Blood Journal
Leading the way in experimental and clinical research in hematology

Inherited genetic susceptibility to monoclonal gammopathy of unknown significance

  1. Neils Weinhold1,
  2. David C. Johnson2,
  3. Andrew C. Rawstron3,
  4. Asta Försti4,
  5. Chi Doughty3,
  6. Jayaram Vijayakrishnan5,
  7. Peter Broderick5,
  8. Nasrin B. Dahir2,
  9. Dil B. Begum2,
  10. Fay J. Hosking5,
  11. Kwee Yong6,
  12. Brian A. Walker2,
  13. Per Hoffmann7,
  14. Thomas W. Mühleisen8,
  15. Christian Langer9,
  16. Elisabeth Dörner9,
  17. Karl-Heinz Jöckel10,
  18. Lewin Eisele10,
  19. Markus M. Nöthen11,
  20. Dirk Hose1,
  21. Faith E. Davies2,
  22. Hartmut Goldschmidt1,
  23. Gareth J. Morgan2,
  24. Kari Hemminki12, and
  25. Richard S. Houlston13,*
  1. 1 Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany;
  2. 2 Centre for Myeloma Research, Division of Molecular Pathology, Institute of Cancer Research, Sutton, United Kingdom;
  3. 3 Haematological Malignancy Diagnostic Service Laboratory, St James University Hospital, York, United Kingdom;
  4. 4 German Cancer Research Center, Heidelberg, Germany;
  5. 5 Molecular and Population Genetics, Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, United Kingdom;
  6. 6 Department of Haematology, University College London Hospital, London, United Kingdom;
  7. 7 Institute of Human Genetics, University of Bonn, Bonn, Germany;
  8. 8 Institute of Human Genetics, University of Bonn, Bonn, United Kingdom;
  9. 9 Department of Internal Medicine III, University of Ulm, Ulm, Germany;
  10. 10 Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;
  11. 11 German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany;
  12. 12 Center for Primary Health Care Research, Lund University, Malmo, Sweden;
  13. 13 Molecular and Population Genetics, Division of Genetics and Epidemiology, Insitute of Cancer Research, Sutton, United Kingdom
  1. * Corresponding author; email: richard.houlston{at}

Key points

  • Inherited genetic variation increases risk to developing multiple myeloma through predisposition to MGUS.

  • Loci identified that increase risk of developing MGUS include 2p23.3, 3p22.1, 3q26.2, 6p21.33, 7p15.3, 17p11.2 and 22q13.1.


Monoclonal gammopathy of undetermined significance (MGUS), a pre-malignant clone of plasma cells producing a monoclonal paraprotein, is present in ~2% of individuals >50 years. The increased risk of multiple myeloma (MM) in the relatives of individuals with MGUS is consistent with MGUS being a marker of inherited genetic susceptibility to MM. Common SNPs at 2p23.3(rs6746082), 3p22.1(rs1052501), 3q26.2(rs10936599), 6p21.33(rs2285803), 7p15.3(rs4487645), 17p11.2(rs4273077) and 22q13.1(rs877529) have recently been shown to influence MM risk. To examine the impact of these 7 SNPs on MGUS we analyzed two case-control series totaling 492 cases and 7,306 controls. Each SNP independently influenced MGUS risk with statistically significant associations (P<0.02) for rs1052501, rs2285803, rs4487645, rs4273077. SNP associations were independent with risk increasing with a larger number of risk alleles carried (per allele odds ratio=1.18; P<10-7). Collectively these data are consistent with a polygenic model of disease susceptibility to MGUS and provide support for genetic variation influencing MM risk through predisposition to MGUS.

  • Submitted October 21, 2013.
  • Accepted January 5, 2014.