TY - JOUR
T1 - Haplotype analysis identifies functional elements in monoclonal gammopathy of unknown significance
AU - Thomsen, Hauke
AU - Chattopadhyay, Subhayan
AU - Weinhold, Niels
AU - Vodicka, Pavel
AU - Vodickova, Ludmila
AU - Hoffmann, Per
AU - Nöthen, Markus M.
AU - Jöckel, Karl Heinz
AU - Schmidt, Börge
AU - Hajek, Roman
AU - Hallmans, Göran
AU - Pettersson-Kymmer, Ulrika
AU - Späth, Florentin
AU - Goldschmidt, Hartmut
AU - Hemminki, Kari
AU - Försti, Asta
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - 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 × 10−8) 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.
AB - 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 × 10−8) 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.
U2 - 10.1038/s41408-024-01121-8
DO - 10.1038/s41408-024-01121-8
M3 - Article
C2 - 39164264
AN - SCOPUS:85201603885
SN - 2044-5385
VL - 14
SP - 1
EP - 12
JO - Blood Cancer Journal
JF - Blood Cancer Journal
M1 - 140
ER -