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

Ram Ajore, Abhishek Niroula, Maroulio Pertesi, Caterina Cafaro, Malte Thodberg, Molly Went, Erik L. Bao, Laura Duran-Lozano, Aitzkoa Lopez de Lapuente Portilla, Thorunn Olafsdottir, Nerea Ugidos-Damboriena, Olafur Magnusson, Mehmet Samur, Caleb A. Lareau, Gisli H. Halldorsson, Gudmar Thorleifsson, Gudmundur L. Norddahl, Kristbjorg Gunnarsdottir, Asta Försti, Hartmut Goldschmidt, Kari Hemminki, Frits van Rhee, Scott Kimber, Adam S. Sperling, Martin Kaiser, Kenneth Anderson, Ingileif Jonsdottir, Nikhil Munshi, Thorunn Rafnar, Anders Waage, Niels Weinhold, Unnur Thorsteinsdottir, Vijay G. Sankaran, Kari Stefansson, Richard Houlston and Björn Nilsson ()
Additional contact information
Ram Ajore: Hematology and Transfusion Medicine, Department of Laboratory Medicine
Abhishek Niroula: Hematology and Transfusion Medicine, Department of Laboratory Medicine
Maroulio Pertesi: Hematology and Transfusion Medicine, Department of Laboratory Medicine
Caterina Cafaro: Hematology and Transfusion Medicine, Department of Laboratory Medicine
Malte Thodberg: Hematology and Transfusion Medicine, Department of Laboratory Medicine
Molly Went: Division of Genetics and Epidemiology, The Institute of Cancer Research
Erik L. Bao: Broad Institute of Massachusetts Institute of Technology and Harvard University
Laura Duran-Lozano: Hematology and Transfusion Medicine, Department of Laboratory Medicine
Aitzkoa Lopez de Lapuente Portilla: Hematology and Transfusion Medicine, Department of Laboratory Medicine
Thorunn Olafsdottir: deCODE Genetics/Amgen Inc.
Nerea Ugidos-Damboriena: Hematology and Transfusion Medicine, Department of Laboratory Medicine
Olafur Magnusson: deCODE Genetics/Amgen Inc.
Mehmet Samur: Dana-Farber Cancer Institute, Harvard Medical School
Caleb A. Lareau: Broad Institute of Massachusetts Institute of Technology and Harvard University
Gisli H. Halldorsson: deCODE Genetics/Amgen Inc.
Gudmar Thorleifsson: deCODE Genetics/Amgen Inc.
Gudmundur L. Norddahl: deCODE Genetics/Amgen Inc.
Kristbjorg Gunnarsdottir: deCODE Genetics/Amgen Inc.
Asta Försti: German Cancer Research Center (DKFZ)
Hartmut Goldschmidt: University Hospital of Heidelberg
Kari Hemminki: German Cancer Research Center (DKFZ)
Frits van Rhee: Hopp Children’s Cancer Center
Scott Kimber: Division of Genetics and Epidemiology, The Institute of Cancer Research
Adam S. Sperling: Dana-Farber Cancer Institute, Harvard Medical School
Martin Kaiser: Division of Genetics and Epidemiology, The Institute of Cancer Research
Kenneth Anderson: Dana-Farber Cancer Institute, Harvard Medical School
Ingileif Jonsdottir: deCODE Genetics/Amgen Inc.
Nikhil Munshi: Dana-Farber Cancer Institute, Harvard Medical School
Thorunn Rafnar: deCODE Genetics/Amgen Inc.
Anders Waage: Norwegian University of Science and Technology
Niels Weinhold: German Cancer Research Center (DKFZ)
Unnur Thorsteinsdottir: deCODE Genetics/Amgen Inc.
Vijay G. Sankaran: Broad Institute of Massachusetts Institute of Technology and Harvard University
Kari Stefansson: deCODE Genetics/Amgen Inc.
Richard Houlston: Division of Genetics and Epidemiology, The Institute of Cancer Research
Björn Nilsson: Hematology and Transfusion Medicine, Department of Laboratory Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27666-x

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