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

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

Title: Functional dissection of inherited non-coding variation influencing multiple myeloma risk
Author: Ajore, Ram
Niroula, Abhishek
Pertesi, Maroulio
Cafaro, Caterina
Thodberg, Malte
Went, Molly
Bao, Erik L.
Duran-Lozano, Laura
Lopez de Lapuente Portilla, Aitzkoa
Olafsdottir, Thorunn
... 26 more authors Show all authors
Date: 2022-01-10
Language: English
Scope: 7237926
School: Health Sciences
Department: Faculty of Industrial Engineering, Mechanical Engineering and Computer Science
Faculty of Medicine
Other departments
Series: Nature Communications; 13(1)
ISSN: 2041-1723
DOI: 10.1038/s41467-021-27666-x
Subject: Adaptor Proteins, Signal Transducing/genetics; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes/immunology; Base Sequence; Cell Cycle Proteins/genetics; Chromatin/chemistry; Chromosomal Proteins, Non-Histone/genetics; DNA, Intergenic/genetics; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Guanine Nucleotide Exchange Factors/genetics; Humans; Inheritance Patterns; Multiple Myeloma/drug therapy; Neoplasm Proteins/genetics; Plasma Cells/immunology; Polymorphism, Genetic; Primary Cell Culture; Quantitative Trait Loci; Repressor Proteins/genetics; Risk Assessment; Transcriptional Elongation Factors/genetics; Multidisciplinary; Physics and Astronomy (all); Chemistry (all); Biochemistry, Genetics and Molecular Biology (all)
URI: https://hdl.handle.net/20.500.11815/3987

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Ajore , R , Niroula , A , Pertesi , M , Cafaro , C , Thodberg , M , Went , M , Bao , E L , Duran-Lozano , L , Lopez de Lapuente Portilla , A , Olafsdottir , T , Ugidos-Damboriena , N , Magnusson , O , Samur , M , Lareau , C A , Halldorsson , G H , Thorleifsson , G , Norddahl , G L , Gunnarsdottir , K , Försti , A , Goldschmidt , H , Hemminki , K , van Rhee , F , Kimber , S , Sperling , A S , Kaiser , M , Anderson , K , Jonsdottir , I , Munshi , N , Rafnar , T , Waage , A , Weinhold , N , Thorsteinsdottir , U , Sankaran , V G , Stefansson , K , Houlston , R & Nilsson , B 2022 , ' Functional dissection of inherited non-coding variation influencing multiple myeloma risk ' , Nature Communications , vol. 13 , no. 1 , 151 , pp. 151 . https://doi.org/10.1038/s41467-021-27666-x


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.


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).

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