Meta-Analysis

. 2018 Sep 13;9(1):3707.

doi: 10.1038/s41467-018-04989-w.

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

Molly Went¹, Amit Sud¹, Asta Försti^{2

3}, Britt-Marie Halvarsson⁴, Niels Weinhold^{5

6}, Scott Kimber⁷, Mark van Duin⁸, Gudmar Thorleifsson⁹, Amy Holroyd¹, David C Johnson⁷, Ni Li¹, Giulia Orlando¹, Philip J Law¹, Mina Ali⁴, Bowang Chen², Jonathan S Mitchell¹, Daniel F Gudbjartsson^{9

10}, Rowan Kuiper⁸, Owen W Stephens⁵, Uta Bertsch^{2

11}, Peter Broderick¹, Chiara Campo², Obul R Bandapalli², Hermann Einsele¹², Walter A Gregory¹³, Urban Gullberg⁴, Jens Hillengass⁶, Per Hoffmann^{14

15}, Graham H Jackson¹⁶, Karl-Heinz Jöckel¹⁷, Ellinor Johnsson⁴, Sigurður Y Kristinsson¹⁸, Ulf-Henrik Mellqvist¹⁹, Hareth Nahi²⁰, Douglas Easton^{21

22}, Paul Pharoah^{21

22}, Alison Dunning²¹, Julian Peto²³, Federico Canzian²⁴, Anthony Swerdlow^{1

25}, Rosalind A Eeles^{1

26}, ZSofia Kote-Jarai¹, Kenneth Muir^{27

28}, Nora Pashayan^{21

29}, Jolanta Nickel⁶, Markus M Nöthen^{14

30}, Thorunn Rafnar⁹, Fiona M Ross³¹, Miguel Inacio da Silva Filho², Hauke Thomsen², Ingemar Turesson³², Annette Vangsted³³, Niels Frost Andersen³⁴, Anders Waage³⁵, Brian A Walker⁵, Anna-Karin Wihlborg⁴, Annemiek Broyl⁸, Faith E Davies⁵, Unnur Thorsteinsdottir^{9

36}, Christian Langer³⁷, Markus Hansson^{4

32}, Hartmut Goldschmidt^{6

11}, Martin Kaiser⁷, Pieter Sonneveld⁸, Kari Stefansson⁹, Gareth J Morgan⁵, Kari Hemminki^{38

39}, Björn Nilsson^{40

41}, Richard S Houlston^{42

43}; PRACTICAL consortium

Collaborators, Affiliations

Collaborators

PRACTICAL consortium:
Brian E Henderson, Christopher A Haiman, Sara Benlloch, Fredrick R Schumacher, Ali Amin Al Olama, Sonja I Berndt, David V Conti, Fredrik Wiklund, Stephen Chanock, Victoria L Stevens, Catherine M Tangen, Jyotsna Batra, Judith Clements, Henrik Gronberg, Johanna Schleutker, Demetrius Albanes, Stephanie Weinstein, Alicja Wolk, Catharine West, Lorelei Mucci, Géraldine Cancel-Tassin, Stella Koutros, Karina Dalsgaard Sorensen, Eli Marie Grindedal, David E Neal, Freddie C Hamdy, Jenny L Donovan, Ruth C Travis, Robert J Hamilton, Sue Ann Ingles, Barry Rosenstein, Yong-Jie Lu, Graham G Giles, Adam S Kibel, Ana Vega, Manolis Kogevinas, Kathryn L Penney, Jong Y Park, Janet L Stanford, Cezary Cybulski, Børge G Nordestgaard, Hermann Brenner, Christiane Maier, Jeri Kim, Esther M John, Manuel R Teixeira, Susan L Neuhausen, Kim De Ruyck, Azad Razack, Lisa F Newcomb, Davor Lessel, Radka Kaneva, Nawaid Usmani, Frank Claessens, Paul A Townsend, Manuela Gago-Dominguez, Monique J Roobol, Florence Menegaux, Kay-Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Stephen N Thibodeau

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK.
² German Cancer Research Center, 69120, Heidelberg, Germany.
³ Center for Primary Health Care Research, Lund University, SE-205 02, Malmo, Sweden.
⁴ Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, Lund University, SE-221 84, Lund, Sweden.
⁵ Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
⁶ Department of Internal Medicine V, University of Heidelberg, 69117, Heidelberg, Germany.
⁷ Division of Molecular Pathology, The Institute of Cancer Research, London, SW7 3RP, UK.
⁸ Department of Hematology, Erasmus MC Cancer Institute, 3075 EA, Rotterdam, The Netherlands.
⁹ deCODE Genetics, Sturlugata 8, IS-101, Reykjavik, Iceland.
¹⁰ School of Engineering and Natural Sciences, University of Iceland, IS-101, Reykjavik, Iceland.
¹¹ National Centre of Tumor Diseases, 69120, Heidelberg, Germany.
¹² University Clinic of Würzburg, 97080, Würzburg, Germany.
¹³ Clinical Trials Research Unit, University of Leeds, Leeds, LS2 9PH, UK.
¹⁴ Institute of Human Genetics, University of Bonn, D-53127, Bonn, Germany.
¹⁵ Division of Medical Genetics, Department of Biomedicine, University of Basel, 4003, Basel, Switzerland.
¹⁶ Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.
¹⁷ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, D-45147, Germany.
¹⁸ Department of Hematology, Landspitali, National University Hospital of Iceland, IS-101, Reykjavik, Iceland.
¹⁹ Section of Hematology, Sahlgrenska University Hospital, Gothenburg, 413 45, Sweden.
²⁰ Center for Hematology and Regenerative Medicine, SE-171 77, Stockholm, Sweden.
²¹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
²² Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
²³ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
²⁴ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
²⁵ Division of Breast Cancer Research, The Institute of Cancer Research, London, SW7 3RP, UK.
²⁶ Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK.
²⁷ Institute of Population Health, University of Manchester, Manchester, M13 9PL, UK.
²⁸ Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
²⁹ Department of Applied Health Research, University College London, London, WC1E 7HB, UK.
³⁰ Department of Genomics, Life & Brain Center, University of Bonn, D-53127, Bonn, Germany.
³¹ Wessex Regional Genetics Laboratory, University of Southampton, Salisbury, SP2 8BJ, UK.
³² Hematology Clinic, Skåne University Hospital, SE-221 85, Lund, Sweden.
³³ Department of Haematology, University Hospital of Copenhagen at Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.
³⁴ Department of Haematology, Aarhus University Hospital, Tage-Hansens Gade 2, DK-8000, Aarhus C, Denmark.
³⁵ Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Box 8905, N-7491, Trondheim, Norway.
³⁶ Faculty of Medicine, University of Iceland, IS-101, Reykjavik, Iceland.
³⁷ Department of Internal Medicine III, University of Ulm, D-89081, Ulm, Germany.
³⁸ German Cancer Research Center, 69120, Heidelberg, Germany. K.Hemminki@dkfz-heidelberg.de.
³⁹ Center for Primary Health Care Research, Lund University, SE-205 02, Malmo, Sweden. K.Hemminki@dkfz-heidelberg.de.
⁴⁰ Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, Lund University, SE-221 84, Lund, Sweden. bjorn.nilsson@med.lu.se.
⁴¹ Broad Institute, 7 Cambridge Center, Cambridge, MA, 02142, USA. bjorn.nilsson@med.lu.se.
⁴² Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK. richard.houlston@icr.ac.uk.
⁴³ Division of Molecular Pathology, The Institute of Cancer Research, London, SW7 3RP, UK. richard.houlston@icr.ac.uk.

PMID: 30213928
PMCID: PMC6137048
DOI: 10.1038/s41467-018-04989-w

Meta-Analysis

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

Molly Went et al. Nat Commun. 2018.

. 2018 Sep 13;9(1):3707.

doi: 10.1038/s41467-018-04989-w.

Authors

Collaborators

PRACTICAL consortium:
Brian E Henderson, Christopher A Haiman, Sara Benlloch, Fredrick R Schumacher, Ali Amin Al Olama, Sonja I Berndt, David V Conti, Fredrik Wiklund, Stephen Chanock, Victoria L Stevens, Catherine M Tangen, Jyotsna Batra, Judith Clements, Henrik Gronberg, Johanna Schleutker, Demetrius Albanes, Stephanie Weinstein, Alicja Wolk, Catharine West, Lorelei Mucci, Géraldine Cancel-Tassin, Stella Koutros, Karina Dalsgaard Sorensen, Eli Marie Grindedal, David E Neal, Freddie C Hamdy, Jenny L Donovan, Ruth C Travis, Robert J Hamilton, Sue Ann Ingles, Barry Rosenstein, Yong-Jie Lu, Graham G Giles, Adam S Kibel, Ana Vega, Manolis Kogevinas, Kathryn L Penney, Jong Y Park, Janet L Stanford, Cezary Cybulski, Børge G Nordestgaard, Hermann Brenner, Christiane Maier, Jeri Kim, Esther M John, Manuel R Teixeira, Susan L Neuhausen, Kim De Ruyck, Azad Razack, Lisa F Newcomb, Davor Lessel, Radka Kaneva, Nawaid Usmani, Frank Claessens, Paul A Townsend, Manuela Gago-Dominguez, Monique J Roobol, Florence Menegaux, Kay-Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Stephen N Thibodeau

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK.
² German Cancer Research Center, 69120, Heidelberg, Germany.
³ Center for Primary Health Care Research, Lund University, SE-205 02, Malmo, Sweden.
⁴ Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, Lund University, SE-221 84, Lund, Sweden.
⁵ Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
⁶ Department of Internal Medicine V, University of Heidelberg, 69117, Heidelberg, Germany.
⁷ Division of Molecular Pathology, The Institute of Cancer Research, London, SW7 3RP, UK.
⁸ Department of Hematology, Erasmus MC Cancer Institute, 3075 EA, Rotterdam, The Netherlands.
⁹ deCODE Genetics, Sturlugata 8, IS-101, Reykjavik, Iceland.
¹⁰ School of Engineering and Natural Sciences, University of Iceland, IS-101, Reykjavik, Iceland.
¹¹ National Centre of Tumor Diseases, 69120, Heidelberg, Germany.
¹² University Clinic of Würzburg, 97080, Würzburg, Germany.
¹³ Clinical Trials Research Unit, University of Leeds, Leeds, LS2 9PH, UK.
¹⁴ Institute of Human Genetics, University of Bonn, D-53127, Bonn, Germany.
¹⁵ Division of Medical Genetics, Department of Biomedicine, University of Basel, 4003, Basel, Switzerland.
¹⁶ Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.
¹⁷ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, D-45147, Germany.
¹⁸ Department of Hematology, Landspitali, National University Hospital of Iceland, IS-101, Reykjavik, Iceland.
¹⁹ Section of Hematology, Sahlgrenska University Hospital, Gothenburg, 413 45, Sweden.
²⁰ Center for Hematology and Regenerative Medicine, SE-171 77, Stockholm, Sweden.
²¹ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, CB1 8RN, UK.
²² Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK.
²³ Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
²⁴ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.
²⁵ Division of Breast Cancer Research, The Institute of Cancer Research, London, SW7 3RP, UK.
²⁶ Royal Marsden NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK.
²⁷ Institute of Population Health, University of Manchester, Manchester, M13 9PL, UK.
²⁸ Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
²⁹ Department of Applied Health Research, University College London, London, WC1E 7HB, UK.
³⁰ Department of Genomics, Life & Brain Center, University of Bonn, D-53127, Bonn, Germany.
³¹ Wessex Regional Genetics Laboratory, University of Southampton, Salisbury, SP2 8BJ, UK.
³² Hematology Clinic, Skåne University Hospital, SE-221 85, Lund, Sweden.
³³ Department of Haematology, University Hospital of Copenhagen at Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.
³⁴ Department of Haematology, Aarhus University Hospital, Tage-Hansens Gade 2, DK-8000, Aarhus C, Denmark.
³⁵ Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Box 8905, N-7491, Trondheim, Norway.
³⁶ Faculty of Medicine, University of Iceland, IS-101, Reykjavik, Iceland.
³⁷ Department of Internal Medicine III, University of Ulm, D-89081, Ulm, Germany.
³⁸ German Cancer Research Center, 69120, Heidelberg, Germany. K.Hemminki@dkfz-heidelberg.de.
³⁹ Center for Primary Health Care Research, Lund University, SE-205 02, Malmo, Sweden. K.Hemminki@dkfz-heidelberg.de.
⁴⁰ Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, Lund University, SE-221 84, Lund, Sweden. bjorn.nilsson@med.lu.se.
⁴¹ Broad Institute, 7 Cambridge Center, Cambridge, MA, 02142, USA. bjorn.nilsson@med.lu.se.
⁴² Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP, UK. richard.houlston@icr.ac.uk.
⁴³ Division of Molecular Pathology, The Institute of Cancer Research, London, SW7 3RP, UK. richard.houlston@icr.ac.uk.

PMID: 30213928
PMCID: PMC6137048
DOI: 10.1038/s41467-018-04989-w

Erratum in

Author Correction: Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma.
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 Z, Muir K, Pashayan N; PRACTICAL consortium; Nickel J, Nöthen MM, Rafnar T, Ross FM, da Silva Filho MI, Thomsen H, Turesson I, Vangsted A, Andersen NF, Waage A, Walker BA, Wihlborg AK, Broyl A, Davies FE, Thorsteinsdottir U, Langer C, Hansson M, Goldschmidt H, Kaiser M, Sonneveld P, Stefansson K, Morgan GJ, Hemminki K, Nilsson B, Houlston RS. Went M, et al. Nat Commun. 2019 Jan 10;10(1):213. doi: 10.1038/s41467-018-08107-8. Nat Commun. 2019. PMID: 30631080 Free PMC 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.

PubMed Disclaimer

Conflict of interest statement

G.T., D.F.G., T.R., K.S. and U.T. are employed by deCode Genetics/Amgen Inc. The remaining authors declare no competing interests.

Figures

**Fig. 1**
GWAS study design. Details of the new and existing GWAS samples, including recruitment centres or trials and quality control, are provided in Supplementary Tables 1 and 2. Trials or centres from which replication samples were recruited are detailed in Supplementary Table 3. Ca.: cases, Co.: controls, eQTL: expression quantitative trait loci, SNP: single-nucleotide polymorphism, LD: linkage disequilibrium

**Fig. 2**
Regional plots of the six new risk loci. Regional plots of loci a 2q31.1, b 5q23.2, c 7q22.3, d 7q31.33, e 16p11.2 and f 19p13.11. Plots show results of the meta-analysis for both genotyped (triangles) and imputed (circles) single-nucleotide polymorphisms (SNPs) and recombination rates. −log₁₀(P) (y axes) of the SNPs are shown according to their chromosomal positions (x axes). The sentinel SNP in each combined analysis is shown as a large circle or triangle and is labelled by its rsID. The colour intensity of each symbol reflects the extent of LD with the top SNP, white (r² = 0) through to dark red (r² = 1.0). Genetic recombination rates, estimated using 1000 Genomes Project samples, are shown with a light blue line. Physical positions are based on NCBI build 37 of the human genome. Also shown are the relative positions of genes and transcripts mapping to the region of association. Genes have been redrawn to show their relative positions; therefore maps are not to physical scale. The middle track represents the chromatin-state segmentation track (ChromHMM) for KMS11

See this image and copyright information in PMC

References

1. Altieri A, Chen B, Bermejo JL, Castro F, Hemminki K. Familial risks and temporal incidence trends of multiple myeloma. Eur. J. Cancer. 2006;42:1661–1670. doi: 10.1016/j.ejca.2005.11.033. - DOI - PubMed
1. Broderick P, et al. Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk. Nat. Genet. 2011;44:58–61. doi: 10.1038/ng.993. - DOI - PMC - PubMed
1. Chubb D, et al. Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk. Nat. Genet. 2013;45:1221–1225. doi: 10.1038/ng.2733. - DOI - PMC - PubMed
1. Mitchell JS, et al. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nat. Commun. 2016;7:12050. doi: 10.1038/ncomms12050. - DOI - PMC - PubMed
1. Swaminathan B, et al. Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma. Nat. Commun. 2015;6:7213. doi: 10.1038/ncomms8213. - DOI - PMC - PubMed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Erratum in

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases