Mechanism of the epilepsy associated Impulsivity risk variant linked to the neuronal transporter SLCO5A1

Common epilepsies, especially the “idiopathic generalised (IGE)” group, have high heritability but complex inheritance. Juvenile myoclonic epilepsy (JME) is an archetype IGE that typically develops in adolescence. It is characterised by tonic-clonic, absence and myoclonic seizure types. At the heart of “the JME personality” is impulsivity, “acting or speaking without thought for consequences. Impulsivity is also a typical feature of ADHD, bipolar disorder and substance abuse. It is an important trait to target in JME because of its strong correlation with seizure frequency, its links to the antiseizure medication levetiracetam and its association with adverse life outcomes including failed social adjustment and interpersonal relationships, risky behaviours, reduced treatment compliance and other psychological symptoms. A GWAS study of impulsivity in JME patients identified high risk impulsivity DNA variants linked to SLCO5A1 that appear to reduce SLCO5A1 in the brain cortex. Further work also found association with risk-taking in a non-epilepsy cohort from UK Biobank. Little is known about SLCO5A1 function, although it’s probably an organic anion-transporter. Knockout of SLCO5A1 homologue Oatp30b in drosophila leads to neuronal overactivity and increased seizures. This project will expand our knowledge of SLCO5A1, its regulation and function, which together will allow us to develop cell and animal models suitable for drug development.
Specifically, the project aims to, 1) characterise the genetic mechanism underlying association between the impulsivity risk variant and SLCO5A1; 2) improve our knowledge of SLCO5A1 function, and 3) develop an in vitro cell assay for screening drugs that modulate or utilise SLCO5A1 for their transport. Skills in cell culture, molecular biology and biochemical assays will be developed to achieve these aims. Work will involve characterising a novel regulatory RNA linked to the variant (Yr1); over-expression and knock-down of endogenous SLCO5A1 to establish SLCO5A1-dependent cellular pathways (Yr2) and development of a SLCO5A1 transporter assay (Yr3).