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

Thumbnail Image

Files

Functional dissection of inherited non-coding variation influencing multiple myeloma risk.pdf (6.9 MB)

Embargo End Date

ICR Authors

Went, Molly
 Kaiser, Martin
 Houlston, Richard

Authors

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

Document Type

Journal Article

Date

2022-01-10

Date Accepted

2021-12-02

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 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.

Citation

Nature communications, 2022, 13 (1), pp. 151 - ?

DOI

10.1038/s41467-021-27666-x
10.1038/s41467-021-27666-x

URI

https://repository.icr.ac.uk/handle/internal/5036

Rights

http://creativecommons.org/licenses/by/4.0/

Source Title

Publisher

NATURE PORTFOLIO

ISSN

2041-1723

eISSN

2041-1723
2041-1723

Collections

Genetics and Epidemiology

Research Team

Cancer Genomics
Myeloma Molecular Therapy

Notes