| Title: |
Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals |
| Authors: |
Epi25 Collaborative; Columbia University Institute for Genomic Medicine analysis group; Epi25 sequencing; analysis; project management; and browser development at the Broad Institute; Epi25 executive committee; Epi25 strategy; phenotyping; informatics; and project management committees; Authors from individual Epi25 cohorts; Montanucci, Ludovica; Lewis-Smith, David; Collins, Ryan L. |
| Contributors: |
HUS Children and Adolescents; Children's Hospital; Lastenneurologian yksikkö; Department of Medical and Clinical Genetics; Medicum |
| Publisher Information: |
Nature Publishing Group |
| Publication Year: |
2023 |
| Collection: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| Subject Terms: |
Biomedicine; Genetics; developmental biology; physiology |
| Description: |
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. ; Peer reviewed |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISBN: |
978-0-01-040020-5; 0-01-040020-6 |
| Relation: |
This research was funded in whole, or in part, by the Wellcome Trust [203914/Z/16/Z], supporting D.L.S. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. I.H. was supported by The Hartwell Foundation (Individual Biomedical Research Award), the National Institute for Neurological Disorders and Stroke (K02 NS112600), the 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), and by the German Research Foundation (HE5415/3-1, HE5415/5-1, HE5415/6-1, HE5415/7-1). Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001878), by the Institute for Translational Medicine and Therapeutics’ (ITMAT) at the Perelman School of Medicine of the University of Pennsylvania, and by Children’s Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative (ENGIN). R.L.C. was supported by NHGRI T32HG002295 and NSF GRFP #2017240332. We thank the Epi25 principal investigators, local staff from individual cohorts, and all of the patients with epilepsy who participated in the study for making this global collaboration and resource possible to advance epilepsy genetics research. This work is part of the Centers for Common Disease Genomics (CCDG) program, funded by the National Human Genome Research Institute (NHGRI) and the National Heart, Lung, and Blood Institute (NHLBI). CCDG-funded Epi25 research activities at the Broad Institute, including genomic data generation in the Broad Genomics Platform, are supported by NHGRI grant UM1 HG008895 (PIs: Eric Lander, Stacey Gabriel, Mark Daly, Sekar Kathiresan). The Genome Sequencing Program efforts were also supported by NHGRI grant 5U01HG009088-02. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank the Stanley Center for Psychiatric Research at the Broad Institute for supporting the genomic data generation efforts and control sample aggregation.; https://hdl.handle.net/10138/565986; 85165735871; 001040020600007 |
| Availability: |
https://hdl.handle.net/10138/565986 |
| Rights: |
cc_by ; info:eu-repo/semantics/openAccess ; openAccess |
| Accession Number: |
edsbas.ACD02D3E |
| Database: |
BASE |