title: Genomewide association study on monoclonal gammopathy of unknown significance (MGUS).
abstract: OBJECTIVE
  To identify germ line variants contributing to the development of monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic premalignant precursor for multiple myeloma (MM).
  
  
  METHODS
  We conducted the first genomewide association study (GWAS) on MGUS on 243 German cases with a replication on 294 Czech cases. Identified loci were further analyzed in 1508 German MM patients. New MM loci recently reported in a meta-analysis were also tested in the MGUS GWAS.
  
  
  RESULTS
  In GWAS, we identified 10 loci contributing to development of MGUS at P-value threshold of 10-5. The Czech cohort gave support for two associations (6q26, rs6933936; 7p21.3 rs10251201). In GWAS, rs974120 (8p23.2) reached genomewide significance (P=2.94×10-9), with a nominal significance in MM. The locus of rs974120 shows marks of transcriptional activity in leukemia according to ENCODE data. rs10251201 (7p21.3), rs9318227 (13q22.1), and rs10405859 (19q13.32) were associated with markers related to leukemogenesis and immune and inflammatory responses. Two newly identified candidate loci for MM, rs1948915 (8q24.21) and rs8058578 (16p11.2), were nominally associated with MGUS.
  
  
  CONCLUSIONS
  These data allow a cautious first proposal for a germ line architecture of MGUS with links to leukemia and autoimmune conditions, the latter agreeing with a family study showing clustering of MGUS with autoimmune diseases.
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hauke
authors.identifier: http://orcid.org/0000-0001-5951-3116
authors.initials: H
authors.lastname: Thomsen
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Chiara
authors.initials: C
authors.lastname: Campo
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Niels
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Miguel Inacio
authors.initials: MI
authors.lastname: da Silva Filho
authors.affiliation: Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic.
authors.forename: Luděk
authors.initials: L
authors.lastname: Pour
authors.affiliation: Department of Hematology, University Hospital Kralovske Vinohrady, Prague, Czech Republic.
authors.forename: Evžen
authors.initials: E
authors.lastname: Gregora
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.|Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.|Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic.|Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vodickova
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Biomedicine, University of Basel, Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Research Center, University of Bonn, Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Jöckel
authors.affiliation: Department of Internal Medicine III, University of Ulm, Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Langer
authors.affiliation: Department of Hematooncology, University Hospital Ostrava, Ostrava, Czech Republic.
authors.forename: Roman
authors.initials: R
authors.lastname: Hajek
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|National Center of Tumor Diseases, Heidelberg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
mesh_terms: D000368:Aged; D000483:Alleles; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000175:diagnosis / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D018570:Risk Assessment
keywords: germ line; low-risk genes; myeloma; susceptibility