Germline variants at SOHLH2 influence multiple myeloma risk

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.

Fig. 1. Region plots of the 13q13.3 association.

a −log₁₀(P) for association in the meta-analysis of the four Nordic discovery sets (y-axis). The colour reflects the extent of LD with the 13q13.3 lead variant rs200203825. b Genes mapping to the region of association, based on NCBI build 38 of the human genome. c Chromatin looping interaction between rs75712673 and the SOHLH2 promoter, detected in promoter-capture HiC in transformed fibroblasts, data from GeneHancer d ATAC-seq chromatin accessibility across primary blood cell types; rs75712673 maps to a region that is selectively open in plasma cells. e Chromatin immunoprecipitation and sequencing (ChIP-seq) data for H3K4me3 histone mark in L363 MM plasma cell line.

Fig. 2. Candidate variant rs75712673 eQTL effect on SOHLH2.

a Correlation of genotype and log transformed RNA-seq data from CD138 + plasma cell isolated from the bone marrow of 188 MM patients (Wilcoxon p = 0.0081). b Luciferase activity of rs75712673 reference and alternative alleles in two MM cell lines, L363 (t-test p = 0.0284) and OPM2 (t-test p = 0.0068) shows that regulation of SOHLH2 expression varies in the two alleles of rs75712673. Error bars indicate standard deviation.