Haplotype analysis identifies functional elements in monoclonal gammopathy of unknown significance
Genome-wide association studies (GWASs) based on common single nucleotide polymorphisms (SNPs) have identified several loci associated with the risk of monoclonal gammopathy of unknown significance (MGUS), a precursor condition for multiple myeloma (MM). We hypothesized that analyzing haplotypes might be more useful than analyzing individual SNPs, as it could identify functional chromosomal units that collectively contribute to MGUS risk. To test this hypothesis, we used data from our previous GWAS on 992 MGUS cases and 2910 controls from three European populations. We identified 23 haplotypes that were associated with the risk of MGUS at the genome-wide significance level (p < 5 × 10<sup>-8</sup>) and showed consistent results among all three populations. In 10 genomic regions, strong promoter, enhancer and regulatory element-related histone marks and their connections to target genes as well as genome segmentation data supported the importance of these regions in MGUS susceptibility. Several associated haplotypes affected pathways important for MM cell survival such as ubiquitin-proteasome system (RNF186, OTUD3), PI3K/AKT/mTOR (HINT3), innate immunity (SEC14L1, ZBP1), cell death regulation (BID) and NOTCH signaling (RBPJ). These pathways are important current therapeutic targets for MM, which may highlight the advantage of the haplotype approach homing to functional units.
Authors
- Pavel Vodička (ORCID: https://orcid.org/0000-0003-2376-1243)
- Hauke Thomsen (ORCID: https://orcid.org/0000-0001-5951-3116)
- Asta Försti (ORCID: https://orcid.org/0000-0002-9857-4728)
- Per Hoffmann (ORCID: https://orcid.org/0000-0002-6573-983X)
- Ľudmila Vodičková (ORCID: https://orcid.org/0000-0002-8277-539X)
- Niels Weinhold (ORCID: https://orcid.org/0000-0002-5464-3234)
- Hartmut Goldschmidt (ORCID: https://orcid.org/0000-0003-0961-0035)
- Florentin Späth (ORCID: https://orcid.org/0000-0002-0711-0830)
- Subhayan Chattopadhyay (ORCID: https://orcid.org/0000-0002-8599-2971)
- U. Pettersson (ORCID: https://orcid.org/0000-0002-0557-9803)
- Kari Hemminki (ORCID: https://orcid.org/0000-0002-2769-3316)
- Roman Hájek (ORCID: https://orcid.org/0000-0001-6955-6267)
- Markus M. Nöthen (ORCID: https://orcid.org/0000-0002-8770-2464)
- Göran Hallmans (ORCID: https://orcid.org/0000-0001-9581-3845)
- Börge Schmidt
- Karl‐Heinz Jöckel
Institutions
- University of Bonn (DE)
- German Cancer Research Center (DE)
- University of Basel (CH)
- University of Ostrava (CZ)
- Lund University (SE)
- Charles University (CZ)
- Heidelberg University (DE)
- University Hospital Ostrava (CZ)
- MSB Medical School Berlin (DE)
- National Center for Tumor Diseases (DE)
- Hopp Children's Cancer Center Heidelberg (DE)
- Czech Academy of Sciences, Institute of Experimental Medicine (CZ)
- University of Duisburg-Essen (DE)
- Umeå University (SE)
Publication Details
- Journal
- Blood Cancer Journal
- Published
- 2024-08-20
- DOI
- https://doi.org/10.1038/s41408-024-01121-8
- Citations
- 2
- Primary Topic
- Chronic Lymphocytic Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 0.88
Funders
- European Commission
- Grantová Agentura České Republiky
- Bundesministerium für Bildung und Forschung
- Dietmar Hopp Stiftung