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.

Broad Institute of Massachusetts Institute of Technology and Harvard University 415 Main Street Boston MA 02142 USA

Dana Farber Cancer Institute Harvard Medical School Boston MA USA

Department of Cancer Research and Molecular Medicine Norwegian University of Science and Technology Box 8905 N 7491 Trondheim Norway

Department of Internal Medicine 5 University Hospital of Heidelberg 69120 Heidelberg Germany

Division of Genetics and Epidemiology The Institute of Cancer Research 123 Old Brompton Road London SW7 3RP United Kingdom

Division of Hematology Oncology Boston Children's Hospital Harvard Medical School Boston MA USA

eCODE Genetics Amgen Inc Sturlugata 8 101 Reykjavik Iceland

Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague Prague 30605 Czech Republic

German Cancer Research Center Im Neuenheimer Feld 580 D 69120 Heidelberg Germany

Harvard Stem Cell Institute Cambridge MA USA

Hematology and Transfusion Medicine Department of Laboratory Medicine BMC B13 221 84 Lund Sweden

Hopp Children's Cancer Center Heidelberg Germany

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Nat Commun. 2022 Dec 13;13(1):7725. doi: 10.1038/s41467-022-35411-1. PubMed

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Deciphering the genetics and mechanisms of predisposition to multiple myeloma

Investigation of Rare Non-Coding Variants in Familial Multiple Myeloma