Transcriptome-wide association study of multiple myeloma identifies candidate susceptibility genes

Abstract

Background: While genome-wide association studies (GWAS) of multiple myeloma (MM) have identified variants at 23 regions influencing risk, the genes underlying these associations are largely unknown. To identify candidate causal genes at these regions and search for novel risk regions, we performed a multi-tissue transcriptome-wide association study (TWAS). Results: GWAS data on 7319 MM cases and 234,385 controls was integrated with Genotype-Tissue Expression Project (GTEx) data assayed in 48 tissues (sample sizes, N = 80-491), including lymphocyte cell lines and whole blood, to predict gene expression. We identified 108 genes at 13 independent regions associated with MM risk, all of which were in 1 Mb 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. Conclusions: Our findings highlight the value of leveraging expression data from multiple tissues to identify candidate genes responsible for GWAS associations which provide insight into MM tumorigenesis. Among the genes identified, a number have plausible roles in MM biology, notably APOBEC3C, APOBEC3H, APOBEC3D, APOBEC3F, APOBEC3G, or have been previously implicated in other malignancies. The genes identified in this TWAS can be explored for follow-up and validation to further understand their role in MM biology.

Mutagenic Activity of AID/APOBEC Deaminases in Antiviral Defense and Carcinogenesis

“…The association of AID/APOBEC proteins with the formation of a tumor clone may be direct, through mutations in the deaminase gene leading to an increase in its activity. The role of mutations in the APOBEC3 genes (paralogs C, D, F, G, and H) in the pathogenesis of multiple myeloma has been revealed [69]; mutations in the genes of deaminases can increase their mutagenic potential in tumors. The appearance of single nucleotide polymorphisms and deletions in APOBEC3 genes correlates with an increased risk of developing bladder and breast cancer, respectively [70][71][72].…”

Genome Instability in Multiple Myeloma: Facts and Factors

“…In total, genes affecting several biological pathways have been tightened to MM development risk, including histone modification and chromatin remodeling, transcription, and co-transcriptional RNA maturation, IRF4-MYC regulatory network, B-cell differentiation, genome stability, and telomere maintenance (see Table S3 ). A recent approach taking advantage of a transcriptome-wide association study allowed for the expansion of GWAS analysis and identified new MM risk genes, including DNA/RNA-editing cytosine deaminases APOBEC3C , APOBEC3D , APOBEC3F , APOBEC3G, and APOBEC3H at 22q13.1, responsible for immunity, and RNF40 at 16p11.2, involved in DSB-repair [ 354 ].…”

“…The minor allele [A] of this SNP downregulates TERT promoter activity and has been associated with the increased breast and ovarian cancer but decreased risk of prostate cancer and MM [ 689 , 697 ]. Additionally, SNP rs10936600 is located in the same 3q26.2 locus and is associated with an increased risk of MM [ 354 ]. This SNP is located within the LRRC34 gene—a predicted ribonuclease inhibitor.…”

The Significance of mRNA in the Biology of Multiple Myeloma and Its Clinical Implications

“…Patients reclassified from standard-risk FISH to HR GEP presented with 1q amplification of equal to or over four copies [ 54 ]. Elsewhere, a multi-tissue transcriptome-wide association study (TWAS) aimed at exploring MM biology by Went et al [ 55 ] identified 108 genes at 13 independent regions associated with MM risk; all of these were within 1 Mb of known MM GWAS risk variants [ 56 , 57 , 58 , 59 ].…”