title: A genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy.
abstract: We present the analysis of a prospective multicentre study to investigate genetic effects on the prognosis of newly treated epilepsy. Patients with a new clinical diagnosis of epilepsy requiring medication were recruited and followed up prospectively. The clinical outcome was defined as freedom from seizures for a minimum of 12 months in accordance with the consensus statement from the International League Against Epilepsy (ILAE). Genetic effects on remission of seizures after starting treatment were analysed with and without adjustment for significant clinical prognostic factors, and the results from each cohort were combined using a fixed-effects meta-analysis. After quality control (QC), we analysed 889 newly treated epilepsy patients using 472 450 genotyped and 6.9 × 10(6) imputed single-nucleotide polymorphisms. Suggestive evidence for association (defined as Pmeta < 5.0 × 10(-7)) with remission of seizures after starting treatment was observed at three loci: 6p12.2 (rs492146, Pmeta = 2.1 × 10(-7), OR[G] = 0.57), 9p23 (rs72700966, Pmeta = 3.1 × 10(-7), OR[C] = 2.70) and 15q13.2 (rs143536437, Pmeta = 3.2 × 10(-7), OR[C] = 1.92). Genes of biological interest at these loci include PTPRD and ARHGAP11B (encoding functions implicated in neuronal development) and GSTA4 (a phase II biotransformation enzyme). Pathway analysis using two independent methods implicated a number of pathways in the prognosis of epilepsy, including KEGG categories 'calcium signaling pathway' and 'phosphatidylinositol signaling pathway'. Through a series of power curves, we conclude that it is unlikely any single common variant explains >4.4% of the variation in the outcome of newly treated epilepsy.
authors: UCL Genetics Institute, University College London WC1E 6BT, UK.
authors: Doug
authors: D
authors: Speed
authors: Clive
authors: C
authors: Hoggart
authors: Slave
authors: S
authors: Petrovski
authors: Ioanna
authors: I
authors: Tachmazidou
authors: Alison
authors: A
authors: Coffey
authors: Andrea
authors: A
authors: Jorgensen
authors: Hariklia
authors: H
authors: Eleftherohorinou
authors: Maria
authors: M
authors: De Iorio
authors: Marian
authors: M
authors: Todaro
authors: Tisham
authors: T
authors: De
authors: David
authors: D
authors: Smith
authors: Philip E
authors: PE
authors: Smith
authors: Margaret
authors: M
authors: Jackson
authors: Paul
authors: P
authors: Cooper
authors: Mark
authors: M
authors: Kellett
authors: Stephen
authors: S
authors: Howell
authors: Mark
authors: M
authors: Newton
authors: Raju
authors: R
authors: Yerra
authors: Meng
authors: M
authors: Tan
authors: Chris
authors: C
authors: French
authors: Markus
authors: M
authors: Reuber
authors: Graeme E
authors: GE
authors: Sills
authors: David
authors: D
authors: Chadwick
authors: Munir
authors: M
authors: Pirmohamed
authors: David
authors: D
authors: Bentley
authors: Ingrid
authors: I
authors: Scheffer
authors: Samuel
authors: S
authors: Berkovic
authors: David
authors: D
authors: Balding
authors: Aarno
authors: A
authors: Palotie
authors: Anthony
authors: A
authors: Marson
authors: Terence J
authors: TJ
authors: O'Brien
authors: Michael R
authors: MR
authors: Johnson
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use; D020013:Calcium Signaling / Q000235:genetics; D002884:Chromosomes, Human, Pair 15; D002896:Chromosomes, Human, Pair 6; D002899:Chromosomes, Human, Pair 9; D004827:Epilepsy / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010716:Phosphatidylinositols / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D010716:Phosphatidylinositols
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