Determinants of pleiotropy and monotonic gene dosage responses across human traits

Pleiotropic effects of gene dosage are central to understanding comorbidities in developmental pediatric and psychiatric disorders, yet the underlying biological processes are unknown. We developed Functional Burden analysis (FunBurd) to investigate the association of all protein-coding copy-number-variants (CNVs), genome-wide, with 43 complex traits in ∼500,000 UK-Biobank participants. We tested CNV associations disrupting 172 tissue or cell-type gene-sets, observing associations across 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. Cognition and mental health traits showed specific gene-dosage effects across cortical/sub-cortical and neuronal/glial functional categories. 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. Across most traits, we observed a negative deletion-duplication effect size correlation, indicating that functional gene sets are preferentially sensitive to either deletion or duplication, but rarely both. Our results highlight the key role of genetic constraint and brain-specific mechanisms in shaping CNV-driven pleiotropy, providing a mechanistic basis for the whole-body multimorbidity observed in neurodevelopmental and psychiatric conditions.