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Functional dissection of inherited non-coding variation influencing multiple myeloma risk

Ajore, Ram LU ; Niroula, Abhishek LU ; Pertesi, Maroulio LU ; Cafaro, Caterina LU ; Thodberg, Malte LU ; Went, Molly ; Bao, Erik L. ; Duran-Lozano, Laura LU ; Lopez de Lapuente Portilla, Aitzkoa LU and Olafsdottir, Thorunn , et al. (2022) In Nature Communications 13(1).
Abstract

Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal... (More)

Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
13
issue
1
article number
151
publisher
Nature Publishing Group
external identifiers
  • scopus:85122897580
  • pmid:35013207
ISSN
2041-1723
DOI
10.1038/s41467-021-27666-x
language
English
LU publication?
yes
id
efcd0a27-9162-4483-a417-bc979259d051
date added to LUP
2022-03-01 10:21:01
date last changed
2024-03-06 01:55:06
@article{efcd0a27-9162-4483-a417-bc979259d051,
  abstract     = {{<p>Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.</p>}},
  author       = {{Ajore, Ram and Niroula, Abhishek and Pertesi, Maroulio and Cafaro, Caterina and Thodberg, Malte and Went, Molly and Bao, Erik L. and Duran-Lozano, Laura and Lopez de Lapuente Portilla, Aitzkoa and Olafsdottir, Thorunn and Ugidos-Damboriena, Nerea and Magnusson, Olafur and Samur, Mehmet and Lareau, Caleb A. and Halldorsson, Gisli H. and Thorleifsson, Gudmar and Norddahl, Gudmundur L. and Gunnarsdottir, Kristbjorg and Försti, Asta and Goldschmidt, Hartmut and Hemminki, Kari and van Rhee, Frits and Kimber, Scott and Sperling, Adam S. and Kaiser, Martin and Anderson, Kenneth and Jonsdottir, Ingileif and Munshi, Nikhil and Rafnar, Thorunn and Waage, Anders and Weinhold, Niels and Thorsteinsdottir, Unnur and Sankaran, Vijay G. and Stefansson, Kari and Houlston, Richard and Nilsson, Björn}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Functional dissection of inherited non-coding variation influencing multiple myeloma risk}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-27666-x}},
  doi          = {{10.1038/s41467-021-27666-x}},
  volume       = {{13}},
  year         = {{2022}},
}