Functional dissection of inherited non-coding variation influencing multiple myeloma risk.
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Date
2022-01-10Author
Ajore, R
Niroula, A
Pertesi, M
Cafaro, C
Thodberg, M
Went, M
Bao, EL
Duran-Lozano, L
Lopez de Lapuente Portilla, A
Olafsdottir, T
Ugidos-Damboriena, N
Magnusson, O
Samur, M
Lareau, CA
Halldorsson, GH
Thorleifsson, G
Norddahl, GL
Gunnarsdottir, K
Försti, A
Goldschmidt, H
Hemminki, K
van Rhee, F
Kimber, S
Sperling, AS
Kaiser, M
Anderson, K
Jonsdottir, I
Munshi, N
Rafnar, T
Waage, A
Weinhold, N
Thorsteinsdottir, U
Sankaran, VG
Stefansson, K
Houlston, R
Nilsson, B
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
B-Lymphocytes
Plasma Cells
Chromatin
Humans
Multiple Myeloma
Genetic Predisposition to Disease
Adaptor Proteins, Signal Transducing
Guanine Nucleotide Exchange Factors
Cell Cycle Proteins
Neoplasm Proteins
Chromosomal Proteins, Non-Histone
Repressor Proteins
Transcriptional Elongation Factors
DNA, Intergenic
Antineoplastic Combined Chemotherapy Protocols
Risk Assessment
Gene Expression Regulation, Neoplastic
Base Sequence
Inheritance Patterns
Polymorphism, Genetic
Quantitative Trait Loci
Primary Cell Culture
Research team
Cancer Genomics
Myeloma Molecular Therapy
Language
eng
Date accepted
2021-12-02
License start date
2022-01-10
Citation
Nature communications, 2022, 13 (1), pp. 151 - ?
Publisher
NATURE PORTFOLIO
Except where otherwise noted, this item's license is described
as
http://creativecommons.org/licenses/by/4.0/
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