SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy

Roshandel D 1 , Sanders EJ 1 , Shakeshaft A 2 , Panjwani N 1 , Lin F 1 , Collingwood A 2 Show all authors , Hall A 2 , Keenan K 1 , Deneubourg C 2 , Mirabella F 2 , Topp S 2 , Zarubova J 3 , Thomas RH 4 , Talvik I 5 , Syvertsen M 6 , Striano P 7 , Smith AB 2 , Selmer KK 8 , Rubboli G 9 , Orsini A 10 , Ng CC 11 , Møller RS 9 , Lim KS 12 , Hamandi K 13 , Greenberg DA 14 , Gesche J 15 , Gardella E 9 , Fong CY 16 , Beier CP 15 , Andrade DM 17 , Jungbluth H 18 , Richardson MP 2 , Pastore A 2 , Fanto M 2 , Pal DK 19 , Strug LJ 20 , BIOJUME Consortium

Affiliations 

  • 1 Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada
  • 2 Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
  • 3 Department of Neurology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
  • 4 Newcastle upon Tyne NHS Foundation Trust, Newcastle, UK
  • 5 Tallin Children's Hospital, Tallin, Estonia
  • 6 Department of Neurology, Drammen Hospital, Vestre Viken Health Trust, Oslo, Norway
  • 7 IRCCS Istituto 'G. Gaslini', Genova, Italy
  • 8 Department of Research and Innovation, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway
  • 9 Danish Epilepsy Centre, Dianalund, Denmark
  • 10 Pediatric Neurology, Azienda Ospedaliero-Universitaria Pisana, Pisa University Hospital, Pisa, Italy
  • 11 Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia
  • 12 Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 13 The Welsh Epilepsy Unit, Department of Neurology Cardiff & Vale University Health Board, Cardiff, UK
  • 14 Nationwide Children's Hospital, Columbus, OH, USA
  • 15 Odense University Hospital, Odense, Denmark
  • 16 Division of Paediatric Neurology, Department of Pediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 17 Adult Epilepsy Genetics Program, Krembil Research Institute, University of Toronto, Toronto, Canada
  • 18 Randall Centre for Cell and Molecular Biophysics, Muscle Signalling Section, Faculty of Life Sciences and Medicine, King's College London, London, UK
  • 19 Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK. deb.pal@kcl.ac.uk
  • 20 Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Canada. Lisa.Strug@utoronto.ca
NPJ Genom Med, 2023 Sep 28;8(1):28.
PMID: 37770509 DOI: 10.1038/s41525-023-00370-z

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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