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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00064203%3A_____%2F23%3A10470189" target="_blank" >RIV/00064203:_____/23:10470189 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11130/23:10470189

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=1XGRRKAohc" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=1XGRRKAohc</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41525-023-00370-z" target="_blank" >10.1038/s41525-023-00370-z</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30103 - Neurosciences (including psychophysiology)

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2023

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

npj Genomic Medicine

ISSN

2056-7944

e-ISSN

2056-7944

Svazek periodika

8

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

11

Strana od-do

28

Kód UT WoS článku

001078003600001

EID výsledku v databázi Scopus

2-s2.0-85173085534