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 GoldschmidtKari 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, Björn Nilsson

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number151
JournalNature Communications
Issue number1
Publication statusPublished - 2022

Subject classification (UKÄ)

  • Cancer and Oncology


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