@article{ee4fdac2a9554390b6b8bcebbc48af6a,
title = "A microRNA-328 binding site in PAX6 is associated with centrotemporal spikes of rolandic epilepsy",
abstract = "Objective: 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. Methods: 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. Results: 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. Interpretation: 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.",
author = "Naim Panjwani and Wilson, {Michael D.} and Laura Addis and Jennifer Crosbie and Elaine Wirrell and St{\'e}phane Auvin and Caraballo, {Roberto H.} and Maria Kinali and David McCormick and Caroline Oren and Jacqueline Taylor and John Trounce and Tara Clarke and Akman, {Cigdem I.} and Kugler, {Steven L.} and Mandelbaum, {David E.} and Patricia McGoldrick and Wolf, {Steven M.} and Paul Arnold and Russell Schachar and Pal, {Deb K.} and Strug, {Lisa J.}",
note = "Funding Information: We acknowledge the contributions of the Ontario Science Centre, Toronto, Ontario. We thank members of the IRELAND Study consortium including those who referred patients to the study: Huntley Hardison, Linda Leary, Edward Novotny, Frances Rhoads, Maria Younes, Kum Gomez, Elaine Hughes, John Jackman, David Scott, Jan Stanek, and Rajesh Gupta. We acknowledge Sushma Goyal, Zaloa Agirre-Arrizubieta and the late Lewis Kull for reporting EEGs. We thank Veronica van Heyningen for reviewing and providing comments on early versions of this manuscript. Finally, thanks to the many families across the world who contributed to the study. The Canadian Institutes of Health Research (201503MOP-342469 to LJS and DKP; and MOP-106573 and MOP-93696 to JC, RS and PA); Ontario Ministry of Research and Innovation Early Researcher{\textquoteright}s Award (LJS); Waterloo Foundation (DKP); European Union Marie Curie International Reintegration Award of the Seventh Framework Programme (DKP); European Union Grant agreement 602531: “Strategies for Innovative Research to Improve Diagnosis, Prevention and Treatment in Children with Difficult to Treat Epilepsy (DESIRE)” of the Seventh Framework Programme (DKP); Charles Sykes Epilepsy Research Trust (DKP); Epilepsy Research UK (DKP); NIHR Specialist Biomedical Research Centre for Mental Health of South London and Maudsley NHS Foundation Trust (DKP); American Epilepsy Society, the Epilepsy Foundation, Anna and Jim Fantaci, Fight Against Childhood Epilepsy and Seizures (faces), Neurotherapy Ventures Charitable Research Fund (DKP); Charles L Shor Foundation for Epilepsy Research Inc. (DKP); People Against Childhood Epilepsy (PACE) (DKP); Ali Paris Fund (DKP); National Institutes of Health grants NS047530 (DKP); SickKids Foundation, Canada Research Chair and NSERC (436194-2013) (MDW); and Eli Lilly LIFA Fellowship (LA). Publisher Copyright: {\textcopyright} 2016 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.",
year = "2016",
month = jul,
day = "1",
doi = "10.1002/acn3.320",
language = "English (US)",
pages = "512--522",
journal = "Annals of Clinical and Translational Neurology",
issn = "2328-9503",
publisher = "John Wiley and Sons Inc.",
}