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; The PRACTICAL consortium; Jyotsna Batra

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, The PRACTICAL consortium, Jyotsna Batra

Research output: Contribution to journal › Article › Research › peer-review

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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
Pages (from-to)	1-10
Number of pages	10
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04989-w
Publication status	Published - 1 Dec 2018
Externally published	Yes

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Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myelomaFinal published version, 1.12 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., The PRACTICAL consortium, & Batra, J. (2018). Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nature Communications, 9(1), 1-10. Article 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 {The PRACTICAL consortium} 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 Thorunn Rafnar and Ross, {Fiona M.} and {da Silva Filho}, {Miguel Inacio} and Hauke Thomsen and Ingemar Turesson and Annette Vangsted and Andersen, {Niels Frost} and Anders Waage and Walker, {Brian A.} and Wihlborg, {Anna Karin} and Annemiek Broyl and Davies, {Faith E.} and Unnur Thorsteinsdottir and Christian Langer and Markus Hansson and Hartmut Goldschmidt and Martin Kaiser and Pieter Sonneveld and Kari Stefansson and Morgan, {Gareth J.} and Kari Hemminki and Bj{\"o}rn Nilsson and Houlston, {Richard S.} and Henderson, {Brian E.} and Haiman, {Christopher A.} and Sara Benlloch and Schumacher, {Fredrick R.} and Olama, {Ali Amin Al} and Berndt, {Sonja I.} and Conti, {David V.} and Fredrik Wiklund and Stephen Chanock and Stevens, {Victoria L.} and Tangen, {Catherine M.} and Jyotsna Batra and Judith Clements and Henrik Gronberg and Johanna Schleutker and Demetrius Albanes and Stephanie Weinstein and Alicja Wolk and Catharine West and Lorelei Mucci and G{\'e}raldine Cancel-Tassin and Stella Koutros and Sorensen, {Karina Dalsgaard} and Grindedal, {Eli Marie} and Neal, {David E.} and Hamdy, {Freddie C.} and Donovan, {Jenny L.} and Travis, {Ruth C.} and Hamilton, {Robert J.} and Ingles, {Sue Ann} and Barry Rosenstein and Lu, {Yong Jie} and Giles, {Graham G.} and Kibel, {Adam S.} and Ana Vega and Manolis Kogevinas and Penney, {Kathryn L.} and Park, {Jong Y.} and Stanford, {Janet L.} and Cezary Cybulski and Nordestgaard, {B{\o}rge G.} and Hermann Brenner and Christiane Maier and Jeri Kim and John, {Esther M.} and Teixeira, {Manuel R.} and Neuhausen, {Susan L.} and {De Ruyck}, Kim and Azad Razack and Newcomb, {Lisa F.} and Davor Lessel and Radka Kaneva and Nawaid Usmani and Frank Claessens and Townsend, {Paul A.} and Dominguez, {Manuela Gago} and Roobol, {Monique J.} and Florence Menegaux and Khaw, {Kay Tee} and Lisa Cannon-Albright and Hardev Pandha and Thibodeau, {Stephen N.}",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

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doi = "10.1038/s41467-018-04989-w",

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Went, M, Sud, A, Försti, A, Halvarsson, BM, Weinhold, N, Kimber, S, van Duin, M, Thorleifsson, G, Holroyd, A, Johnson, DC, The PRACTICAL consortium & Batra, J 2018, 'Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma', Nature Communications, vol. 9, no. 1, 3707, pp. 1-10. https://doi.org/10.1038/s41467-018-04989-w

TY - JOUR

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 - The PRACTICAL consortium

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 - Rafnar, Thorunn

AU - Ross, Fiona M.

AU - da Silva Filho, Miguel Inacio

AU - Thomsen, Hauke

AU - Turesson, Ingemar

AU - Vangsted, Annette

AU - Andersen, Niels Frost

AU - Waage, Anders

AU - Walker, Brian A.

AU - Wihlborg, Anna Karin

AU - Broyl, Annemiek

AU - Davies, Faith E.

AU - Thorsteinsdottir, Unnur

AU - Langer, Christian

AU - Hansson, Markus

AU - Goldschmidt, Hartmut

AU - Kaiser, Martin

AU - Sonneveld, Pieter

AU - Stefansson, Kari

AU - Morgan, Gareth J.

AU - Hemminki, Kari

AU - Nilsson, Björn

AU - Houlston, Richard S.

AU - Henderson, Brian E.

AU - Haiman, Christopher A.

AU - Benlloch, Sara

AU - Schumacher, Fredrick R.

AU - Olama, Ali Amin Al

AU - Berndt, Sonja I.

AU - Conti, David V.

AU - Wiklund, Fredrik

AU - Chanock, Stephen

AU - Stevens, Victoria L.

AU - Tangen, Catherine M.

AU - Batra, Jyotsna

AU - Clements, Judith

AU - Gronberg, Henrik

AU - Schleutker, Johanna

AU - Albanes, Demetrius

AU - Weinstein, Stephanie

AU - Wolk, Alicja

AU - West, Catharine

AU - Mucci, Lorelei

AU - Cancel-Tassin, Géraldine

AU - Koutros, Stella

AU - Sorensen, Karina Dalsgaard

AU - Grindedal, Eli Marie

AU - Neal, David E.

AU - Hamdy, Freddie C.

AU - Donovan, Jenny L.

AU - Travis, Ruth C.

AU - Hamilton, Robert J.

AU - Ingles, Sue Ann

AU - Rosenstein, Barry

AU - Lu, Yong Jie

AU - Giles, Graham G.

AU - Kibel, Adam S.

AU - Vega, Ana

AU - Kogevinas, Manolis

AU - Penney, Kathryn L.

AU - Park, Jong Y.

AU - Stanford, Janet L.

AU - Cybulski, Cezary

AU - Nordestgaard, Børge G.

AU - Brenner, Hermann

AU - Maier, Christiane

AU - Kim, Jeri

AU - John, Esther M.

AU - Teixeira, Manuel R.

AU - Neuhausen, Susan L.

AU - De Ruyck, Kim

AU - Razack, Azad

AU - Newcomb, Lisa F.

AU - Lessel, Davor

AU - Kaneva, Radka

AU - Usmani, Nawaid

AU - Claessens, Frank

AU - Townsend, Paul A.

AU - Dominguez, Manuela Gago

AU - Roobol, Monique J.

AU - Menegaux, Florence

AU - Khaw, Kay Tee

AU - Cannon-Albright, Lisa

AU - Pandha, Hardev

AU - Thibodeau, Stephen N.

PY - 2018/12/1

Y1 - 2018/12/1

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.

UR - http://www.scopus.com/inward/record.url?scp=85053336514&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-04989-w

DO - 10.1038/s41467-018-04989-w

M3 - Article

C2 - 30213928

AN - SCOPUS:85053336514

SN - 2041-1723

VL - 9

SP - 1

EP - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3707

ER -

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

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

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