title: A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy.
abstract: Rolandic epilepsy is a common genetic focal epilepsy of childhood characterized by centrotemporal sharp waves on electroencephalogram. In previous genome-wide analysis, we had reported linkage of centrotemporal sharp waves to chromosome 11p13, and fine mapping with 44 SNPs identified the ELP4-PAX6 locus in two independent US and Canadian case-control samples. Here, we aimed to find a causative variant for centrotemporal sharp waves using a larger sample and higher resolution genotyping array.
  
  
  
  We fine-mapped the ELP4-PAX6 locus in 186 individuals from rolandic epilepsy families and 1000 population controls of European origin using the Illumina HumanCoreExome-12 v1.0 BeadChip. Controls were matched to cases on ethnicity using principal component analysis. We used generalized estimating equations to assess association, followed up with a bioinformatics survey and literature search to evaluate functional significance.
  
  
  
  Homozygosity at the T allele of SNP rs662702 in the 3' untranslated region of PAX6 conferred increased risk of CTS: Odds ratio = 12.29 (95% CI: 3.20-47.22), P = 2.6 × 10(-4) and is seen in 3.9% of cases but only 0.3% of controls.
  
  
  
  The minor T allele of SNP rs662702 disrupts regulation by microRNA-328, which is known to result in increased PAX6 expression in vitro. This study provides, for the first time, evidence of a noncoding genomic variant contributing to the etiology of a common human epilepsy via a posttranscriptional regulatory mechanism.
authors.affiliation: Program in Genetics and Genome Biology The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada.
authors.forename: Naim
authors.initials: N
authors.lastname: Panjwani
authors.affiliation: Program in Genetics and Genome Biology The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada; Department of Molecular Genetics University of Toronto Toronto Ontario M5S 1A1 Canada.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wilson
authors.affiliation: Department of Basic and Clinical Neuroscience Institute of Psychiatry, Psychology and Neuroscience King's College London London SE5 9RX United Kingdom; Neuroscience Discovery Research Eli Lilly and Company Erl Wood, Surrey GU20 6PH United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Addis
authors.affiliation: Neurosciences and Mental Health Program Research Institute The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada; Department of Psychiatry The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Crosbie
authors.affiliation: Division of Child and Adolescent Neurology Mayo Clinic Rochester Minnesota 55905.
authors.forename: Elaine
authors.initials: E
authors.lastname: Wirrell
authors.affiliation: Service de neurologie pédiatrique/Inserm 1141 Hôpital Robert Debré AP-HP, 48 boulevard Sérurier Paris 75019 France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Auvin
authors.affiliation: Department of Neurology Hospital de Pediatría "Prof Dr Juan P Garrahan" Combate de los Pozos 1881 C1245AAM Buenos Aires Argentina.
authors.forename: Roberto H
authors.initials: RH
authors.lastname: Caraballo
authors.affiliation: Chelsea and Westminster Hospital London SW10 9NH United Kingdom.
authors.forename: Maria
authors.initials: M
authors.lastname: Kinali
authors.affiliation: King's College Hospital London SE5 9RS United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: McCormick
authors.affiliation: Northwick Park Hospital Middlesex HA1 3UJ United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Oren
authors.affiliation: Barnet and Chase Farm Hospitals Enfield, Greater London EN2 8JL United Kingdom.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Brighton and Sussex University Hospitals Brighton BN1 6AG United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Trounce
authors.affiliation: Department of Epidemiology Columbia University New York New York 10027.
authors.forename: Tara
authors.initials: T
authors.lastname: Clarke
authors.affiliation: Neurological Institute Columbia University Medical Centre New York, New York 10032.
authors.forename: Cigdem I
authors.initials: CI
authors.lastname: Akman
authors.affiliation: Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine Philadelphia Pennsylvania 19104.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kugler
authors.affiliation: Hasbro Children's Hospital and the Warren Alpert Medical School of Brown University Providence Rhode Island 02903.
authors.forename: David E
authors.initials: DE
authors.lastname: Mandelbaum
authors.affiliation: Beth Israel Medical Center New York, New York 10003.
authors.forename: Patricia
authors.initials: P
authors.lastname: McGoldrick
authors.affiliation: Beth Israel Medical Center New York, New York 10003.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Wolf
authors.affiliation: Neurosciences and Mental Health Program Research Institute The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada; Department of Psychiatry The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada; Mathison Centre for Mental Health Research and Education University of Calgary Calgary Alberta T2N 4Z6 Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Arnold
authors.affiliation: Neurosciences and Mental Health Program Research Institute The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada; Department of Psychiatry The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada.
authors.forename: Russell
authors.initials: R
authors.lastname: Schachar
authors.affiliation: Department of Basic and Clinical Neuroscience Institute of Psychiatry, Psychology and Neuroscience King's College London London SE5 9RX United Kingdom; King's College Hospital London SE5 9RS United Kingdom; Evelina London Children's Hospita lLondon SE1 7EH United Kingdom.
authors.forename: Deb K
authors.initials: DK
authors.lastname: Pal
authors.affiliation: Program in Genetics and Genome Biology The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada; Division of Biostatistics Dalla Lana School of Public Health University of Toronto Toronto Ontario M5T 3M7 Canada; The Centre for Applied Genomics The Hospital for Sick Children Toronto Ontario M5G 0A4 Canada.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Strug