Journal Article

DKFZ-2022-00077

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Functional dissection of inherited non-coding variation influencing multiple myeloma risk.

Ajore, R. ; Niroula, A. ; Pertesi, M. ; Cafaro, C. ; Thodberg, M. ; Went, M. ; Bao, E. L. ; Duran-Lozano, L. ; Lopez de Lapuente Portilla, A. ; Olafsdottir, T. ; Ugidos-Damboriena, N. ; Magnusson, O. ; Samur, M. ; Lareau, C. A. ; Halldorsson, G. H. ; Thorleifsson, G. ; Norddahl, G. L. ; Gunnarsdottir, K. ; Försti, A.DKFZ* ; Goldschmidt, H. ; Hemminki, K.DKFZ* ; van Rhee, F. ; Kimber, S. ; Sperling, A. S. ; Kaiser, M. ; Anderson, K. ; Jonsdottir, I. ; Munshi, N. ; Rafnar, T. ; Waage, A. ; Weinhold, N.DKFZ* ; Thorsteinsdottir, U. ; Sankaran, V. G. ; Stefansson, K. ; Houlston, R. ; Nilsson, B.

2022
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-021-27666-x

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.

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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. C020 Epidemiologie von Krebs (C020)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2022

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