Abstract

Copy number variants (CNVs) have large effects on complex traits, but they are rare and remain challenging to study. As a result, our understanding of biological functions linking gene dosage to complex traits remains limited.

FunBurd (functional burden analysis) was applied in 500,000 individuals from the UKBiobank to associate 43 complex traits with CNVs disrupting 172 tissues/cell type gene sets.

All 43 traits showed associations with CNVs. Brain tissue and neuronal cell types showed the highest levels of pleiotropy. Most of the functional gene set associations could, in part, be explained by genetic constraint, except for brain-related processes. Shared genetic contributions between pairs of traits were 2-fold higher for rare compared to common variants. The functional convergence between different types of variants -even between deletions and duplications- was limited. Our findings provide insights to separate the contributions of genetic constraint and gene function to the associations of CNVs with complex traits.