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, Sigurður 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, 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, Sigurður 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
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.
Conflict of interest statement
G.T., P.S., G.M., D.F.G., T.R., K.S. and U.T. are employed by deCode Genetics/Amgen Inc. The remaining authors declare no competing financial interests.
Figures
References
- Morgan G. J. et al. Inherited genetic susceptibility to multiple myeloma. Leukemia 28, 518–524 (2014).
- Chubb D. et al. Common variation at 3q26.2, 6p21.33, 17p11.2 and 22q13.1 influences multiple myeloma risk. Nat. Genet. 45, 1221–1225 (2013).
- Weinhold N. et al. The CCND1 c.870G>A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma. Nat. Genet. 45, 522–525 (2013).
- Broderick P. et al. Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk. Nat. Genet. 44, 58–61 (2012).
- Swaminathan B. et al. Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma. Nat. Commun. 6, 7213 (2015).
- Mitchell J. S. et al. Implementation of genome-wide complex trait analysis to quantify the heritability in multiple myeloma. Sci. Rep. 5, 12473 (2015).
- Erickson S. W. et al. Genome-wide scan identifies variant in 2q12.3 associated with risk for multiple myeloma. Blood 124, 2001–2003 (2014).
- Genomes Project, C. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010).
- Huang J. et al. Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel. Nat. Commun. 6, 8111 (2015).
- Gudbjartsson D. F. et al. Large-scale whole-genome sequencing of the Icelandic population. Nat. Genet. 47, 435–444 (2015).
- Fletcher O. & Houlston R. S. Architecture of inherited susceptibility to common cancer. Nat. Rev. Cancer 10, 353–361 (2010).
- Cerhan J. R. et al. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat. Genet. 46, 1233–1238 (2014).
- Enciso-Mora V. et al. A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat. Genet. 42, 1126–1130 (2010).
- Crowther-Swanepoel D. et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat. Genet. 42, 132–136 (2010).
- Sherborne A. L. et al. Variation in CDKN2A at 9p21.3 influences childhood acute lymphoblastic leukemia risk. Nat. Genet. 42, 492–494 (2010).
- Joachim J., Wirth M., McKnight N. C. & Tooze S. A. Coiling up with SCOC and WAC: two new regulators of starvation-induced autophagy. Autophagy 8, 1397–1400 (2012).
- Rao S. S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014).
- Gaulton K. J. et al. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nat. Genet. 47, 1415–1425 (2015).
- Tatetsu H. et al. Down-regulation of PU.1 by methylation of distal regulatory elements and the promoter is required for myeloma cell growth. Cancer Res. 67, 5328–5336 (2007).
- Jia L. et al. Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet. 5, e1000597 (2009).
- Ahmadiyeh N. et al. 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc, Natl Acad. Sci. USA 107, 9742–9746 (2010).
- Xiang J. F. et al. Human colorectal cancer-specific CCAT1-L lncRNA regulates long-range chromatin interactions at the MYC locus. Cell Res. 24, 513–531 (2014).
- Kryukov G. V. et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351, 1214–1218 (2016).
- Cenci S. Autophagy a new determinant of plasma cell differentiation and antibody responses. Mol. Immunol. 62, 289–295 (2014).
- Pengo N. et al. Plasma cells require autophagy for sustainable immunoglobulin production. Nat. Immunol. 14, 298–305 (2013).
- Fu X. et al. RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage. Proc. Natl Acad. Sci. USA 107, 4579–4584 (2010).
- Chung C. C. et al. Meta-analysis identifies four new loci associated with testicular germ cell tumor. Nat. Genet. 45, 680–685 (2013).
- Kinkel S. A. et al. Jarid2 regulates hematopoietic stem cell function by acting with polycomb repressive complex 2. Blood 125, 1890–1900 (2015).
- Walker B. A. et al. A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value. Blood 116, e56–e65 (2010).
- Pawlyn C., Kaiser M. F., Davies F. E. & Morgan G. J. Current and potential epigenetic targets in multiple myeloma. Epigenomics 6, 215–228 (2014).
- Toh P. P. et al. Myc inhibition impairs autophagosome formation. Hum. Mol. Genet. 22, 5237–5248 (2013).
- Nelson M. R. et al. The support of human genetic evidence for approved drug indications. Nat. Genet. 47, 856–860 (2015).
- Ocio E. M., Mateos M. V., Maiso P., Pandiella A. & San-Miguel J. F. New drugs in multiple myeloma: mechanisms of action and phase I/II clinical findings. Lancet Oncol. 9, 1157–1165 (2008).
- Zheng H. F. et al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature 526, 112–117 (2015).
- Howie B. N., Donnelly P. & Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).
- Marchini J., Howie B., Myers S., McVean G. & Donnelly P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).
- Clayton D. G. et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat. Genet. 37, 1243–1246 (2005).
- Patterson N., Price A. L. & Reich D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).
- Liu J. Z. et al. Meta-analysis and imputation refines the association of 15q25 with smoking quantity. Nat. Genet. 42, 436–440 (2010).
- Higgins J. P. & Thompson S. G. Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).
- Yang J., Lee S. H., Goddard M. E. & Visscher P. M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76–82 (2011).
- Eisen T., Matakidou A., Houlston R. & Consortium G. Identification of low penetrance alleles for lung cancer: the GEnetic Lung CAncer Predisposition Study (GELCAPS). BMC Cancer 8, 244 (2008).
- Penegar S. et al. National study of colorectal cancer genetics. Br. J. Cancer 97, 1305–1309 (2007).
- Chiecchio L. et al. Deletion of chromosome 13 detected by conventional cytogenetics is a critical prognostic factor in myeloma. Leukemia 20, 1610–1617 (2006).
- Neben K. et al. Combining information regarding chromosomal aberrations t(4;14) and del(17p13) with the International Staging System classification allows stratification of myeloma patients undergoing autologous stem cell transplantation. Haematologica 95, 1150–1157 (2010).
- Walker B. A. et al. APOBEC family mutational signatures are associated with poor prognosis translocations in multiple myeloma. Nat. Commun. 6, 6997 (2015).
- Goldschmidt H. et al. Joint HOVON-50/GMMG-HD3 randomized trial on the effect of thalidomide as part of a high-dose therapy regimen and as maintenance treatment for newly diagnosed myeloma patients. Ann. Hematol. 82, 654–659 (2003).
- Merz M. et al. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica 100, 964–969 (2015).
- Morgan G. J. et al. Cyclophosphamide, thalidomide, and dexamethasone as induction therapy for newly diagnosed multiple myeloma patients destined for autologous stem-cell transplantation: MRC Myeloma IX randomized trial results. Haematologica 97, 442–450 (2012).
- Morgan G. J. et al. Long-term follow-up of MRC Myeloma IX trial: survival outcomes with bisphosphonate and thalidomide treatment. Clin. Cancer Res. 19, 6030–6038 (2013).
- Johnson D. C. et al. Genome-wide association study identifies variation at 6q25.1 associated with survival in multiple myeloma. Nat. Commun. 7, 10290 (2016).
- Stegle O., Parts L., Piipari M., Winn J. & Durbin R. Using probabilistic estimation of expression residuals (PEER) to obtain increased power and interpretability of gene expression analyses. Nat. Protoc. 7, 500–507 (2012).
- Grundberg E. et al. Mapping cis- and trans-regulatory effects across multiple tissues in twins. Nat. Genet. 44, 1084–1089 (2012).
- Westra H. J. et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45, 1238–1243 (2013).
- Ward L. D. & Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 40, D930–D934 (2012).
- Boyle A. P. et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 22, 1790–1797 (2012).
- Ng S. B. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–276 (2009).
- de Souza N. The ENCODE project. Nat. Methods 9, 1046 (2012).
- Cooper G. M. et al. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 15, 901–913 (2005).
- Kircher M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310–315 (2014).
- Adzhubei I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).
- Andersson R. et al. An atlas of active enhancers across human cell types and tissues. Nature 507, 455–461 (2014).
- Hnisz D. et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).
- Jager R. et al. Capture Hi-C identifies the chromatin interactome of colorectal cancer risk loci. Nat. Commun. 6, 6178 (2015).
- Chapman M. A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467–472 (2011).
- Yang J., Lee S. H., Goddard M. E. & Visscher P. M. Genome-wide complex trait analysis (GCTA): methods, data analyses, and interpretations. Methods Mol. Biol. 1019, 215–236 (2013).
- Yang J. et al. Genome partitioning of genetic variation for complex traits using common SNPs. Nat. Genet. 43, 519–525 (2011).
- Lu Y. et al. Most common ‘sporadic' cancers have a significant germline genetic component. Hum. Mol. Genet. 23, 6112–6118 (2014).
- Lee S. H. et al. Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer's disease, multiple sclerosis and endometriosis. Hum. Mol. Genet. 22, 832–841 (2013).
- Scales M., Jager R., Migliorini G., Houlston R. S. & Henrion M. Y. visPIG--a web tool for producing multi-region, multi-track, multi-scale plots of genetic data. PLoS ONE 9, e107497 (2014).
Source: PubMed