Background:
Large copy-number variants (CNVs) are linked to a broad spectrum of outcomes, with carriers of the same CNV exhibiting variable disease severity. Although additional rare and common variants have been proposed as modifiers of CNVs' expressivity, their interplay still remains largely understudied.

Material and Methods:
We explored the impact of polygenic scores (PGS) on shaping CNV carriers' heterogeneity in the UK Biobank, focusing on 119 established CNV-trait associations comprising 43 traits and 27 CNVs. Linear regressions assessed the individual, joint, and synergistic contributions of CNVs and PGSs. Due to participation bias in population biobanks, we expected trait-increasing CNV carriers to have lower PGSs.

Results:
We demonstrate additive contribution of PGS and CNV for 45 (38%) CNV-trait pairs, as well as two interactions between the 22q11.23 duplication and PGSs for grip strength and gamma-glutamyltransferase levels. Strikingly, CNVs and PGSs exhibited a widespread positive correlation, revealing a tendency for PGSs to exacerbate CNV effects—a pattern that could be explained by linkage disequilibrium only for a single CNV-trait pair. Given a non-null inheritance rate for all 17 testable CNVs, we investigated whether assortative mating could account for this phenomenon. We found strong agreement between the empirical CNV-PGS correlation and the one predicted by assortment (r=0.45, p=3.9e-7). Similar trends of positive correlation were observed between PGSs and genome-wide burden of CNVs or loss-of-function variants.

Conclusion:
PGSs improve stratification of CNV carriers at risk of developing clinically-relevant comorbidities, compounding the impact of rare damaging variants through assortative mating.

Co-authors: Chiara Auwerx, Robin Hofmeister, Théo Cavinato, Tabea Schoeler, Zoltán Kutalik, Alexandre Reymond