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Lookup NU author(s): Dr David Lewis-Smith, Dr Rhys ThomasORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.
Author(s): Montanucci L, Lewis-Smith D, Collins RL, Niestroj L-M, Parthasarathy S, Xian J, Ganesan S, Macnee M, Brünger T, Thomas RH, Talkowski M, Epi25 Collaborative, Helbig I, Leu C, Lal D
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2023
Volume: 14
Online publication date: 20/07/2023
Acceptance date: 16/06/2023
Date deposited: 16/08/2023
ISSN (electronic): 2041-1723
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-023-39539-6
DOI: 10.1038/s41467-023-39539-6
Data Access Statement: All genome-wide CNV association summary statistics are available at Zenodo (https://zenodo.org/record/7939126#.ZGK7yi-B29Y with https://doi.org/10.5281/zenodo.7939126). Individual-level CNV data for epilepsy patients are available from the Epi25 Consortium (http://epi-25.org/) upon signing the Epi25 charter (See Epi25 page http://epi-25.org/) and submission and acceptance of a full research proposal. Furthermore, raw data is deposited at dbGAP https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001551.v1.p1. All HPO-based phenome-wide summary statistics are available in Supplementary Data 3 of this manuscript. Fine-mapping results are available in Supplementary Data 1 and 2 of this manuscript. The CNV data of the Neuropsychiatric cohort are described in the Supplementary Materials of Collins et al.97. They can be accessed from existing publications, public resources, or, upon request, from the authors of Collins et al.
PubMed id: 37474567
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