Germline variants at SOHLH2 influence multiple myeloma risk
Duran-Lozano, Laura; Thorleifsson, Gudmar; Lopez de Lapuente Portilla, Aitzkoa; Niroula, Abhishek; Went, Molly; Thodberg, Malte; Pertesi, Maroulio; Ajore, Ram; Cafaro, Caterina; Olason, P; Stefansdottir, Lilja; Bragi Walters, Walters; Halldorsson, Gisli H.; Turesson, Ingemar; Kaiser, Martin; Weinhold, Niels; Abildgaard, Niels; Andersen, Niels Frost; Mellqvist, Ulf-Henrik; Waage, Anders; Vangsted, Annette; Thorsteinsdottir, Unnur; Hansson, Markus; Houlston, Richard S.; Rafnar, Thorunn; Stefansson, Kari; Nilsson, Björn
Peer reviewed, Journal article
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Date
2021Metadata
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- Institutt for klinisk og molekylær medisin [3578]
- Publikasjoner fra CRIStin - NTNU [38484]
- St. Olavs hospital [2558]
Abstract
Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10−14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.