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 van 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 S. Kote-Jarai; Kenneth Muir; Nora Pashayan; Jolanta Nickel; Markus M. Nöthen; Annette Vangsted; Niels Frost Andersen; Björn Nilsson; Børge G. Nordestgaard; The Practical Consortium

doi:10.1038/s41467-018-04989-w

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 van 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 BertschPeter 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 S. Kote-Jarai, Kenneth Muir, Nora Pashayan, Jolanta Nickel, Markus M. Nöthen, Annette Vangsted, Niels Frost Andersen, Björn Nilsson, Børge G. Nordestgaard, The Practical Consortium

Department of Clinical Medicine

36 Citations (Scopus)

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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.

Original language	English
Article number	3707
Journal	Nature Communications
Volume	9
Number of pages	10
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-018-04989-w
Publication status	Published - 13 Sept 2018

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Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myelomaFinal published version, 1.09 MBLicence: CC BY

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Went, M., Sud, A., Försti, A., Halvarsson, B. M., Weinhold, N., Kimber, S., van Duin, M., Thorleifsson, G., Holroyd, A., Johnson, D. C., Li, N., Orlando, G., Law, P. J., Ali, M., Chen, B., Mitchell, J. S., Gudbjartsson, D. F., Kuiper, R., Stephens, O. W., ... The Practical Consortium (2018). Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nature Communications, 9, Article 3707. https://doi.org/10.1038/s41467-018-04989-w

Went, M, Sud, A, Försti, A, Halvarsson, BM, Weinhold, N, Kimber, S, van Duin, M, Thorleifsson, G, Holroyd, A, Johnson, DC, Li, N, Orlando, G, Law, PJ, Ali, M, Chen, B, Mitchell, JS, Gudbjartsson, DF, Kuiper, R, Stephens, OW, Bertsch, U, Broderick, P, Campo, C, Bandapalli, OR, Einsele, H, Gregory, WA, Gullberg, U, Hillengass, J, Hoffmann, P, Jackson, GH, Jöckel, KH, Johnsson, E, Kristinsson, SY, Mellqvist, UH, Nahi, H, Easton, D, Pharoah, P, Dunning, A, Peto, J, Canzian, F, Swerdlow, A, Eeles, RA, Kote-Jarai, ZSS, Muir, K, Pashayan, N, Nickel, J, Nöthen, MM, Vangsted, A, Andersen, NF, Nilsson, B, Nordestgaard, BG & The Practical Consortium 2018, 'Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma', Nature Communications, vol. 9, 3707. https://doi.org/10.1038/s41467-018-04989-w

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title = "Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma",

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.",

author = "Molly Went and Amit Sud and Asta F{\"o}rsti and Halvarsson, {Britt Marie} and Niels Weinhold and Scott Kimber and {van Duin}, Mark and Gudmar Thorleifsson and Amy Holroyd and Johnson, {David C.} and Ni Li and Giulia Orlando and Law, {Philip J.} and Mina Ali and Bowang Chen and Mitchell, {Jonathan S.} and Gudbjartsson, {Daniel F.} and Rowan Kuiper and Stephens, {Owen W.} and Uta Bertsch and Peter Broderick and Chiara Campo and Bandapalli, {Obul R.} and Hermann Einsele and Gregory, {Walter A.} and Urban Gullberg and Jens Hillengass and Per Hoffmann and Jackson, {Graham H.} and J{\"o}ckel, {Karl Heinz} and Ellinor Johnsson and Kristinsson, {Sigur{\dh}ur Y.} and Mellqvist, {Ulf Henrik} and Hareth Nahi and Douglas Easton and Paul Pharoah and Alison Dunning and Julian Peto and Federico Canzian and Anthony Swerdlow and Eeles, {Rosalind A.} and Kote-Jarai, {ZSofia S.} and Kenneth Muir and Nora Pashayan and Jolanta Nickel and N{\"o}then, {Markus M.} and Annette Vangsted and Andersen, {Niels Frost} and Bj{\"o}rn Nilsson and Nordestgaard, {B{\o}rge G.} and {The Practical Consortium}",

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T1 - Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

AU - Went, Molly

AU - Sud, Amit

AU - Försti, Asta

AU - Halvarsson, Britt Marie

AU - Weinhold, Niels

AU - Kimber, Scott

AU - van Duin, Mark

AU - Thorleifsson, Gudmar

AU - Holroyd, Amy

AU - Johnson, David C.

AU - Li, Ni

AU - Orlando, Giulia

AU - Law, Philip J.

AU - Ali, Mina

AU - Chen, Bowang

AU - Mitchell, Jonathan S.

AU - Gudbjartsson, Daniel F.

AU - Kuiper, Rowan

AU - Stephens, Owen W.

AU - Bertsch, Uta

AU - Broderick, Peter

AU - Campo, Chiara

AU - Bandapalli, Obul R.

AU - Einsele, Hermann

AU - Gregory, Walter A.

AU - Gullberg, Urban

AU - Hillengass, Jens

AU - Hoffmann, Per

AU - Jackson, Graham H.

AU - Jöckel, Karl Heinz

AU - Johnsson, Ellinor

AU - Kristinsson, Sigurður Y.

AU - Mellqvist, Ulf Henrik

AU - Nahi, Hareth

AU - Easton, Douglas

AU - Pharoah, Paul

AU - Dunning, Alison

AU - Peto, Julian

AU - Canzian, Federico

AU - Swerdlow, Anthony

AU - Eeles, Rosalind A.

AU - Kote-Jarai, ZSofia S.

AU - Muir, Kenneth

AU - Pashayan, Nora

AU - Nickel, Jolanta

AU - Nöthen, Markus M.

AU - Vangsted, Annette

AU - Andersen, Niels Frost

AU - Nilsson, Björn

AU - Nordestgaard, Børge G.

AU - The Practical Consortium

PY - 2018/9/13

Y1 - 2018/9/13

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-018-04989-w

DO - 10.1038/s41467-018-04989-w

M3 - Journal article

C2 - 30213928

AN - SCOPUS:85053336514

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

M1 - 3707

ER -

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

Abstract

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