Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27666-x
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Funding
- Knut and Alice Wallenberg Foundation [2012.0193, 2017.0436]
- Swedish Research Council [2017-02023, 2018-00424]
- Swedish Cancer Society [2017/265]
- Nordic Cancer Union [R217-A13329-18-S65]
- Arne and Inga-Britt Lundberg's Stiftelse [2017-0055]
- European Research Council (EU-MSCA-COFUND) [754299, 847583]
- Myeloma UK
- Cancer Research UK [C1298/A8362]
- National Institute of Health [R01 DK103794, R01HL146500]
- New York Stem Cell Foundation
- Marie Curie Actions (MSCA) [847583] Funding Source: Marie Curie Actions (MSCA)
- Swedish Research Council [2018-00424, 2017-02023] Funding Source: Swedish Research Council
- Vinnova [2018-00424] Funding Source: Vinnova
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This integrative study investigates over a thousand variants associated with multiple myeloma, identifying potential causal variants at six risk loci and highlighting the role of gene-regulatory changes in plasma cells and B-cells in mediating disease susceptibility.
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. The causality and functional roles of disease-associated variants revealed by genome-wide association studies (GWAS) are mostly unexplored. Here the authors identify putative causal variants in multiple myeloma and find their association with gene expression and chromatin accessibility.
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