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

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.