Search for multiple myeloma risk factors using Mendelian randomization

Abstract

The etiology of multiple myeloma (MM) is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited in a Mendelian randomization (MR) phenome-wide association study (PheWAS) to search for factors influencing MM risk. We performed an MR-PheWAS analyzing 249 phenotypes, proxied by 10 225 genetic variants, and summary genetic data from a GWAS of 7717 MM cases and 29 304 controls. Odds ratios (ORs) per 1 standard deviation increase in each phenotype were estimated under an inverse variance weighted random effects model. A Bonferroni-corrected threshold of P = 2 × 10-4 was considered significant, whereas P < .05 was considered suggestive of an association. 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 = 1.1 × 10-3) with greater MM risk and ω-3 fatty acids (P = 5.4 × 10-4) with reduced MM risk. A suggestive association between increased telomere length and reduced MM risk was also noted; however, this association was primarily driven by the previously identified risk variant rs10936599 at 3q26 (TERC). Although not statistically significant, increased body mass index was associated with increased risk (OR, 1.10; 95% confidence interval, 0.99-1.22), supporting findings from a previous meta-analysis of prospective observational studies. Our study did not provide evidence supporting any modifiable factors examined as having a major influence on MM risk; however, it provides insight into factors for which the evidence has previously been mixed.

Graphical abstract

Figure 1.

Principles of MR and the assumptions that need to be satisfied to derive unbiased causal effect estimates. Dashed lines represent direct causal and potential pleiotropic effects that would violate MR assumptions. A indicates genetic variants used as IVs are only associated with the modifiable risk factor; B indicates genetic variants only influence the risk of developing MM through the modifiable risk factor; C indicates genetic variants are not associated with any measured or unmeasured confounders. SNP, single-nucleotide polymorphism.

Figure 2.

Volcano plot of the OR_SD from IVW-RE or Wald ratio MR analysis of 249 phenotypes with risk of MM. Dashed gray line corresponds to P = .05. ln, natural logarithm; PVE, proportion of variance explained.

Figure 3.

Forest plot of 28 phenotypes suggestively associated with risk of MM. 95% CIs indicated by horizontal lines. Vertical line denotes the null value (OR_SD, 1).

Figure 4.

Forest plot showing the effect of alleles associated with longer telomere length on MM risk. 95% CIs indicated by horizontal lines. Diamonds represent overall causal effects estimated using IVW fixed effect (IVW-FE) and IVW-RE models, respectively, with CIs indicated by diamond width. Vertical line denotes the null value (OR_SD, 1).