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.
Funding
Wellcome Trust [203914/Z/16/Z]
The Hartwell Foundation (Individual Biomedical Research Award)
National Institute for Neurological Disorders and Stroke (K02 NS112600)
Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Intellectual and Developmental Disabilities Research Center (IDDRC) at Children’s Hospital of Philadelphia and the University of Pennsylvania (U54 HD086984)
German Research Foundation (HE5415/3-1, HE5415/5-1, HE5415/6-1, HE5415/7-1)
National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001878)
Institute for Translational Medicine and Therapeutics’ (ITMAT) at the Perelman School of Medicine of the University of Pennsylvania
Children’s Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative (ENGIN)
NHGRI T32HG002295
NSF GRFP #2017240332
National Human Genome Research Institute (NHGRI)
National Heart, Lung, and Blood Institute (NHLBI)
NHGRI grant UM1 HG008895
NHGRI grant 5U01HG009088-02
History
Data Availability 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.97 (see “Key resources table” and Table S2 in Collins et al.97). The CNV data reported by GeneDx and Indiana University clinical testing sites were not consented for public release. All datasets used in this study are detailed in Supplementary Table 1 of our manuscript.
Comments
The original article is available at https://www.nature.com/
Published Citation
Montanucci L. et al. Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals. Nat Commun. 2023;14(1):4392.