eprintid: 24729 rev_number: 12 eprint_status: archive userid: 1589 dir: disk0/00/02/47/29 datestamp: 2018-06-25 07:20:03 lastmod: 2024-04-16 10:24:05 status_changed: 2018-06-25 07:20:03 type: article metadata_visibility: show creators_name: Chattopadhyay, Subhayan creators_name: Thomsen, Hauke creators_name: Filho, Miguel Inacio da Silva creators_name: Weinhold, Niels creators_name: Hoffmann, Per creators_name: Nöthen, Markus M. creators_name: Marina, Arendt creators_name: Jöckel, Karl-Heinz creators_name: Schmidt, Börge creators_name: Pechlivanis, Sonali creators_name: Langer, Christian creators_name: Goldschmidt, Hartmut creators_name: Hemminki, Kari creators_name: Försti, Asta 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 subjects: ddc-610 divisions: i-850300 divisions: i-910100 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). 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. date: 2018 publisher: BioMed Central ; Springer id_scheme: DOI ppn_swb: 1654738689 own_urn: urn:nbn:de:bsz:16-heidok-247294 language: eng bibsort: CHATTOPADHENRICHMENT2018 full_text_status: public publication: Molecular medicine volume: 24 number: 30 place_of_pub: London ; New York pagerange: 1-13 issn: 1528-3658 citation: Chattopadhyay, Subhayan ; Thomsen, Hauke ; Filho, Miguel Inacio da Silva ; Weinhold, Niels ; Hoffmann, Per ; Nöthen, Markus M. ; Marina, Arendt ; Jöckel, Karl-Heinz ; Schmidt, Börge ; Pechlivanis, Sonali ; Langer, Christian ; Goldschmidt, Hartmut ; Hemminki, Kari ; Försti, Asta (2018) Enrichment of B cell receptor signaling and epidermal growth factor receptor pathways in monoclonal gammopathy of undetermined significance: a genome-wide genetic interaction study. Molecular medicine, 24 (30). pp. 1-13. ISSN 1528-3658 document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/24729/1/10020_2018_Article_31.pdf