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

Subhayan Chattopadhyay
Subhayan Chattopadhyay
School of Mathematics and Statistics
Islamabad | Pakistan
Hauke Thomsen, Dr.
Hauke Thomsen, Dr.
GeneWerk GmbH
Senior Bioinformatician
Bioinformatics, Biostatistics, Genetics
Heidelberg, Baden-Württemberg/Germany | Germany
Niels Weinhold
Niels Weinhold
Institute of Cancer Research
United Kingdom
Per Hoffmann
Per Hoffmann
Institute of Human Genetics
Markus M Nothen
Markus M Nothen
1] Institute of Human Genetics
Ahmedabad | India
Arendt Marina
Arendt Marina
Institute for Medical Informatics

Mol Med 2018 06 11;24(1):30. Epub 2018 Jun 11.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.

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) downstream to allograft rejection pathway (P < 5.6 × 10) and autoimmune thyroid disease pathway (P < 9.3 × 10) as well as epidermal growth factor receptor regulation pathway (P < 2.4 × 10) 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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June 2018
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