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

Chattopadhyay, Subhayan LU ; Thomsen, Hauke LU ; Yadav, Pankaj; da Silva Filho, Miguel Inacio LU ; Weinhold, Niels; Nöthen, Markus M; Hoffman, Per; Bertsch, Uta; Huhn, Stefanie and Morgan, Gareth J, et al. (2019) In Communications Biology 2(1).
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... (More)

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.

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Communications Biology
volume
2
issue
1
publisher
Nature Research
external identifiers
  • scopus:85071167538
ISSN
2399-3642
DOI
10.1038/s42003-019-0329-2
language
English
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yes
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9253cf35-05d9-49a9-b824-5209eaa64e5b
date added to LUP
2019-03-18 12:50:10
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2019-09-26 04:31:29
@article{9253cf35-05d9-49a9-b824-5209eaa64e5b,
  abstract     = {<p>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.</p>},
  articleno    = {89},
  author       = {Chattopadhyay, Subhayan and Thomsen, Hauke and Yadav, Pankaj and da Silva Filho, Miguel Inacio and Weinhold, Niels and Nöthen, Markus M and Hoffman, Per and Bertsch, Uta and Huhn, Stefanie and Morgan, Gareth J and Goldschmidt, Hartmut and Houlston, Richard and Hemminki, Kari and Försti, Asta},
  issn         = {2399-3642},
  language     = {eng},
  number       = {1},
  publisher    = {Nature Research},
  series       = {Communications Biology},
  title        = {Genome-wide interaction and pathway-based identification of key regulators in multiple myeloma},
  url          = {http://dx.doi.org/10.1038/s42003-019-0329-2},
  volume       = {2},
  year         = {2019},
}