Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

Haplotype analysis identifies functional elements in monoclonal gammopathy of unknown significance

Thomsen, Hauke LU orcid ; Chattopadhyay, Subhayan LU orcid ; Weinhold, Niels ; Vodicka, Pavel ; Vodickova, Ludmila ; Hoffmann, Per ; Nöthen, Markus M. ; Jöckel, Karl Heinz ; Schmidt, Börge and Hajek, Roman , et al. (2024) In Blood Cancer Journal 14. p.1-12
Abstract

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... (More)

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.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and , et al. (More)
; ; ; ; ; ; ; ; ; ; ; ; ; ; and (Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Blood Cancer Journal
volume
14
article number
140
pages
1 - 12
publisher
Nature Publishing Group
external identifiers
  • pmid:39164264
  • scopus:85201603885
ISSN
2044-5385
DOI
10.1038/s41408-024-01121-8
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2024.
id
3b130e65-a24a-46ea-820f-9835ab39babc
date added to LUP
2024-09-08 16:15:18
date last changed
2024-09-10 02:56:24
@article{3b130e65-a24a-46ea-820f-9835ab39babc,
  abstract     = {{<p>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 &lt; 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.</p>}},
  author       = {{Thomsen, Hauke and Chattopadhyay, Subhayan and Weinhold, Niels and Vodicka, Pavel and Vodickova, Ludmila and Hoffmann, Per and Nöthen, Markus M. and Jöckel, Karl Heinz and Schmidt, Börge and Hajek, Roman and Hallmans, Göran and Pettersson-Kymmer, Ulrika and Späth, Florentin and Goldschmidt, Hartmut and Hemminki, Kari and Försti, Asta}},
  issn         = {{2044-5385}},
  language     = {{eng}},
  pages        = {{1--12}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Blood Cancer Journal}},
  title        = {{Haplotype analysis identifies functional elements in monoclonal gammopathy of unknown significance}},
  url          = {{http://dx.doi.org/10.1038/s41408-024-01121-8}},
  doi          = {{10.1038/s41408-024-01121-8}},
  volume       = {{14}},
  year         = {{2024}},
}