Combinatorial effects of gene dosage, polygenic background and environment on complex traits
Complex traits arise from the combined effects of rare and common genetic variation, development and environment, but resolving their joint contributions has been limited by statistical power. Here, we meta-analyze effects of recurrent copy number variants (CNVs), polygenic scores, sex, age and medications on height and body mass index in 1,447,001 individuals across 6 biobanks and clinical cohorts. CNVs show largely mirror dose-dependent effects of deletions and duplications on both traits, but a subset of loci exhibit asymmetric dose-responses on adult height, consistent with buffering of one allele but not the other. Polygenic background and medications combine with CNVs in ways broadly consistent with additivity. However, detailed analyses of loci at 16p11.2 and 22q11.2 reveal context-dependent effects that vary across development, physiology and sex. At 22q11.2, the net effect of a CNV reflects opposing and reinforcing contributions of multiple genes, providing a potential mechanism for buffering of dosage effects. These results indicate that genetic effects follow additive patterns in aggregate, while context-dependent deviations are widespread for specific loci.
Authors
- Jacquelyn Johnson
- Margit Nõukas
- Michael Francis (ORCID: https://orcid.org/0000-0002-1320-7161)
- Anjali Srinivasan (ORCID: https://orcid.org/0009-0005-0606-4229)
- Jessica H. Hall (ORCID: https://orcid.org/0000-0002-3433-4784)
- Mihaela Aslan (ORCID: https://orcid.org/0000-0002-5041-010X)
- Murray Stein (ORCID: https://orcid.org/0009-0006-4459-1780)
- Omar Shanta (ORCID: https://orcid.org/0000-0003-2387-2787)
- Iskander Said (ORCID: https://orcid.org/0000-0003-1159-4548)
- Jeffrey R. MacDonald (ORCID: https://orcid.org/0000-0001-5058-2393)
- Ann Swillen (ORCID: https://orcid.org/0000-0003-4258-4537)
- Christa Lese Martin (ORCID: https://orcid.org/0000-0002-8071-5780)
- Josephine E. Haddon (ORCID: https://orcid.org/0000-0001-5975-813X)
- Vincent-Raphaël Bourque (ORCID: https://orcid.org/0000-0001-9420-1724)
- Mieke M. van Haelst (ORCID: https://orcid.org/0000-0002-7519-0246)
- David H. Ledbetter
- Mamad Ahangari
- Tim Bigdeli
- David Linden
- Bryan Gorman
- Marianne B.M. van den Bree
- Adam Maihofer
- James Guevara
- Kelli Lehto (ORCID: https://orcid.org/0000-0003-2735-7643)
- Sebastien Jacquemont
- Donna M. MacDonald-McGinn
- Elaine H. Zackai
- Kyriacos Markianos
- Mart Kals
- T. Blaine Crowley
- Beverly S. Emanuel
- Georgios Voloudakis
- Marieke Klein
- Matthew Oetjens
- Carrie E. Bearden
- Therese van Amelsvoort
- Peter M. Visscher
- Saiju Pyarajan
- Philip D. Harvey
- Florian Benetiere
- Bhooma Thiruvahindrapuram
- Molly F. Sacks (ORCID: https://orcid.org/0009-0007-6990-607X)
- Million Veteran Program
- Claudia Vingerhoets
- Panos Roussos
- Raquel E. Gur
- Daniel E. McGinn
- Jacob Vorstman
- Giulio Genovese
- Jonathan Sebat
- Caroline M. Nievergelt
- Anne S. Bassett
- Joel Gelernter
Institutions
- Florida State University (US)
- Broad Institute (US)
- Florida Department of Education (US)
- Allen Institute for Brain Science (US)
- Booz Allen Hamilton (United States) (US)
- Children's Hospital of Philadelphia (US)
- Centre for Addiction and Mental Health (CA)
- Harvard University (US)
- University of Miami (US)
- Radboud University Nijmegen (NL)
- University of California, Los Angeles (US)
- The University of Queensland (AU)
- SUNY Downstate Health Sciences University (US)
- University of Toronto (CA)
- Veterans Health Administration (US)
- VA NY Harbor Healthcare System (US)
- Mental Health Research UK (GB)
- Hospital for Sick Children (CA)
- VA Boston Healthcare System (US)
- Toronto General Hospital (CA)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Radboud University Medical Center (NL)
- Yale University (US)
- Maastricht University (NL)
- University of California San Diego (US)
- University of Oxford (GB)
- VA Connecticut Healthcare System (US)
- VA San Diego Healthcare System (US)
- Bruce W. Carter VA Medical Center (US)
- James J. Peters VA Medical Center (US)
- Translational Therapeutics (United States) (US)
- Human Longevity (United States) (US)
- SickKids Foundation (CA)
- Department of Veterans Affairs (AU)
- Genomics (United Kingdom) (GB)
- 's Heeren Loo (NL)
- McGill University (CA)
- Geisinger Health System (US)
- University of Tartu (EE)
- Université de Montréal (CA)
- Cardiff University (GB)
- University of Pennsylvania (US)
- University of Amsterdam (NL)
- Icahn School of Medicine at Mount Sinai (US)
- KU Leuven (BE)
Publication Details
- Journal
- medRxiv
- Published
- 2026-05-01
- DOI
- https://doi.org/10.64898/2026.04.30.26352063
- Primary Topic
- Genomic variations and chromosomal abnormalities
- Type
- article
- Field-Weighted Citation Impact
- 0.00