학술논문
SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy
Document Type
Original Paper
Author
Roshandel, Delnaz; Sanders, Eric J.; Shakeshaft, Amy; Panjwani, Naim; Lin, Fan; Collingwood, Amber; Hall, Anna; Keenan, Katherine; Deneubourg, Celine; Mirabella, Filippo; Topp, Simon; Zarubova, Jana; Thomas, Rhys H.; Talvik, Inga; Syvertsen, Marte; Striano, Pasquale; Smith, Anna B.; Selmer, Kaja K.; Rubboli, Guido; Orsini, Alessandro; Ng, Ching Ching; Møller, Rikke S.; Lim, Kheng Seang; Hamandi, Khalid; Greenberg, David A.; Gesche, Joanna; Gardella, Elena; Fong, Choong Yi; Beier, Christoph P.; Andrade, Danielle M.; Jungbluth, Heinz; Richardson, Mark P.; Pastore, Annalisa; Fanto, Manolis; Pal, Deb K.; Strug, Lisa J.
Source
npj Genomic Medicine. 8(1)
Subject
Language
English
ISSN
2056-7944
Abstract
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.