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SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy
D. Roshandel, EJ. Sanders, A. Shakeshaft, N. Panjwani, F. Lin, A. Collingwood, A. Hall, K. Keenan, C. Deneubourg, F. Mirabella, S. Topp, J. Zarubova, RH. Thomas, I. Talvik, M. Syvertsen, P. Striano, AB. Smith, KK. Selmer, G. Rubboli, A. Orsini,...
Status not-indexed Language English Country England, Great Britain
Document type Journal Article
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Epilepsy Research UK (ERUK)
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- Publication type
- Journal Article MeSH
Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.
Adult Epilepsy Genetics Program Krembil Research Institute University of Toronto Toronto Canada
Danish Epilepsy Centre Dianalund Denmark
Department of Neurology Drammen Hospital Vestre Viken Health Trust Oslo Norway
Department of Psychological Medicine and Clinical Neuroscience Cardiff University Cardiff UK
Department of Regional Health Research University of Southern Denmark Odense Denmark
Departments of Statistical Sciences and Computer Science The University of Toronto Toronto Canada
Genetics and Genome Biology Program The Hospital for Sick Children Toronto Canada
Institute of Biological Sciences Faculty of Science University of Malaya Kuala Lumpur Malaysia
IRCCS Istituto 'G Gaslini' Genova Italy
King's College Hospital London UK
MRC Centre for Neurodevelopmental Disorders King's College London London UK
National Centre for Epilepsy Oslo University Hospital Oslo Norway
Nationwide Children's Hospital Columbus OH USA
Newcastle upon Tyne NHS Foundation Trust Newcastle UK
Odense University Hospital Odense Denmark
Pediatric Neurology Azienda Ospedaliero Universitaria Pisana Pisa University Hospital Pisa Italy
Tallin Children's Hospital Tallin Estonia
The Centre for Applied Genomics The Hospital for Sick Children Toronto Canada
The Welsh Epilepsy Unit Department of Neurology Cardiff and Vale University Health Board Cardiff UK
References provided by Crossref.org
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