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

Publikace na 2. lékařská fakulta |
2023

Tento text není v aktuálním jazyce dostupný. Zobrazuje se verze "en".Abstrakt

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 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 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 x 10-3) and increased seizure-like events (P = 6.8 x 10-7).

Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 x 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.