SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.
Delnaz RoshandelEric J SandersAmy ShakeshaftNaim PanjwaniFan LinAmber CollingwoodAnna HallKatherine KeenanCeline DeneubourgFilippo MirabellaSimon D ToppJana ZarubovaRhys Huw ThomasInga TalvikMarte SyvertsenPasquale StrianoAnna B SmithKaja K SelmerGuido RubboliAlessandro OrsiniChing Ching NgRikke S MøllerKheng-Seang LimKhalid HamandiDavid A GreenbergJoanna GescheElena GardellaChoong Yi FongChristoph P BeierDanielle M AndradeHeinz JungbluthMark P RichardsonAnnalisa PastoreManolis FantoDeb K PalLisa J Strugnull nullPublished in: NPJ genomic medicine (2023)
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.
Keyphrases
- genome wide
- attention deficit hyperactivity disorder
- dna methylation
- obsessive compulsive disorder
- autism spectrum disorder
- bipolar disorder
- borderline personality disorder
- genome wide association
- copy number
- working memory
- genome wide identification
- public health
- major depressive disorder
- gene expression
- mental health
- subarachnoid hemorrhage
- poor prognosis
- risk assessment
- health information
- genome wide analysis
- brain injury
- mass spectrometry
- water soluble
- prefrontal cortex
- social media
- binding protein