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.
Highlights
Multiple myeloma (MM) is characterized by an uncontrolled, clonal expansion of plasma cells in the bone marrow, producing a monoclonal immunoglobulin (“M protein”)
MM is preceded by monoclonal gammopathy of undetermined significance (MGUS)[2,3], detectable in 3% of individuals older than 50 years[4], which progresses to MM at an annual rate of about 1%5
To advance our understanding of MM genetics, we carried out a Genome-wide association studies (GWAS) based on cases and controls from four Nordic populations, with follow-up in additional data sets of European ancestry
Summary
Multiple myeloma (MM) is characterized by an uncontrolled, clonal expansion of plasma cells in the bone marrow, producing a monoclonal immunoglobulin (“M protein”). MM is preceded by monoclonal gammopathy of undetermined significance (MGUS)[2,3], detectable in 3% of individuals older than 50 years[4], which progresses to MM at an annual rate of about 1%5. Genome-wide association studies (GWAS) have identified inherited sequence variants at 24 loci that influence MM risk and sequencing studies of familial cases have implicated candidate genes where rare MM-predisposing variants might reside[12]. We detect a novel MM risk locus at 13q13.3, spanning the SOHLH2 gene. Dissecting the functional architecture, we identify a putative causal variant within the linkage disequilibrium (LD) block that likely acts by upregulating SOHLH2 in plasma cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
