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 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. Gene dosage can help explain comorbidities in developmental pediatric and psychiatric disorders. Here, the authors map how rare copy-number variants disrupting tissue and cell-type gene sets shape 43 human traits.

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Publication Details

Journal
Nature Communications
Published
2026-08-14
DOI
https://doi.org/10.1038/s41467-026-76676-0
Primary Topic
Growth Hormone and Insulin-like Growth Factors
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Celia M.T. Greenwood, Guillaume Dumas, Sayeh Kazem, Guillaume Huguet et al.
Nature Communications
Growth Hormone and Insulin-like Growth Factors
article

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

Celia M.T. Greenwood, Guillaume Dumas, Sayeh Kazem, Guillaume Huguet, Bhooma Thiruvahindrapuram, Stephen W. Scherer, Kuldeep Kumar, Omar Shanta, Worrawat Engchuan, Jeffrey R. MacDonald, Josephine Mollon, Florian Bénitière, Emma E. M. Knowles, Thomas Renne, David C. Glahn, Sébastien Jacquemont, Laura M. Schultz, Jonathan Sebat, Laura Almasy, Jane Yang
article en

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. Gene dosage can help explain comorbidities in developmental pediatric and psychiatric disorders. Here, the authors map how rare copy-number variants disrupting tissue and cell-type gene sets shape 43 human traits.

Nature Communications
Boston Children's Hospital (US), Children's Hospital of Philadelphia (US), Harvard University (US), University of Toronto (CA), Massachusetts Mental Health Center (US), Hospital for Sick Children (CA), McGill University Health Centre (CA), Jewish General Hospital (CA), Centre Hospitalier Universitaire Sainte-Justine (CA), University of California San Diego (US), SickKids Foundation (CA), Mila - Quebec Artificial Intelligence Institute (CA), McGill University (CA), University of Pennsylvania (US)
Fondation Brain Canada, Compute Canada, Canada First Research Excellence Fund, Institut de Valorisation des Données, National Institutes of Health, Canadian Institutes of Health Research
Openalex Percentile: Top 10%
Growth Hormone and Insulin-like Growth Factors
DOIOpen Access PDFOpenAlex
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