TY - JOUR
T1 - Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals
AU - Epi25 Collaborative
AU - Columbia University Institute for Genomic Medicine analysis group
AU - Epi25 sequencing, analysis, project management, and browser development at the Broad Institute
AU - Epi25 executive committee
AU - Epi25 strategy, phenotyping, analysis, informatics, and project management committees
AU - Authors from individual Epi25 cohorts:
AU - Montanucci, Ludovica
AU - Lewis-Smith, David
AU - Collins, Ryan L.
AU - Niestroj, Lisa Marie
AU - Parthasarathy, Shridhar
AU - Xian, Julie
AU - Ganesan, Shiva
AU - Macnee, Marie
AU - Brünger, Tobias
AU - Thomas, Rhys H.
AU - Talkowski, Michael
AU - Motelow, Joshua E.
AU - Povysil, Gundula
AU - Dhindsa, Ryan S.
AU - Stanley, Kate E.
AU - Allen, Andrew S.
AU - Goldstein, David B.
AU - Feng, Yen Chen Anne
AU - Howrigan, Daniel P.
AU - Abbott, Liam E.
AU - Tashman, Katherine
AU - Cerrato, Felecia
AU - Cusick, Caroline
AU - Singh, Tarjinder
AU - Heyne, Henrike
AU - Byrnes, Andrea E.
AU - Churchhouse, Claire
AU - Watts, Nick
AU - Solomonson, Matthew
AU - Lal, Dennis
AU - Gupta, Namrata
AU - Neale, Benjamin M.
AU - Berkovic, Samuel F.
AU - Lerche, Holger
AU - Lowenstein, Daniel H.
AU - Cavalleri, Gianpiero L.
AU - Cossette, Patrick
AU - Cotsapas, Chris
AU - De Jonghe, Peter
AU - Dixon-Salazar, Tracy
AU - Guerrini, Renzo
AU - Hakonarson, Hakon
AU - Heinzen, Erin L.
AU - Helbig, Ingo
AU - Kwan, Patrick
AU - Marson, Anthony G.
AU - Petrovski, Slavé
AU - Kamalakaran, Sitharthan
AU - Korczyn, Amos D.
AU - Cherny, Stacey S.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85165735871&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-39539-6
DO - 10.1038/s41467-023-39539-6
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C2 - 37474567
AN - SCOPUS:85165735871
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4392
ER -