TY - JOUR AB - 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 Europ AU - Leu,C AU - Stevelink,R AU - Smith,AW AU - Goleva,SB AU - Kanai,M AU - Ferguson,L AU - Campbell,C AU - Kamatani,Y AU - Okada,Y AU - Sisodiya,SM AU - Cavalleri,GL AU - Koeleman,BPC AU - Lerche,H AU - Jehi,L AU - Davis,LK AU - Najm,IM AU - Palotie,A AU - Daly,MJ AU - Busch,RM AU - Epi25,Consortium AU - Lal,D DO - brain/awz292 EP - 3481 PY - 2019/// SP - 3473 TI - Polygenic burden in focal and generalized epilepsies. T2 - Brain UR - http://dx.doi.org/10.1093/brain/awz292 UR - https://www.ncbi.nlm.nih.gov/pubmed/31608925 UR - http://hdl.handle.net/10044/1/78519 VL - 142 ER -