Haplotype analysis identifies functional elements in monoclonal gammopathy of unknown significance

Author:

Thomsen Hauke,Chattopadhyay Subhayan,Weinhold Niels,Vodicka Pavel,Vodickova Ludmila,Hoffmann PerORCID,Nöthen Markus M.ORCID,Jöckel Karl-Heinz,Schmidt Börge,Hajek RomanORCID,Hallmans Göran,Pettersson-Kymmer UlrikaORCID,Späth FlorentinORCID,Goldschmidt HartmutORCID,Hemminki KariORCID,Försti AstaORCID

Abstract

AbstractGenome-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 × 10−8) 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.

Funder

Dietmar Hopp Stiftung

Black Swan Research Initiative/International Myeloma Foundation Transcan ERA-NET funding from the German Federal Ministry of Education and Research

Publisher

Springer Science and Business Media LLC

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