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Functional dissection of inherited non-coding variation influencing multiple myeloma risk
Authors
Ram Ajore
Kenneth Anderson
+34 more
Erik L. Bao
Caterina Cafaro
Laura Duran-Lozano
Asta Försti
Hartmut Goldschmidt
Kristbjorg Gunnarsdottir
Gisli H. Halldorsson
Kari Hemminki
Richard Houlston
Ingileif Jonsdottir
Martin Kaiser
Scott Kimber
Caleb A. Lareau
Aitzkoa Lopez de Lapuente Portilla
Olafur Magnusson
Nikhil Munshi
Björn Nilsson
Abhishek Niroula
Gudmundur L. Norddahl
Thorunn Olafsdottir
Maroulio Pertesi
Thorunn Rafnar
Mehmet Samur
Vijay G. Sankaran
Adam S. Sperling
Kari Stefansson
Malte Thodberg
Gudmar Thorleifsson
Unnur Thorsteinsdottir
Nerea Ugidos-Damboriena
Frits van Rhee
Anders Waage
Niels Weinhold
Molly Went
Publication date
10 January 2022
Publisher
'Springer Science and Business Media LLC'
Doi
Cite
Abstract
Funding Information: This work was supported by grants from the Knut and Alice Wallenberg Foundation (2012.0193 and 2017.0436), the Swedish Research Council (2017-02023 and 2018-00424), the Swedish Cancer Society (2017/265), the Nordic Cancer Union (R217-A13329-18-S65), Arne and Inga-Britt Lundberg’s Stiftelse (2017-0055), European Research Council (EU-MSCA-COFUND 754299 CanFaster), Myeloma UK and Cancer Research UK (C1298/A8362), The National Institute of Health (R01 DK103794 and R01HL146500), the New York Stem Cell Foundation, a gift from the Lodish Family to Boston Children’s Hospital, and Mr. Ralph Stockwell. We thank Ellinor Johnsson for her assistance between 2011 and 2020. We are indebted to the patients who participated in the study. Publisher Copyright: © 2022, The Author(s).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.Peer reviewe
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Last time updated on 09/03/2023