Roshandel, D., Sanders, E.J., Shakeshaft, A., Panjwani, N., Lin, F., Collingwood, A., Hall, A., Keenan, K., Deneubourg, C., Mirabella, F., Topp, S., Zarubova, J., Thomas, R.H., Talvik, I., Syvertsen, M., Striano, P., Smith, A.B., Selmer, K.K., Rubboli, G., Orsini, A., Ng, C.C., Møller, R.S., Lim, K.S., Hamandi, K., Greenberg, D.A., Gesche, J., Gardella, E., Fong, C.Y., Beier, C.P., Andrade, D.M., Jungbluth, H., Richardson, M.P., Pastore, A., Fanto, M., Pal, D.K., Strug, L.J., BIOJUME Consortium, (2023). SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.  NPJ Genom Med 8(1): 28.

FBrf0257661

Research paper

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.

PMC10539321 (PMC) (EuropePMC)