Roshandel, Delnaz and Sanders, Eric J. and Shakeshaft, Amy and Panjwani, Naim and Lin, Fan and Collingwood, Amber and Hall, Anna and Keenan, Katherine and Deneubourg, Celine and Mirabella, Filippo and Topp, Simon and Zarubova, Jana and Thomas, Rhys H. and Talvik, Inga and Syvertsen, Marte and Striano, Pasquale and Smith, Anna B. and Selmer, Kaja K. and Rubboli, Guido and Orsini, Alessandro and Ng, Ching Ching and Moller, Rikke S. and Lim, Kheng Seang and Hamandi, Khalid and Greenberg, David A. and Gesche, Joanna and Gardella, Elena and Fong, Choong Yi and Beier, Christoph P. and Andrade, Danielle M. and Jungbluth, Heinz and Richardson, Mark P. and Pastore, Annalisa and Fanto, Manolis and Pal, Deb K. and Strug, Lisa J. (2023) SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy. npj Genomic Medicine, 8 (1). ISSN 2056-7944, DOI https://doi.org/10.1038/s41525-023-00370-z.
Full text not available from this repository.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 x 10-9) and 10p11.21 (P = 3.6 x 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 x 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 x 10-3) and increased seizure-like events (P = 6.8 x 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 x 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.
| Item Type: | Article |
|---|---|
| Funders: | UNSPECIFIED |
| Subjects: | R Medicine > R Medicine (General) |
| Divisions: | Faculty of Medicine > Medicine Department Faculty of Medicine > Paediatrics Department Faculty of Science > Institute of Biological Sciences |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 27 Oct 2025 08:04 |
| Last Modified: | 27 Oct 2025 08:04 |
| URI: | http://eprints.um.edu.my/id/eprint/50145 |
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