, Owen W.
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Bertsch, Uta
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Broderick, Peter
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Campo, Chiara
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Hillengass, Jens
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Hoffmann, Per
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Jackson, Graham H.
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Jöckel, Karl Heinz
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Johnsson, Ellinor
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Kristinsson, Sigurður Y.
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Mellqvist, Ulf Henrik
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Nahi, Hareth
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Easton, Douglas
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Pharoah, Paul
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Dunning, Alison
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Peto, Julian
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Canzian, Federico
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Swerdlow, Anthony
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Eeles, Rosalind A.
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Kote-Jarai, ZSofia S.
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Muir, Kenneth
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Pashayan, Nora
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Nickel, Jolanta
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Nöthen, Markus M.
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Rafnar, Thorunn
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Ross, Fiona M.
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da Silva Filho, Miguel Inacio
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Townsend, Paul A.
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Went, Molly, Sud, Amit, Försti, Asta, Halvarsson, Britt Marie, Weinhold, Niels, Kimber, Scott, van Duin, Mark, Thorleifsson, Gudmar, Holroyd, Amy, Johnson, David C., Li, Ni, Orlando, Giulia, Law, Philip J., Ali, Mina, Chen, Bowang, Mitchell, Jonathan S., Gudbjartsson, Daniel F., Kuiper, Rowan, Stephens, Owen W., Bertsch, Uta, Broderick, Peter, Campo, Chiara, Bandapalli, Obul R., Einsele, Hermann, Gregory, Walter A., Gullberg, Urban, Hillengass, Jens, Hoffmann, Per, Jackson, Graham H., Jöckel, Karl Heinz, Johnsson, Ellinor, Kristinsson, Sigurður Y., Mellqvist, Ulf Henrik, Nahi, Hareth, Easton, Douglas, Pharoah, Paul, Dunning, Alison, Peto, Julian, Canzian, Federico, Swerdlow, Anthony, Eeles, Rosalind A., Kote-Jarai, ZSofia S., Muir, Kenneth, Pashayan, Nora, Nickel, Jolanta, Nöthen, Markus M., Rafnar, Thorunn, Ross, Fiona M., da Silva Filho, Miguel Inacio and Townsend, Paul A. , The PRACTICAL consortium (2018) Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nature Communications, 9 (1), [3707]. (doi:10.1038/s41467-018-04989-w).

Record type: Article

Abstract

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.

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e-pub ahead of print date: 13 September 2018
Published date: 1 December 2018

Identifiers

Local EPrints ID: 423658
URI: http://eprints.soton.ac.uk/id/eprint/423658
PURE UUID: a5c01eee-da04-426e-98f4-a369ccbaa344

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Date deposited: 27 Sep 2018 16:30
Last modified: 16 Dec 2019 17:58

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Contributors

Author: Molly Went
Author: Amit Sud
Author: Asta Försti
Author: Britt Marie Halvarsson
Author: Niels Weinhold
Author: Scott Kimber
Author: Mark van Duin
Author: Gudmar Thorleifsson
Author: Amy Holroyd
Author: David C. Johnson
Author: Ni Li
Author: Giulia Orlando
Author: Philip J. Law
Author: Mina Ali
Author: Bowang Chen
Author: Jonathan S. Mitchell
Author: Daniel F. Gudbjartsson
Author: Rowan Kuiper
Author: Owen W. Stephens
Author: Uta Bertsch
Author: Peter Broderick
Author: Chiara Campo
Author: Obul R. Bandapalli
Author: Hermann Einsele
Author: Walter A. Gregory
Author: Urban Gullberg
Author: Jens Hillengass
Author: Per Hoffmann
Author: Graham H. Jackson
Author: Karl Heinz Jöckel
Author: Ellinor Johnsson
Author: Sigurður Y. Kristinsson
Author: Ulf Henrik Mellqvist
Author: Hareth Nahi
Author: Douglas Easton
Author: Paul Pharoah
Author: Alison Dunning
Author: Julian Peto
Author: Federico Canzian
Author: Anthony Swerdlow
Author: Rosalind A. Eeles
Author: ZSofia S. Kote-Jarai
Author: Kenneth Muir
Author: Nora Pashayan
Author: Jolanta Nickel
Author: Markus M. Nöthen
Author: Thorunn Rafnar
Author: Fiona M. Ross
Author: Miguel Inacio da Silva Filho
Author: Paul A. Townsend
Corporate Author: The PRACTICAL consortium

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