Determinants of pleiotropy and monotonic gene dosage responses across human traits

While pleiotropic effects of gene dosage are of particular relevance for comorbidities observed in the developmental pediatric and psychiatric clinic, the biological processes underlying such pleiotropy remain unknown. We developed a new functional burden analysis (FunBurd) to investigate all CNVs, genome-wide, beyond well-studied recurrent CNVs. In ~500,000 UK-Biobank participants, we tested the association between 43 traits and CNVs disrupting 172 tissue or cell-type gene-sets. CNVs affected all traits. Pleiotropy was correlated with genetic constraint and was higher in the brain compared to non-brain functions, even after normalizing for genetic constraint. The levels of pleiotropy, measured by burden correlation, were similar in deletions and loss-of-function SNVs and higher compared to common variants and duplications. Gene sets under high genetic constraint showed less monotonic gene dosage responses across traits. Even in the absence of a monotonic response, we observed a negative correlation between deletion and duplication effect sizes across most traits. Overall, functional gene sets are preferentially associated with a given trait when either deleted or duplicated, but rarely both.