Pleiotropic and Distributed Neuropsychiatric Effects of Neurodevelopmental Copy Number Variants in the All of Us Biobank
- 1UT Health San Antonio
Abstract
BackgroundNeurodevelopmental copy number variants (ND-CNVs) are associated with diverse neuropsychiatric outcomes, but most evidence derives from clinically ascertained cohorts enriched for severe disease. Whether these associations generalize to large, heterogeneous population biobanks, and whether they reflect locus-specific or distributed genetic effects, remains unclear.
MethodsWe developed a scalable analytic pipeline within the All of Us Research Program to identify ND-CNV carriers from structural variant callsets and evaluate associations across neuropsychiatric phenotypes derived from electronic health records (EHRs). Logistic regression models estimated associations between carrier status and individual phenotypes, adjusting for age, healthcare utilization, observation time, and genetic ancestry principal components. Sensitivity analyses included exclusion of mosaic chromosomal alteration (mCA)-suspected events and leave-one-locus-out (LOLO) models. Phenotypes were further grouped into Research Domain Criteria (RDoC) domains to assess domain-level structure and cross-domain burden.
ResultsND-CNV carrier status was associated with modest but consistent enrichment across neuropsychiatric phenotypes spanning affective, psychotic, neurodevelopmental, and trauma-related domains. Although no individual phenotype survived false discovery rate correction, global permutation analyses demonstrated directional enrichment exceeding expectations under randomized exposure assignment. Effects were distributed rather than driven by a single phenotype or locus, with deletion-overlapping carriers showing stronger associations than duplication-overlapping carriers. Associations remained stable after mCA exclusion and LOLO analyses. Domain-level analyses revealed correlated enrichment across RDoC systems, while cross-domain burden measures demonstrated strong interdependence but limited discriminative separation.
ConclusionsND-CNV carriers exhibit distributed, pleiotropic neuropsychiatric risk in a large biobank. These findings provide empirical support for a distributed model of ND-CNV-associated neuropsychiatric liability in which numerous modest, directionally concordant phenotype associations collectively contribute to pleiotropic risk across neuropsychiatric domains.
Related
- Identification of pleiotropic genes and biological mechanisms underlying the shared genetic component between asthma, neuropsychiatric disorders, and substance use behaviors
- Schizophrenia-associated polygenic liability and structural genomic risk demonstrate broadly distributed neuropsychiatric associations in the All of Us Research Program
- Biallelic BECN1 variants cause neurodevelopmental disorders via AMPA receptor dysregulation
- Recessive loss-of-function and dominant gain-of-function variants in FBXO31 are associated with distinct neurodevelopmental disorders
- Rare genetic variants influence participation in cognitive components of the UK Biobank
BibTeX
@misc{wells2026pleiotropic,
title = {{Pleiotropic and Distributed Neuropsychiatric Effects of Neurodevelopmental Copy Number Variants in the All of Us Biobank}},
author = {A. M. Wells and F. Zhao and S. Seshadri and J. E. Cavazos and A. Ruiz Laza},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.13.26362959},
url = {https://www.medrxiv.org/content/10.64898/2026.09.13.26362959v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - Pleiotropic and Distributed Neuropsychiatric Effects of Neurodevelopmental Copy Number Variants in the All of Us Biobank
AU - A. M. Wells
AU - F. Zhao
AU - S. Seshadri
AU - J. E. Cavazos
AU - A. Ruiz Laza
PY - 2026
DA - 2026/09/13
PB - medRxiv
DO - 10.64898/2026.09.13.26362959
UR - https://www.medrxiv.org/content/10.64898/2026.09.13.26362959v1
AB - BackgroundNeurodevelopmental copy number variants (ND-CNVs) are associated with diverse neuropsychiatric outcomes, but most evidence derives from clinically ascertained cohorts enriched for severe disease. Whether these associations generalize to large, heterogeneous population biobanks, and whether they reflect locus-specific or distributed genetic effects, remains unclear. MethodsWe developed a scalable analytic pipeline within the All of Us Research Program to identify ND-CNV carriers from structural variant callsets and evaluate associations across neuropsychiatric phenotypes derived from electronic health records (EHRs). Logistic regression models estimated associations between carrier status and individual phenotypes, adjusting for age, healthcare utilization, observation time, and genetic ancestry principal components. Sensitivity analyses included exclusion of mosaic chromosomal alteration (mCA)-suspected events and leave-one-locus-out (LOLO) models. Phenotypes were further grouped into Research Domain Criteria (RDoC) domains to assess domain-level structure and cross-domain burden. ResultsND-CNV carrier status was associated with modest but consistent enrichment across neuropsychiatric phenotypes spanning affective, psychotic, neurodevelopmental, and trauma-related domains. Although no individual phenotype survived false discovery rate correction, global permutation analyses demonstrated directional enrichment exceeding expectations under randomized exposure assignment. Effects were distributed rather than driven by a single phenotype or locus, with deletion-overlapping carriers showing stronger associations than duplication-overlapping carriers. Associations remained stable after mCA exclusion and LOLO analyses. Domain-level analyses revealed correlated enrichment across RDoC systems, while cross-domain burden measures demonstrated strong interdependence but limited discriminative separation. ConclusionsND-CNV carriers exhibit distributed, pleiotropic neuropsychiatric risk in a large biobank. These findings provide empirical support for a distributed model of ND-CNV-associated neuropsychiatric liability in which numerous modest, directionally concordant phenotype associations collectively contribute to pleiotropic risk across neuropsychiatric domains.
ER -