| Title: |
Polygenic burden in focal and generalized epilepsies |
| Authors: |
Leu, C; Stevelink, R; Smith, AW; Goleva, SB; Kanai, M; Ferguson, L; Campbell, C; Kamatani, Y; Okada, Y; Sisodiya, SM; Cavalleri, GL; Koeleman, BPC; Lerche, H; Jehi, L; Davis, LK; Najm, IM; Palotie, A; Daly, MJ; Busch, RM; Lal, D; Feng, YCA; Howrigan, DP; Abbott, LE; Tashman, K; Cerrato, F; Churchhouse, C; Gupta, N; Neale, BM; Berkovic, SF; Goldstein, DB; Lowenstein, DH; Cossette, P; Cotsapas, C; De Jonghe, P; Dixon-Salazar, T; Guerrini, R; Hakonarson, H; Heinzen, EL; Helbig, I; Kwan, P; Marson, AG; Petrovski, S; Kamalakaran, S; Stewart, R; Weckhuysen, S; Depondt, C; Dlugos, DJ; Scheffer, IE; Striano, P; Freyer, C; Krause, R; May, P; McKenna, K; Regan, BM; Bellows, ST; Bennett, CA; Johns, EMC; Macdonald, A; Shilling, H; Burgess, R; Weckhuysen, D; Bahlo, M; O'Brien, TJ; Todaro, M; Stamberger, H; Andrade, DM; Sadoway, TR; Mo, K; Krestel, H; Gallati, S; Papacostas, SS; Kousiappa, I; Tanteles, GA; Šterbová, K; Vlcková, M; Sedlácková, L; Laššuthová, P; Klein, KM; Rosenow, F; Reif, PS; Knake, S; Kunz, WS; Zsurka, G; Elger, CE; Bauer, J; Rademacher, M; Pendziwiat, M; Muhle, H; Rademacher, A; Van Baalen, A; Von Spiczak, S; Stephani, U; Afawi, Z; Korczyn, AD; Kanaan, M; Canavati, C; Kurlemann, G; Müller-Schlüter, K; Kluger, G; Häusler, M |
| Publisher Information: |
OXFORD UNIV PRESS |
| Publication Year: |
2019 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
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 Japanese-ancestry 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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
0006-8950 |
| Relation: |
pii: 5585821; https://hdl.handle.net/11343/246261 |
| Availability: |
https://hdl.handle.net/11343/246261 |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0 ; CC BY-NC |
| Accession Number: |
edsbas.9C52BD2B |
| Database: |
BASE |