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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.    Electronic supplementary material  The online version of this article (10.1186/s10020-018-0031-8) contains supplementary material, which is available to authorized users.

molecular medicine

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