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Enrichment of B cell receptor signaling and epidermal growth factor receptor pathways in monoclonal gammopathy of undetermined significance : a genome-wide genetic interaction study

Chattopadhyay, Subhayan LU ; Thomsen, Hauke LU ; da Silva Filho, Miguel Inacio LU ; Weinhold, Niels; Hoffmann, Per; Nöthen, Markus M; Marina, Arendt; Jöckel, Karl-Heinz; Schmidt, Börge and Pechlivanis, Sonali, et al. (2018) In Molecular Medicine 24(1).
Abstract

BACKGROUND: Recent identification of 10 germline variants predisposing to monoclonal gammopathy of undetermined significance (MGUS) explicates genetic dependency of this asymptomatic precursor condition with multiple myeloma (MM). Yet much of genetic burden as well as functional links remain unexplained. We propose a workflow to expand the search for susceptibility loci with genome-wide interaction and for subsequent identification of genetic clusters and pathways.

METHODS: Polygenic interaction analysis on 243 cases/1285 controls identified 14 paired risk loci belonging to unique chromosomal bands which were then replicated in two independent sets (case only study, 82 individuals; case/control study 236 cases/ 2484 controls).... (More)

BACKGROUND: Recent identification of 10 germline variants predisposing to monoclonal gammopathy of undetermined significance (MGUS) explicates genetic dependency of this asymptomatic precursor condition with multiple myeloma (MM). Yet much of genetic burden as well as functional links remain unexplained. We propose a workflow to expand the search for susceptibility loci with genome-wide interaction and for subsequent identification of genetic clusters and pathways.

METHODS: Polygenic interaction analysis on 243 cases/1285 controls identified 14 paired risk loci belonging to unique chromosomal bands which were then replicated in two independent sets (case only study, 82 individuals; case/control study 236 cases/ 2484 controls). Further investigation on gene-set enrichment, regulatory pathway and genetic network was carried out with stand-alone in silico tools separately for both interaction and genome-wide association study-detected risk loci.

RESULTS: Intronic-PREX1 (20q13.13), a reported locus predisposing to MM was confirmed to have contribution to excess MGUS risk in interaction with SETBP1, a well-established candidate predisposing to myeloid malignancies. Pathway enrichment showed B cell receptor signaling pathway (P < 5.3 × 10- 3) downstream to allograft rejection pathway (P < 5.6 × 10- 4) and autoimmune thyroid disease pathway (P < 9.3 × 10- 4) as well as epidermal growth factor receptor regulation pathway (P < 2.4 × 10- 2) to be differentially regulated. Oncogene ALK and CDH2 were also identified to be moderately interacting with rs10251201 and rs16966921, two previously reported risk loci for MGUS.

CONCLUSIONS: We described novel pathways and variants potentially causal for MGUS. The methodology thus proposed to facilitate our search streamlines risk locus-based interaction, genetic network and pathway enrichment analyses.

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Molecular Medicine
volume
24
issue
1
publisher
The Feinstein Institute for Medical Research
external identifiers
  • scopus:85057233114
ISSN
1528-3658
DOI
10.1186/s10020-018-0031-8
language
English
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yes
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2d6c4e63-9a82-4dc0-abff-29615a036852
date added to LUP
2018-10-10 13:50:22
date last changed
2019-04-10 04:14:47
@article{2d6c4e63-9a82-4dc0-abff-29615a036852,
  abstract     = {<p>BACKGROUND: Recent identification of 10 germline variants predisposing to monoclonal gammopathy of undetermined significance (MGUS) explicates genetic dependency of this asymptomatic precursor condition with multiple myeloma (MM). Yet much of genetic burden as well as functional links remain unexplained. We propose a workflow to expand the search for susceptibility loci with genome-wide interaction and for subsequent identification of genetic clusters and pathways.</p><p>METHODS: Polygenic interaction analysis on 243 cases/1285 controls identified 14 paired risk loci belonging to unique chromosomal bands which were then replicated in two independent sets (case only study, 82 individuals; case/control study 236 cases/ 2484 controls). Further investigation on gene-set enrichment, regulatory pathway and genetic network was carried out with stand-alone in silico tools separately for both interaction and genome-wide association study-detected risk loci.</p><p>RESULTS: Intronic-PREX1 (20q13.13), a reported locus predisposing to MM was confirmed to have contribution to excess MGUS risk in interaction with SETBP1, a well-established candidate predisposing to myeloid malignancies. Pathway enrichment showed B cell receptor signaling pathway (P &lt; 5.3 × 10- 3) downstream to allograft rejection pathway (P &lt; 5.6 × 10- 4) and autoimmune thyroid disease pathway (P &lt; 9.3 × 10- 4) as well as epidermal growth factor receptor regulation pathway (P &lt; 2.4 × 10- 2) to be differentially regulated. Oncogene ALK and CDH2 were also identified to be moderately interacting with rs10251201 and rs16966921, two previously reported risk loci for MGUS.</p><p>CONCLUSIONS: We described novel pathways and variants potentially causal for MGUS. The methodology thus proposed to facilitate our search streamlines risk locus-based interaction, genetic network and pathway enrichment analyses.</p>},
  articleno    = {30},
  author       = {Chattopadhyay, Subhayan and Thomsen, Hauke and da Silva Filho, Miguel Inacio and Weinhold, Niels and Hoffmann, Per and Nöthen, Markus M and Marina, Arendt and Jöckel, Karl-Heinz and Schmidt, Börge and Pechlivanis, Sonali and Langer, Christian and Goldschmidt, Hartmut and Hemminki, Kari and Försti, Asta},
  issn         = {1528-3658},
  language     = {eng},
  month        = {06},
  number       = {1},
  publisher    = {The Feinstein Institute for Medical Research},
  series       = {Molecular Medicine},
  title        = {Enrichment of B cell receptor signaling and epidermal growth factor receptor pathways in monoclonal gammopathy of undetermined significance : a genome-wide genetic interaction study},
  url          = {http://dx.doi.org/10.1186/s10020-018-0031-8},
  volume       = {24},
  year         = {2018},
}