The impact of rare pathogenic CNVs is exacerbated by assortative mating.

Copy-number variants (CNVs) are linked to a spectrum of outcomes and carriers of the same variant exhibit variable disease severity. We explored the impact of an individuals polygenic score (PGS) on explaining these differences, focusing on 119 established CNV-trait associations involving 43 clinically-relevant phenotypes. We called CNVs among white British UK Biobank participants, then divided samples into a training set (n = 264,372) to derive independent PGS weights, and a CNV-carrier-enriched test set (n = 96,716) for which PGSs were evaluated. Assessing the individual, joint, and synergistic contribution of CNVs and PGS, we identified a significant additive effect for 45 (38%) CNV-trait pairs but no evidence for interactions. A (spurious) negative correlation between an individuals CNV carrier status and their PGS would be expected under selective participation-induced collider bias. Instead, we observed a widespread positive correlation, which could only be partially accounted for by linkage disequilibrium. Given a non-null inheritance rate for all 17 testable CNVs, we explored whether assortative mating could explain the positive CNV-PGS association. We found strong agreement between this correlation and the one predicted by assortment (r = 0.45, p = 3.9 x 10-7). Similar trends of positive correlation were observed between PGS and genome-wide burden of CNVs or rare loss-of-function variants. Our results suggest that PGSs contribute to the variable expressivity of CNVs and rare variants, and improve the identification of those at higher risk of clinically relevant comorbidities. We also highlight pervasive assortative mating as a likely mechanism contributing to the compounding of genetic effects across mutational classes.