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Roshandel, Delnaz; Sanders, Eric J.; Shakeshaft, Amy; Panjwani, Naim; Lin, Fan; Collingwood, Amber; Hall, Anna; Keenan, Katherine; Deneubourg, Celine; Mirabella, Filippo; Topp, Simon; Zarubova, Jana; Thomas, Rhys H.; Talvik, Inga; Syvertsen, Marte; Striano, Pasquale; Smith, Anna B.; Selmer, Kaja K.; Rubboli, Guido; Orsini, Alessandro; Ng, Ching Ching; Møller, Rikke S.; Lim, Kheng Seang; Hamandi, Khalid; [...]

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

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  • Medientyp: E-Artikel
  • Titel: SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy
  • Beteiligte: Roshandel, Delnaz; Sanders, Eric J.; Shakeshaft, Amy; Panjwani, Naim; Lin, Fan; Collingwood, Amber; Hall, Anna; Keenan, Katherine; Deneubourg, Celine; Mirabella, Filippo; Topp, Simon; Zarubova, Jana; Thomas, Rhys H.; Talvik, Inga; Syvertsen, Marte; Striano, Pasquale; Smith, Anna B.; Selmer, Kaja K.; Rubboli, Guido; Orsini, Alessandro; Ng, Ching Ching; Møller, Rikke S.; Lim, Kheng Seang; Hamandi, Khalid; [...]
  • Erschienen: Springer Science and Business Media LLC, 2023
  • Erschienen in: npj Genomic Medicine
  • Sprache: Englisch
  • DOI: 10.1038/s41525-023-00370-z
  • ISSN: 2056-7944
  • Entstehung:
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  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>n</jats:italic> = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (<jats:italic>P</jats:italic> = 7.5 × 10<jats:sup>−9</jats:sup>) and 10p11.21 (<jats:italic>P</jats:italic> = 3.6 × 10<jats:sup>−8</jats:sup>). The 8q13.3 locus colocalizes with <jats:italic>SLCO5A1</jats:italic> expression quantitative trait loci in cerebral cortex (<jats:italic>P</jats:italic> = 9.5 × 10<jats:sup>−3</jats:sup>). <jats:italic>SLCO5A1</jats:italic> codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (<jats:italic>P</jats:italic> = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (<jats:italic>P</jats:italic> = 0.0005) including <jats:italic>NLGN1</jats:italic> and <jats:italic>PTPRD</jats:italic>. RNAi knockdown of <jats:italic>Oatp30B</jats:italic>, the <jats:italic>Drosophila</jats:italic> polypeptide with the highest homology to <jats:italic>SLCO5A1</jats:italic>, causes over-reactive startling behaviour (<jats:italic>P</jats:italic> = 8.7 × 10<jats:sup>−3</jats:sup>) and increased seizure-like events (<jats:italic>P</jats:italic> = 6.8 × 10<jats:sup>−7</jats:sup>). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (<jats:italic>P</jats:italic> = 1.60 × 10<jats:sup>−3</jats:sup>). <jats:italic>SLCO5A1</jats:italic> loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.</jats:p>
  • Zugangsstatus: Freier Zugang