Abstract
The genetic basis underlying the inherited risk of developing multiple myeloma (MM) is largely unknown. To examine the impact of rare protein altering variants on the risk of developing MM we analyzed high-coverage exome sequencing data on 513 MM cases and 1,569 healthy controls, performing both single variant and gene burden tests. We did not identify any recurrent coding low-frequency alleles (1–5%) with moderate effect that were statistically associated with MM. In a gene burden analysis we did however identify a promising relationship between variation in the marrow kinetochore microtubule stromal gene KIF18A, which plays a role in control mitotic chromosome positioning dynamics, and risk of MM (P =3.6×10−6). Further analysis showed KIF18A displays a distinct pattern of expression across molecular subgroups of MM as well as being associated with patient survival. Our results inform future study design and provide a resource for contextualizing the impact of candidate MM susceptibility genes.
Highlights
Multiple myeloma (MM) is a malignancy of plasma cells [1] for which there is an increasing incidence as the population ages
In a gene burden analysis we did identify a promising relationship between variation in the marrow kinetochore microtubule stromal gene KIF18A, which plays a role in control mitotic chromosome positioning dynamics, and risk of MM (P =3.6x10−6)
Mapping to the gene encoding RFWD3, which was of borderline significance. rs7188880 is in strong linkage disequilibrium with the missense variant rs7193541 (r2=0.65, D’=0.96) previously shown by genome-wide association studies (GWAS) to influence MM risk [6]
Summary
Multiple myeloma (MM) is a malignancy of plasma cells [1] for which there is an increasing incidence as the population ages. The level of expression of KIF18A in normal plasma cells was found to be lower than that seen in MM (P
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