Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals
<p>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 va...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2023
|
| _version_ | 1797111893799731200 |
|---|---|
| author | Montanucci, L Lewis-Smith, D Collins, RL Niestroj, L-M Parthasarathy, S Xian, J Ganesan, S Macnee, M Brünger, T Thomas, RH Talkowski, M Helbig, I Leu, C Lal, D |
| author2 | Epi25 Collaborative |
| author_facet | Epi25 Collaborative Montanucci, L Lewis-Smith, D Collins, RL Niestroj, L-M Parthasarathy, S Xian, J Ganesan, S Macnee, M Brünger, T Thomas, RH Talkowski, M Helbig, I Leu, C Lal, D |
| author_sort | Montanucci, L |
| collection | OXFORD |
| description | <p>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.</p> |
| first_indexed | 2024-03-07T08:16:51Z |
| format | Journal article |
| id | oxford-uuid:342033db-6858-4aa3-bb9f-c41d2c7bf850 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:16:51Z |
| publishDate | 2023 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:342033db-6858-4aa3-bb9f-c41d2c7bf8502024-01-10T08:04:45ZGenome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individualsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:342033db-6858-4aa3-bb9f-c41d2c7bf850EnglishSymplectic ElementsSpringer Nature2023Montanucci, LLewis-Smith, DCollins, RLNiestroj, L-MParthasarathy, SXian, JGanesan, SMacnee, MBrünger, TThomas, RHTalkowski, MHelbig, ILeu, CLal, DEpi25 CollaborativeNewton, CRJ<p>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.</p> |
| spellingShingle | Montanucci, L Lewis-Smith, D Collins, RL Niestroj, L-M Parthasarathy, S Xian, J Ganesan, S Macnee, M Brünger, T Thomas, RH Talkowski, M Helbig, I Leu, C Lal, D Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals |
| title | Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals |
| title_full | Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals |
| title_fullStr | Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals |
| title_full_unstemmed | Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals |
| title_short | Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals |
| title_sort | genome wide identification and phenotypic characterization of seizure associated copy number variations in 741 075 individuals |
| work_keys_str_mv | AT montanuccil genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT lewissmithd genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT collinsrl genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT niestrojlm genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT parthasarathys genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT xianj genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT ganesans genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT macneem genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT brungert genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT thomasrh genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT talkowskim genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT helbigi genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT leuc genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals AT lald genomewideidentificationandphenotypiccharacterizationofseizureassociatedcopynumbervariationsin741075individuals |