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Polygenic burden in focal and generalized epilepsies

Leu, Costin, Stevelink, Remi, Smith, Alexander W., Goleva, Slavina B., Kanai, Masahiro, Ferguson, Lisa, Campbell, Ciaran, Kamatani, Yoichiro, Okada, Yukinor, Sisodiya, Sanjay M., Cavalleri, Gianpiero L., Koeleman, Bobby P.C., Lerche, Holger, Jehi, Lara, Davis, Lea K., Najm, Imad M., Palotie, Aarno, Daly, Mark J., Busch, Robyn M., Lal, Dennis and Bellows, Susannah 2019, Polygenic burden in focal and generalized epilepsies, Brain, vol. 142, no. 11, pp. 3473-3481, doi: 10.1093/brain/awz292.

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Title Polygenic burden in focal and generalized epilepsies
Author(s) Leu, Costin
Stevelink, Remi
Smith, Alexander W.
Goleva, Slavina B.
Kanai, Masahiro
Ferguson, Lisa
Campbell, Ciaran
Kamatani, Yoichiro
Okada, Yukinor
Sisodiya, Sanjay M.
Cavalleri, Gianpiero L.
Koeleman, Bobby P.C.
Lerche, Holger
Jehi, Lara
Davis, Lea K.
Najm, Imad M.
Palotie, Aarno
Daly, Mark J.
Busch, Robyn M.
Lal, Dennis
Bellows, Susannah
Journal name Brain
Volume number 142
Issue number 11
Start page 3473
End page 3481
Total pages 9
Publisher Oxford United Press
Place of publication Oxford, Eng.
Publication date 2019-11
ISSN 0006-8950
1460-2156
Keyword(s) common variant risk
epilepsy
genetic generalized epilepsy
genetics
Epi25 Consortium
Summary Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japaneseancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.39×10-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.
Language eng
DOI 10.1093/brain/awz292
Indigenous content off
Field of Research 11 Medical and Health Sciences
17 Psychology and Cognitive Sciences
HERDC Research category C1 Refereed article in a scholarly journal
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30149419

Document type: Journal Article
Collections: Faculty of Health
School of Psychology
Open Access Collection
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.