Deciphering genetic susceptibility to multiple myeloma

Abstract

Multiple myeloma (MM) is a malignancy characterised by the clonal expansion of plasma cells primarily from the bone marrow. The two- to four-fold increased risk observed in relatives of MM patients provides support for inherited susceptibility to the disease. Genome-wide association studies (GWAS) have implicated common, low penetrance variants in MM susceptibility, however much of the heritability remains unexplained. To search for novel risk loci, a new GWAS and a meta-analysis with previous GWAS and a replication series, totalling 9,974 MM cases and 247,566 controls of European ancestry was performed. These data provide evidence for six new MM risk loci, bringing the total number to 23. Information from gene expression, regulatory profiling and in situ Hi-C data was integrated for the 23 risk loci. Collectively these data implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation, dysregulation of autophagy/apoptosis and cell cycle signalling as key mechanisms. To identify candidate causal genes at GWAS loci and search for novel risk regions, a multi-tissue transcriptome-wide association study (TWAS) was performed by integrating GWAs data with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues. 108 genes at 13 independent regions associated with MM risk were identified, all of which were within 1Mb of known MM GWAS risk variants. Of these, 94 genes, located in eight regions, had not previously been considered as a candidate gene for that locus. Clustering of chronic lymphocytic leukaemia (CLL) and MM is observed in families, suggesting an element of shared inherited susceptibility. To examine this, cross-trait linkage disequilibrium (LD)-score regression of MM and CLL GWAS data sets was performed. A significant genetic correlation between these two B-cell malignancies was shown (Rg=0.4, P=0.0046). Furthermore, nine loci pleiotropic to MM and CLL were identified and integration and expression data demonstrated that these pleiotropic risk loci were enriched for B-cell regulatory elements, and implicated B-cell developmental genes. No lifestyle or environmental exposures have been consistently linked to an increased risk of MM. Summary data from GWAS of multiple phenotypes can be exploited in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to search for factors influencing MM risk. An MR-PheWAS was performed analysing 249 phenotypes, proxied by 10,225 genetic variants, and summary GWAS data. Although no significant associations with MM risk were observed among the 249 phenotypes, 28 phenotypes showed evidence suggestive of association, including increased levels of serum vitamin B6 and blood carnitine (P=1.1x10-3) with greater MM risk, and increased levels of total cholesterol, blood esterified cholesterol and omega-3 fatty acids (P=5.4x10-4) with reduced MM risk. Collectively these findings provide insight into genetic and genomic architecture, as well as the aetiology of MM.