Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Ludovica Montanucci, David Lewis-Smith, Ryan L. Collins, Lisa-Marie Niestroj, Shridhar Parthasarathy, Julie Xian, Shiva Ganesan, Marie Macnee, Tobias Brünger, Rhys H. Thomas, Michael Talkowski, Ingo Helbig, Costin Leu and Dennis Lal ()
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Ludovica Montanucci: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic
David Lewis-Smith: Translational and Clinical Research Institute, Newcastle University
Ryan L. Collins: Center for Genomic Medicine, Massachusetts General Hospital
Lisa-Marie Niestroj: University of Cologne
Shridhar Parthasarathy: The Epilepsy NeuroGenetics Initiative, Children’s Hospital of Philadelphia
Julie Xian: The Epilepsy NeuroGenetics Initiative, Children’s Hospital of Philadelphia
Shiva Ganesan: The Epilepsy NeuroGenetics Initiative, Children’s Hospital of Philadelphia
Marie Macnee: University of Cologne
Tobias Brünger: University of Cologne
Rhys H. Thomas: Translational and Clinical Research Institute, Newcastle University
Michael Talkowski: Center for Genomic Medicine, Massachusetts General Hospital
Ingo Helbig: The Epilepsy NeuroGenetics Initiative, Children’s Hospital of Philadelphia
Dennis Lal: Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39539-6

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