Universität zu Köln

Leu, Costin, Stevelink, Remi, Smith, Alexander W., Goleva, Slavina B., Kanai, Masahiro ORCID: 0000-0001-5165-4408, Ferguson, Lisa, Campbell, Ciaran, Kamatani, Yoichiro, Okada, Yukinori, 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. and Lal, Dennis (2019). Polygenic burden in focal and generalized epilepsies. Brain, 142. S. 3473 - 3482. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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Abstract

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 x 10(-15); Cleveland: P = 2.85 x 10(-4); Finnish-ancestry Epi25: P = 1.80 x 10(-4)) or population controls (Epi25: P = 2.35 x 10(-70); Cleveland: P = 1.43 x 10(-7); Finnish-ancestry Epi25: P = 3.11 x 10(-4); UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99 x 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 x 10(-19); Cleveland: P = 1.69 x 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 x 10(-15); Cleveland: P = 1.39 x 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Leu, Costin UNSPECIFIED UNSPECIFIED UNSPECIFIED Stevelink, Remi UNSPECIFIED UNSPECIFIED UNSPECIFIED Smith, Alexander W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Goleva, Slavina B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kanai, Masahiro UNSPECIFIED orcid.org/0000-0001-5165-4408 UNSPECIFIED Ferguson, Lisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Campbell, Ciaran UNSPECIFIED UNSPECIFIED UNSPECIFIED Kamatani, Yoichiro UNSPECIFIED UNSPECIFIED UNSPECIFIED Okada, Yukinori UNSPECIFIED UNSPECIFIED UNSPECIFIED Sisodiya, Sanjay M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cavalleri, Gianpiero L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Koeleman, Bobby P. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lerche, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Jehi, Lara UNSPECIFIED UNSPECIFIED UNSPECIFIED Davis, Lea K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Najm, Imad M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Palotie, Aarno UNSPECIFIED UNSPECIFIED UNSPECIFIED Daly, Mark J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Busch, Robyn M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lal, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-128650
DOI:	10.1093/brain/awz292
Journal or Publication Title:	Brain
Volume:	142
Page Range:	S. 3473 - 3482
Date:	2019
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2156
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GENOME-WIDE ASSOCIATION; SEIZURE RECURRENCE; RISK PREDICTION; 1ST SEIZURE; METAANALYSIS; POPULATION; FEATURES; HISTORY; BIOBANK; SCORES Multiple languages Clinical Neurology; Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12865