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

Naim Panjwani; Amy Shakeshaft; Delnaz Roshandel; Lin Fan; Amber Collingwood; Anna Hall; Katherine Keenan; Celine Deneubourg; Filippo Mirabella; Simon D. Topp; Jana Zárubová; Rhys Huw Thomas; Inga Talvik; Marte Roa Syvertsen; Pasquale Striano; Anna B Smith; Kaja Kristine Selmer; Guido Rubboli; Alessandro Ascani Orsini; Ching Ching Ng; Rikke Steensbjerre Møller; Kheng Seang Lim; Khalid Hamandi; David A. Greenberg; Joanna Gesche; Elena Gardella; Choong Yi Fong; Christoph Patrick Beier; Danielle Molinari Andrade; Heinz Jungbluth

doi:10.1101/2022.04.19.22273994

Genetic & Genomic MedicinemedRxivApr 19, 2022

Preprint

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

Naim Panjwani iD, Amy Shakeshaft iD, Delnaz Roshandel iD, Lin Fan iD, Amber Collingwood iD, Anna Hall, Katherine Keenan, Celine Deneubourg iD, Filippo Mirabella iD, Simon D. Topp iD, Jana Zárubová iD, Rhys Huw Thomas iD, Inga Talvik, Marte Roa Syvertsen iD, Pasquale Striano iD, Anna B Smith iD, Kaja Kristine Selmer iD, Guido Rubboli iD, Alessandro Ascani Orsini iD, Ching Ching Ng iD, Rikke Steensbjerre Møller iD, Kheng Seang Lim iD, Khalid Hamandi iD, David A. Greenberg, Joanna Gesche iD, , Lisa J. Strug iD

Abstract

Introductory ParagraphElevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and epilepsy1-5. We performed a genome-wide association, colocalization and pathway analysis of impulsivity in juvenile myoclonic epilepsy (JME). We identify 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 a membrane-bound organic anion transporter6 and upregulates synapse assembly/organisation genes7. Pathway analysis also demonstrates 9.3-fold enrichment for synaptic assembly genes (p=0.03) including NRXN1, NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila homolog of SLCO5A1, causes both 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 correlates with impulsivity scores (p=1.60 x 10-3), demonstrating shared genetic contributions. SLCO5A1 loss-of-function represents a novel impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

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