Estimation of the proportion of familial MM cases associated with enrichment of common MM risk alleles and other etiologies, respectively. Theoretically, the risk score of an individual with familial MM can be drawn from either of 2 underlying distributions, depending on the etiology: cases of familial MM associated with enrichment of common risk alleles are expected to follow a right-shifted distribution, whereas cases of MM on the basis of etiologies that are not quantified by our polygenic risk scores will follow the same distribution as population controls (solid blue). The risk score distribution for the group as a whole will be a mixture of these 2 components (C1 and C2; dotted) with proportions π and 1-π, respectively. To estimate π, we fit this 2-component Gaussian mixture distribution (dashed red) to the observed risk scores (solid red): (A) with the number-of-risk-alleles score, the corresponding proportion was 30%, and mean of the enriched component was 17.6; (B) with the sum-of-log-OR score, we estimated π at 37%, and the mean of the enriched component was 2.91. These results support that about one-third of familial MM cases are caused by polygenic inheritance of a high risk allele burden. (C-D) Corresponding density distribution plots for the same data.