Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

Jonathan S. Mitchell; Ni Li; Niels Weinhold; Asta Försti; Mina Ali; Mark Van Duin; Gudmar Thorleifsson; David C. Johnson; Bowang Chen; Britt Marie Halvarsson; Daniel F. Gudbjartsson; Rowan Kuiper; Owen W. Stephens; Uta Bertsch; Peter Broderick; Chiara Campo; Hermann Einsele; Walter A. Gregory; Urban Gullberg; Marc Henrion; Jens Hillengass; Per Hoffmann; Graham H. Jackson; Ellinor Johnsson; Magnus Jöud; Sigurur Y. Kristinsson; Stig Lenhoff; Oleg Lenive; Ulf Henrik Mellqvist; Gabriele Migliorini; Hareth Nahi; Sven Nelander; Jolanta Nickel; Markus M. Nöthen; Thorunn Rafnar; Fiona M. Ross; Miguel Inacio Da Silva Filho; Bhairavi Swaminathan; Hauke Thomsen; Ingemar Turesson; Annette Vangsted; Ulla Vogel; Anders Waage; Brian A. Walker; Anna Karin Wihlborg; Annemiek Broyl; Faith E. Davies; Unnur Thorsteinsdottir; Christian Langer; Markus Hansson; Martin Kaiser; Pieter Sonneveld; Kari Stefansson; Gareth J. Morgan; Hartmut Goldschmidt; Kari Hemminki; Björn Nilsson; Richard S. Houlston

doi:10.1038/ncomms12050

Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

Jonathan S. Mitchell
, Ni Li
, Niels Weinhold
, Asta Försti
, Mina Ali
, Mark Van Duin
, Gudmar Thorleifsson
, David C. Johnson
, Bowang Chen
, Britt Marie Halvarsson
, Daniel F. Gudbjartsson
, Rowan Kuiper
, Owen W. Stephens
, Uta Bertsch
, Peter Broderick
, Chiara Campo
, Hermann Einsele
, Walter A. Gregory
, Urban Gullberg
, Marc Henrion

Jens Hillengass, Per Hoffmann, Graham H. Jackson, Ellinor Johnsson, Magnus Jöud, Sigurur Y. Kristinsson, Stig Lenhoff, Oleg Lenive, Ulf Henrik Mellqvist, Gabriele Migliorini, Hareth Nahi, Sven Nelander, Jolanta Nickel, Markus M. Nöthen, Thorunn Rafnar, Fiona M. Ross, Miguel Inacio Da Silva Filho, Bhairavi Swaminathan, Hauke Thomsen, Ingemar Turesson, Annette Vangsted, Ulla Vogel, Anders Waage, Brian A. Walker, Anna Karin Wihlborg, Annemiek Broyl, Faith E. Davies, Unnur Thorsteinsdottir, Christian Langer, Markus Hansson, Martin Kaiser, Pieter Sonneveld, Kari Stefansson, Gareth J. Morgan, Hartmut Goldschmidt, Kari Hemminki, Björn Nilsson, Richard S. Houlston

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

152 Scopus citations

Abstract

Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10^-8), 6q21 (rs9372120, P=9.09 × 10^-15), 7q36.1 (rs7781265, P=9.71 × 10^-9), 8q24.21 (rs1948915, P=4.20 × 10^-11), 9p21.3 (rs2811710, P=1.72 × 10^-13), 10p12.1 (rs2790457, P=1.77 × 10^-8), 16q23.1 (rs7193541, P=5.00 × 10^-12) and 20q13.13 (rs6066835, P=1.36 × 10^-13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.

Original language	English
Article number	12050
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12050
State	Published - 1 Jul 2016
Externally published	Yes

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Mitchell, J. S., Li, N., Weinhold, N., Försti, A., Ali, M., Van Duin, M., Thorleifsson, G., Johnson, D. C., Chen, B., Halvarsson, B. M., Gudbjartsson, D. F., Kuiper, R., Stephens, O. W., Bertsch, U., Broderick, P., Campo, C., Einsele, H., Gregory, W. A., Gullberg, U., ... Houlston, R. S. (2016). Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nature Communications, 7, Article 12050. https://doi.org/10.1038/ncomms12050

@article{80bd3534d84c4d169c576004eba15e43,

title = "Genome-wide association study identifies multiple susceptibility loci for multiple myeloma",

abstract = "Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 {\texttimes} 10-8), 6q21 (rs9372120, P=9.09 {\texttimes} 10-15), 7q36.1 (rs7781265, P=9.71 {\texttimes} 10-9), 8q24.21 (rs1948915, P=4.20 {\texttimes} 10-11), 9p21.3 (rs2811710, P=1.72 {\texttimes} 10-13), 10p12.1 (rs2790457, P=1.77 {\texttimes} 10-8), 16q23.1 (rs7193541, P=5.00 {\texttimes} 10-12) and 20q13.13 (rs6066835, P=1.36 {\texttimes} 10-13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.",

author = "Mitchell, \{Jonathan S.\} and Ni Li and Niels Weinhold and Asta F{\"o}rsti and Mina Ali and \{Van Duin\}, Mark and Gudmar Thorleifsson and Johnson, \{David C.\} and Bowang Chen and Halvarsson, \{Britt Marie\} and Gudbjartsson, \{Daniel F.\} and Rowan Kuiper and Stephens, \{Owen W.\} and Uta Bertsch and Peter Broderick and Chiara Campo and Hermann Einsele and Gregory, \{Walter A.\} and Urban Gullberg and Marc Henrion and Jens Hillengass and Per Hoffmann and Jackson, \{Graham H.\} and Ellinor Johnsson and Magnus J{\"o}ud and Kristinsson, \{Sigurur Y.\} and Stig Lenhoff and Oleg Lenive and Mellqvist, \{Ulf Henrik\} and Gabriele Migliorini and Hareth Nahi and Sven Nelander and Jolanta Nickel and N{\"o}then, \{Markus M.\} and Thorunn Rafnar and Ross, \{Fiona M.\} and \{Da Silva Filho\}, \{Miguel Inacio\} and Bhairavi Swaminathan and Hauke Thomsen and Ingemar Turesson and Annette Vangsted and Ulla Vogel 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 Martin Kaiser and Pieter Sonneveld and Kari Stefansson and Morgan, \{Gareth J.\} and Hartmut Goldschmidt and Kari Hemminki and Bj{\"o}rn Nilsson and Houlston, \{Richard S.\}",

note = "Funding Information: In the United Kingdom, Myeloma UK and Bloodwise provided principal funding. Additional funding was provided by Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and The Rosetrees Trust. This study made use of genotyping data on the 1958 Birth Cohort generated by the Wellcome Trust Sanger Institute (http:// www.wtccc.org.uk). We are grateful to all investigators who contributed to NSCCG and GELCAPS, from which controls in the replication were drawn. We also thank the staff of the CTRU University of Leeds and the NCRI haematology Clinical Studies Group. The US GWAS was supported by a grant from the National Institutes of Health (P01CA055819). The German study was supported by the Dietmar-Hopp-Stiftung, Germany, the German Cancer Aid (110,131), the German Ministry of Education and Science (CLIOMMICS 01ZX1309), the German Research Council (DFG; Project SI 236/ 8-1, SI236/9-1, ER 155/6-1 and the DFG CRU 216) and the Multiple Myeloma Research Foundation. The patients were collected by the GMMG and DSMM studies. The German GWAS made use of genotyping data from the population-based HNR study, which is supported by the Heinz Nixdorf Foundation (Germany). The genotyping of the Illumina HumanOmni-1 Quad BeadChips of the HNR subjects was financed by the German Center for Neurodegenerative Disorders (DZNE), Bonn. We are grateful to all investigators who contributed to the generation of this data set. The German replication controls were collected by Peter Bugert, Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-W{\"u}rttemberg-Hessen, Mannheim, Germany. This work was supported by research grants from the Swedish Foundation for Strategic Research (KF10-0009), the Marianne and Marcus Wallenberg Foundation (2010.0112), the Knut and Alice Wallenberg Foundation (2012.0193), the Swedish Research Council (2012-1753), the Royal Swedish Academy of Science, ALF grants to the University and Regional Laboratories (Labmedicin Sk{\aa}ne), the Siv-Inger and Per-Erik Andersson Foundation, the Medical Faculty at Lund University and the Swedish Society of Medicine. We thank J{\"o}rgen Adolfsson, Tomas Axelsson, Anna Collin, Ildik{\'o} Frigyesi, Patrik Magnusson, Bertil Johansson, Jan Westin and Helga{\"O}gmundsd{\'o}ttir for their assistance. We are indebted to the clinicians who contributed samples to Swedish, Icelandic, Norwegian and Danish biobanks. We are indebted to the patients and other individuals who participated in the project.",

year = "2016",

month = jul,

day = "1",

doi = "10.1038/ncomms12050",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Mitchell, JS, Li, N, Weinhold, N, Försti, A, Ali, M, Van Duin, M, Thorleifsson, G, Johnson, DC, Chen, B, Halvarsson, BM, Gudbjartsson, DF, Kuiper, R, Stephens, OW, Bertsch, U, Broderick, P, Campo, C, Einsele, H, Gregory, WA, Gullberg, U, Henrion, M, Hillengass, J, Hoffmann, P, Jackson, GH, Johnsson, E, Jöud, M, Kristinsson, SY, Lenhoff, S, Lenive, O, Mellqvist, UH, Migliorini, G, Nahi, H, Nelander, S, Nickel, J, Nöthen, MM, Rafnar, T, Ross, FM, Da Silva Filho, MI, Swaminathan, B, Thomsen, H, Turesson, I, Vangsted, A, Vogel, U, Waage, A, Walker, BA, Wihlborg, AK, Broyl, A, Davies, FE, Thorsteinsdottir, U, Langer, C, Hansson, M, Kaiser, M, Sonneveld, P, Stefansson, K, Morgan, GJ, Goldschmidt, H, Hemminki, K, Nilsson, B & Houlston, RS 2016, 'Genome-wide association study identifies multiple susceptibility loci for multiple myeloma', Nature Communications, vol. 7, 12050. https://doi.org/10.1038/ncomms12050

TY - JOUR

T1 - Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

AU - Mitchell, Jonathan S.

AU - Li, Ni

AU - Weinhold, Niels

AU - Försti, Asta

AU - Ali, Mina

AU - Van Duin, Mark

AU - Thorleifsson, Gudmar

AU - Johnson, David C.

AU - Chen, Bowang

AU - Halvarsson, Britt Marie

AU - Gudbjartsson, Daniel F.

AU - Kuiper, Rowan

AU - Stephens, Owen W.

AU - Bertsch, Uta

AU - Broderick, Peter

AU - Campo, Chiara

AU - Einsele, Hermann

AU - Gregory, Walter A.

AU - Gullberg, Urban

AU - Henrion, Marc

AU - Hillengass, Jens

AU - Hoffmann, Per

AU - Jackson, Graham H.

AU - Johnsson, Ellinor

AU - Jöud, Magnus

AU - Kristinsson, Sigurur Y.

AU - Lenhoff, Stig

AU - Lenive, Oleg

AU - Mellqvist, Ulf Henrik

AU - Migliorini, Gabriele

AU - Nahi, Hareth

AU - Nelander, Sven

AU - Nickel, Jolanta

AU - Nöthen, Markus M.

AU - Rafnar, Thorunn

AU - Ross, Fiona M.

AU - Da Silva Filho, Miguel Inacio

AU - Swaminathan, Bhairavi

AU - Thomsen, Hauke

AU - Turesson, Ingemar

AU - Vangsted, Annette

AU - Vogel, Ulla

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 - Kaiser, Martin

AU - Sonneveld, Pieter

AU - Stefansson, Kari

AU - Morgan, Gareth J.

AU - Goldschmidt, Hartmut

AU - Hemminki, Kari

AU - Nilsson, Björn

AU - Houlston, Richard S.

N1 - Funding Information: In the United Kingdom, Myeloma UK and Bloodwise provided principal funding. Additional funding was provided by Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and The Rosetrees Trust. This study made use of genotyping data on the 1958 Birth Cohort generated by the Wellcome Trust Sanger Institute (http:// www.wtccc.org.uk). We are grateful to all investigators who contributed to NSCCG and GELCAPS, from which controls in the replication were drawn. We also thank the staff of the CTRU University of Leeds and the NCRI haematology Clinical Studies Group. The US GWAS was supported by a grant from the National Institutes of Health (P01CA055819). The German study was supported by the Dietmar-Hopp-Stiftung, Germany, the German Cancer Aid (110,131), the German Ministry of Education and Science (CLIOMMICS 01ZX1309), the German Research Council (DFG; Project SI 236/ 8-1, SI236/9-1, ER 155/6-1 and the DFG CRU 216) and the Multiple Myeloma Research Foundation. The patients were collected by the GMMG and DSMM studies. The German GWAS made use of genotyping data from the population-based HNR study, which is supported by the Heinz Nixdorf Foundation (Germany). The genotyping of the Illumina HumanOmni-1 Quad BeadChips of the HNR subjects was financed by the German Center for Neurodegenerative Disorders (DZNE), Bonn. We are grateful to all investigators who contributed to the generation of this data set. The German replication controls were collected by Peter Bugert, Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg-Hessen, Mannheim, Germany. This work was supported by research grants from the Swedish Foundation for Strategic Research (KF10-0009), the Marianne and Marcus Wallenberg Foundation (2010.0112), the Knut and Alice Wallenberg Foundation (2012.0193), the Swedish Research Council (2012-1753), the Royal Swedish Academy of Science, ALF grants to the University and Regional Laboratories (Labmedicin Skåne), the Siv-Inger and Per-Erik Andersson Foundation, the Medical Faculty at Lund University and the Swedish Society of Medicine. We thank Jörgen Adolfsson, Tomas Axelsson, Anna Collin, Ildikó Frigyesi, Patrik Magnusson, Bertil Johansson, Jan Westin and HelgaÖgmundsdóttir for their assistance. We are indebted to the clinicians who contributed samples to Swedish, Icelandic, Norwegian and Danish biobanks. We are indebted to the patients and other individuals who participated in the project.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10-8), 6q21 (rs9372120, P=9.09 × 10-15), 7q36.1 (rs7781265, P=9.71 × 10-9), 8q24.21 (rs1948915, P=4.20 × 10-11), 9p21.3 (rs2811710, P=1.72 × 10-13), 10p12.1 (rs2790457, P=1.77 × 10-8), 16q23.1 (rs7193541, P=5.00 × 10-12) and 20q13.13 (rs6066835, P=1.36 × 10-13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.

AB - Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10-8), 6q21 (rs9372120, P=9.09 × 10-15), 7q36.1 (rs7781265, P=9.71 × 10-9), 8q24.21 (rs1948915, P=4.20 × 10-11), 9p21.3 (rs2811710, P=1.72 × 10-13), 10p12.1 (rs2790457, P=1.77 × 10-8), 16q23.1 (rs7193541, P=5.00 × 10-12) and 20q13.13 (rs6066835, P=1.36 × 10-13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.

UR - https://www.scopus.com/pages/publications/84977123396

U2 - 10.1038/ncomms12050

DO - 10.1038/ncomms12050

M3 - Article

C2 - 27363682

AN - SCOPUS:84977123396

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 12050

ER -

Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

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