| Title: | Determinants of functional burden pleiotropy and gene dosage responses across human traits |
| Journal: | Nature Communications |
| Published: | 14 Aug 2026 |
| DOI: | https://doi.org/10.1038/s41467-026-76676-0 |
| URL: | https://www.nature.com/articles/s41467-026-76676-0_reference.pdf |
Publication 21010
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Abstract
Pleiotropic and monotonic effects of gene dosage are central to understanding comorbidities in developmental pediatric and psychiatric disorders, yet the underlying biological processes are not well characterized. Here we develop a functional burden analysis to investigate the association of all protein-coding copy-number variants, genome-wide, with 43 complex traits in approximately 500,000 UK Biobank participants. We test variant associations disrupting 172 tissue or cell-type gene sets, finding associations for all traits, which we replicate in the All of Us cohort. Functional burden pleiotropy, defined as the number of traits significantly associated with a gene set, correlates with genetic constraint and is higher for brain than non-brain functions, even after normalizing for genetic constraint. Levels of pleiotropy, measured by burden correlation, are similar in deletions and loss-of-function single-nucleotide variants, and higher than in common variants and duplications. Most gene dosage responses are non-monotonic, with deletions and duplications showing same-direction effects, and monotonic responses decrease with genetic constraint. We observe associations between functional gene sets and traits for either deletions or duplications, but rarely both, with negatively correlated effect sizes. Together, these results link genetic constraint and brain-specific mechanisms to the whole-body multimorbidity of neurodevelopmental and psychiatric conditions.</p>
20 Authors
- Sayeh Kazem
- Kuldeep Kumar
- Jane Yang
- Florian Benitiere
- Guillaume Huguet
- Josephine Mollon
- Thomas Renne
- Laura M. Schultz
- Emma E. M. Knowles
- Worrawat Engchuan
- Omar Shanta
- Bhooma Thiruvahindrapuram
- Jeffrey R. MacDonald
- Celia M. T. Greenwood
- Stephen W. Scherer
- Laura Almasy
- Jonathan Sebat
- David C. Glahn
- Guillaume Dumas
- Sébastien Jacquemont
1 Application
| Application ID | Title |
|---|---|
| 40980 | Rare deleterious CNVs share some overlapping effects on brain structure. |
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