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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,...

. 2023 ; 8 (1) : 28. [pub] 20230928

Status neindexováno Jazyk angličtina Země Anglie, Velká Británie

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc23015227

Grantová podpora
NA Epilepsy Research UK (ERUK)

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 Basic and Clinical Neurosciences Institute of Psychiatry Psychology and Neuroscience King's College London London UK

Department of Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Neurology Drammen Hospital Vestre Viken Health Trust Oslo Norway

Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genova Genova Italy

Department of Paediatric Neurology Neuromuscular Service Evelina's Children Hospital Guy's and St Thomas' Hospital NHS Foundation Trust London UK

Department of Psychological Medicine and Clinical Neuroscience Cardiff University Cardiff UK

Department of Regional Health Research University of Southern Denmark Odense Denmark

Department of Research and Innovation Division of Clinical Neuroscience Oslo University Hospital Oslo Norway

Departments of Statistical Sciences and Computer Science The University of Toronto Toronto Canada

Division of Biostatistics Dalla Lana School of Public Health The University of Toronto Toronto Canada

Division of Neurology Department of Medicine Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Division of Paediatric Neurology Department of Pediatrics Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

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

Randall Centre for Cell and Molecular Biophysics Muscle Signalling Section Faculty of Life Sciences and Medicine King's College London London UK

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

Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Newcastle UK

University of Copenhagen Copenhagen Denmark

Citace poskytuje Crossref.org

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