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

Roshandel, Delnaz, Sanders, Eric J., Shakeshaft, Amy ORCID:, Panjwani, Naim, Lin, Fan, Collingwood, Amber, Hall, Anna, Keenan, Katherine, Deneubourg, Celine, Mirabella, Filippo, Topp, Simon, Zarubova, Jana, Thomas, Rhys H. ORCID:, 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, Greenberg, David A., Gesche, Joanna, Gardella, Elena, Fong, Choong Yi, Beier, Christoph P., Andrade, Danielle M., Jungbluth, Heinz, Richardson, Mark P., Pastore, Annalisa, Fanto, Manolis, 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) , 28. 10.1038/s41525-023-00370-z

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Additional Information: License information from Publisher: LICENSE 1: URL:, Type: open-access
Publisher: Nature Research
ISSN: 2056-7944
Date of First Compliant Deposit: 29 September 2023
Date of Acceptance: 29 August 2023
Last Modified: 09 Oct 2023 08:18

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