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

R. Ajore, A. Niroula, M. Pertesi, C. Cafaro, M. Thodberg, M. Went, EL. Bao, L. Duran-Lozano, A. Lopez de Lapuente Portilla, T. Olafsdottir, N. Ugidos-Damboriena, O. Magnusson, M. Samur, CA. Lareau, GH. Halldorsson, G. Thorleifsson, GL. Norddahl,...

. 2022 ; 13 (1) : 151. [pub] 20220110

Language English Country Great Britain

Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22011363

Grant support
K08 CA252174 NCI NIH HHS - United States
P01 CA155258 NCI NIH HHS - United States
R01 HL146500 NHLBI NIH HHS - United States
K12 CA087723 NCI NIH HHS - United States
P50 CA100707 NCI NIH HHS - United States
R01 DK103794 NIDDK NIH HHS - United States
C1298/A8362 Cancer Research UK - United Kingdom

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.

References provided by Crossref.org

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