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.

Keywords: Gene expression; Genome-wide association study; Multiple myeloma; Transcriptome-wide association study.

Fig. 1

Manhattan plots of gene genomic co-ordinates against –log₁₀(P value) of GWAS and TWAS association statistics. a GWAS association statistics. b TWAS association statistics

Fig. 2

Regional plot of association results at 22q13 in MM alongside recombination rates and histone marks in GM12878. Plot shows discovery association results of both genotyped and imputed SNPs in the GWAS samples and recombination rates. −log10 P values (y axes) of the SNPs are shown according to their chromosomal positions (x axes). The colour of each symbol reflects the extent of LD with the top genotyped SNP. Genetic recombination rates, estimated using HapMap samples from Utah residents of western and northern European ancestry (CEU), are shown with a blue line. Physical positions are based on NCBI build 37 of the human genome. Also shown are the relative positions of GENCODE v19 genes mapping to the region of association. Below the association plot are the relative positions of GENCODE v19 genes mapping to the region of association and the histone marks and chromatin loops for lymphoblastoid cell line, GM12878