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Commun Biol. 2019 Mar 4;2:89. doi: 10.1038/s42003-019-0329-2. eCollection 2019.

Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma.

Author information

1
1Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, 69120 Germany.
2
2Faculty of Medicine, University of Heidelberg, Heidelberg, 69117 Germany.
3
University Clinic Heidelberg, Internal Medicine V, Heidelberg, 69117 Germany.
4
4Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, 72205 AR USA.
5
5Institute of Human Genetics, University of Bonn, Bonn, 53127 Germany.
6
6Department of Genomics, Life & Brain Research Center, University of Bonn, Bonn, 53127 Germany.
7
7Department of Biomedicine, University of Basel, Basel, 4003 Switzerland.
8
National Centre of Tumor Diseases, Heidelberg, 69120 Germany.
9
9Division of Genetics and Epidemiology, The Institute of Cancer Research, London, SW7 3RP UK.
10
10Division of Molecular Pathology, The Institute of Cancer Research, London, SW7 3RP UK.
11
11Center for Primary Health Care Research, Lund University, 205 02 Malmö, Sweden.

Abstract

Inherited genetic susceptibility to multiple myeloma has been investigated in a number of studies. Although 23 individual risk loci have been identified, much of the genetic heritability remains unknown. Here we carried out genome-wide interaction analyses on two European cohorts accounting for 3,999 cases and 7,266 controls and characterized genetic susceptibility to multiple myeloma with subsequent meta-analysis that discovered 16 unique interacting loci. These risk loci along with previously known variants explain 17% of the heritability in liability scale. The genes associated with the interacting loci were found to be enriched in transforming growth factor beta signaling and circadian rhythm regulation pathways suggesting immunoglobulin trait modulation, TH17 cell differentiation and bone morphogenesis as mechanistic links between the predisposition markers and intrinsic multiple myeloma biology. Further tissue/cell-type enrichment analysis associated the discovered genes with hemic-immune system tissue types and immune-related cell types indicating overall involvement in immune response.

Conflict of interest statement

The authors declare no competing interests.

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