npj Genomic Medicine (Sep 2023)
SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy
- Delnaz Roshandel,
- Eric J. Sanders,
- Amy Shakeshaft,
- Naim Panjwani,
- Fan Lin,
- Amber Collingwood,
- Anna Hall,
- Katherine Keenan,
- Celine Deneubourg,
- Filippo Mirabella,
- Simon Topp,
- Jana Zarubova,
- Rhys H. Thomas,
- Inga Talvik,
- Marte Syvertsen,
- Pasquale Striano,
- Anna B. Smith,
- Kaja K. Selmer,
- Guido Rubboli,
- Alessandro Orsini,
- Ching Ching Ng,
- Rikke S. Møller,
- Kheng Seang Lim,
- Khalid Hamandi,
- David A. Greenberg,
- Joanna Gesche,
- Elena Gardella,
- Choong Yi Fong,
- Christoph P. Beier,
- Danielle M. Andrade,
- Heinz Jungbluth,
- Mark P. Richardson,
- Annalisa Pastore,
- Manolis Fanto,
- Deb K. Pal,
- Lisa J. Strug,
- the BIOJUME Consortium
Affiliations
- Delnaz Roshandel
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Eric J. Sanders
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Amy Shakeshaft
- Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
- Naim Panjwani
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Fan Lin
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Amber Collingwood
- Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
- Anna Hall
- Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
- Katherine Keenan
- Genetics and Genome Biology Program, The Hospital for Sick Children
- Celine Deneubourg
- Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
- Filippo Mirabella
- Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
- Simon Topp
- Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
- Jana Zarubova
- Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital
- Rhys H. Thomas
- Newcastle upon Tyne NHS Foundation Trust
- Inga Talvik
- Tallin Children’s Hospital
- Marte Syvertsen
- Department of Neurology, Drammen Hospital, Vestre Viken Health Trust
- Pasquale Striano
- IRCCS Istituto ‘G. Gaslini’
- Anna B. Smith
- Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
- Kaja K. Selmer
- Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital
- Guido Rubboli
- Danish Epilepsy Centre
- Alessandro Orsini
- Pediatric Neurology, Azienda Ospedaliero-Universitaria Pisana, Pisa University Hospital
- Ching Ching Ng
- Institute of Biological Sciences, Faculty of Science, University of Malaya
- Rikke S. Møller
- Danish Epilepsy Centre
- Kheng Seang Lim
- Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya
- Khalid Hamandi
- The Welsh Epilepsy Unit, Department of Neurology Cardiff & Vale University Health Board
- David A. Greenberg
- Nationwide Children’s Hospital
- Joanna Gesche
- Odense University Hospital
- Elena Gardella
- Danish Epilepsy Centre
- Choong Yi Fong
- Division of Paediatric Neurology, Department of Pediatrics, Faculty of Medicine, University of Malaya
- Christoph P. Beier
- Odense University Hospital
- Danielle M. Andrade
- Adult Epilepsy Genetics Program, Krembil Research Institute, University of Toronto
- Heinz Jungbluth
- Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine, King’s College London
- Mark P. Richardson
- Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
- Annalisa Pastore
- Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
- Manolis Fanto
- Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
- Deb K. Pal
- Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London
- Lisa J. Strug
- Genetics and Genome Biology Program, The Hospital for Sick Children
- the BIOJUME Consortium
- DOI
- https://doi.org/10.1038/s41525-023-00370-z
- Journal volume & issue
-
Vol. 8,
no. 1
pp. 1 – 11
Abstract
Abstract 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.
