Determinants of functional burden pleiotropy and gene dosage responses across human traits

Pleiotropic and monotonic 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. We observed associations for all traits and replicated these associations in the All of Us cohort. Functional burden pleiotropy, defined as the number of traits significantly associated with a gene set, was correlated with genetic constraint and was higher for brain compared to non-brain functions, even after normalizing for genetic constraint. Levels of pleiotropy, measured by burden correlation, were similar in deletions and loss-of-function SNVs, and higher compared to common variants and duplications. Most gene dosage responses were non-monotonic, with deletions and duplications showing same-direction effects, and the proportions of monotonic responses decreased with genetic constraint. Consistent with this paucity of monotonicity, associations between functional gene sets and traits were observed for either deletions or duplications, but rarely both. In addition, deletion and duplication effect sizes were negatively correlated, demonstrating that associations between traits and functional gene sets are variant-specific. Our results highlight the key role of genetic constraint and brain-specific mechanisms in shaping monotonicity and pleiotropy, providing a mechanistic basis for the whole-body multimorbidity observed in neurodevelopmental and psychiatric conditions.