Abstract
There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53–4.69, p = 3.55 × 10−15 for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34–4.33, p = 1.62 × 10−13 for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population.
Highlights
Multiple myeloma (MM) is the third most common hematological malignancy with a worldwide incidence rate of 2.1/100,000 new cases each year [1]
A possible approach to improve usefulness of genetic risk markers could be to combine the SNPs in a polygenic risk score (PRS) in order to have a better estimation of their cumulative effect on the risk of developing the disease
In order to focus on the extreme parts of the risk distribution, we calculated the difference in risk of subjects in the 95th percentile compared to subjects in the 5th percentile, and we found a substantial difference in risk (OR = 5.77, 95% CI 2.37–14.06, p = 1.12 × 10−4)
Summary
Multiple myeloma (MM) is the third most common hematological malignancy with a worldwide incidence rate of 2.1/100,000 new cases each year (https://gco.iarc.fr/today/home) [1]. Considering the rarity of the disease, the identified variants have a poor clinical use in predicting the individual risk, especially if considering the general population. A possible approach to improve usefulness of genetic risk markers could be to combine the SNPs in a polygenic risk score (PRS) in order to have a better estimation of their cumulative effect on the risk of developing the disease. This method has been successfully applied to several diseases including breast, prostate, colorectal, and pancreatic cancer [22,23,24,25,26,27,28]. A PRS including all the known risk SNPs has been evaluated in African–Americans [30]
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