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

Molly Went, Amit Sud, Asta Försti, Britt-Marie Halvarsson, Niels Weinhold, Scott Kimber, Mark Duin, Gudmar Thorleifsson, Amy Holroyd, David C. Johnson, Ni Li, Giulia Orlando, Philip J. Law, Mina Ali, Bowang Chen, Jonathan S. Mitchell, Daniel F. Gudbjartsson, Rowan Kuiper, Owen W. Stephens, Uta Bertsch, Peter Broderick, Chiara Campo, Obul R Bandapalli, Hermann Einsele, Walter A. Gregory, Urban Gullberg, Jens Hillengass, Per Hoffmann, Graham H. Jackson, Karl-Heinz Jöckel, Ellinor Johnsson, Sigurður Y. Kristinsson, Ulf-Henrik Mellqvist, Hareth Nahi, Douglas Easton, Paul Pharoah, Alison Dunning, Julian Peto, Federico Canzian, Anthony Swerdlow, Rosalind A. Eeles, ZSofia Kote-Jarai, Kenneth Muir, Nora Pashayan, Jolanta Nickel, Markus M. Nöthen, Thorunn Rafnar, Fiona M. Ross, Miguel Inacio Silva Filho, Hauke Thomsen, Ingemar Turesson, Annette Vangsted, Niels Frost Andersen, Anders Waage, Brian A. Walker, Anna-Karin Wihlborg, Annemiek Broyl, Faith E. Davies, Unnur Thorsteinsdottir, Christian Langer, Markus Hansson, Hartmut Goldschmidt, Martin Kaiser, Pieter Sonneveld, Kari Stefansson, Gareth J. Morgan, Kari Hemminki (), Björn Nilsson () and Richard S. Houlston ()
Additional contact information
Molly Went: The Institute of Cancer Research
Amit Sud: The Institute of Cancer Research
Asta Försti: German Cancer Research Center
Britt-Marie Halvarsson: Lund University
Niels Weinhold: University of Arkansas for Medical Sciences
Scott Kimber: The Institute of Cancer Research
Mark Duin: Erasmus MC Cancer Institute
Gudmar Thorleifsson: deCODE Genetics
Amy Holroyd: The Institute of Cancer Research
David C. Johnson: The Institute of Cancer Research
Ni Li: The Institute of Cancer Research
Giulia Orlando: The Institute of Cancer Research
Philip J. Law: The Institute of Cancer Research
Mina Ali: Lund University
Bowang Chen: German Cancer Research Center
Jonathan S. Mitchell: The Institute of Cancer Research
Daniel F. Gudbjartsson: deCODE Genetics
Rowan Kuiper: Erasmus MC Cancer Institute
Owen W. Stephens: University of Arkansas for Medical Sciences
Uta Bertsch: German Cancer Research Center
Peter Broderick: The Institute of Cancer Research
Chiara Campo: German Cancer Research Center
Obul R Bandapalli: German Cancer Research Center
Hermann Einsele: University Clinic of Würzburg
Walter A. Gregory: University of Leeds
Urban Gullberg: Lund University
Jens Hillengass: University of Heidelberg
Per Hoffmann: University of Bonn
Graham H. Jackson: Royal Victoria Infirmary
Karl-Heinz Jöckel: University of Duisburg–Essen
Ellinor Johnsson: Lund University
Sigurður Y. Kristinsson: National University Hospital of Iceland
Ulf-Henrik Mellqvist: Sahlgrenska University Hospital
Hareth Nahi: Center for Hematology and Regenerative Medicine
Douglas Easton: University of Cambridge
Paul Pharoah: University of Cambridge
Alison Dunning: University of Cambridge
Julian Peto: London School of Hygiene and Tropical Medicine
Federico Canzian: German Cancer Research Center (DKFZ)
Anthony Swerdlow: The Institute of Cancer Research
Rosalind A. Eeles: The Institute of Cancer Research
ZSofia Kote-Jarai: The Institute of Cancer Research
Kenneth Muir: University of Manchester
Nora Pashayan: University of Cambridge
Jolanta Nickel: University of Heidelberg
Markus M. Nöthen: University of Bonn
Thorunn Rafnar: deCODE Genetics
Fiona M. Ross: University of Southampton
Miguel Inacio Silva Filho: German Cancer Research Center
Hauke Thomsen: German Cancer Research Center
Ingemar Turesson: Hematology Clinic, Skåne University Hospital
Annette Vangsted: University Hospital of Copenhagen at Rigshospitalet
Niels Frost Andersen: Aarhus University Hospital
Anders Waage: Norwegian University of Science and Technology
Brian A. Walker: University of Arkansas for Medical Sciences
Anna-Karin Wihlborg: Lund University
Annemiek Broyl: Erasmus MC Cancer Institute
Faith E. Davies: University of Arkansas for Medical Sciences
Unnur Thorsteinsdottir: deCODE Genetics
Christian Langer: University of Ulm
Markus Hansson: Lund University
Hartmut Goldschmidt: University of Heidelberg
Martin Kaiser: The Institute of Cancer Research
Pieter Sonneveld: Erasmus MC Cancer Institute
Kari Stefansson: deCODE Genetics
Gareth J. Morgan: University of Arkansas for Medical Sciences
Kari Hemminki: German Cancer Research Center
Björn Nilsson: Lund University
Richard S. Houlston: The Institute of Cancer Research

Nature Communications, 2018, vol. 9, issue 1, 1-10

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04989-w

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