Article, 2023
SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy
Npj Genomic Medicine, ISSN 2056-7944, Volume 8, 1, 10.1038/s41525-023-00370-z
Contributors
Roshandel D.Affiliations
- [1] Hospital for Sick Children [NORA names: Canada; America, North; OECD];
- [2] University of Toronto [NORA names: Canada; America, North; OECD];
- [3] King's College London [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [4] University Hospital Motol [NORA names: Czechia; Europe, EU; OECD];
- [5] Newcastle University [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [6] Newcastle upon Tyne Hospitals NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [7] Tallin Children's Hospital [NORA names: Estonia; Europe, EU; OECD];
- [8] Dipartimento di Fisica [NORA names: Italy; Europe, EU; OECD];
- [9] Istituto Giannina Gaslini [NORA names: Italy; Europe, EU; OECD];
- [10] Oslo University Hospital [NORA names: Norway; Europe, Non-EU; Nordic; OECD];
- [11] University of Copenhagen [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
- [12] Danish Epilepsy Centre [NORA names: Filadelfia - Danish Epilepsy Hospital; Hospital; Denmark; Europe, EU; Nordic; OECD];
- [13] University Hospital of Pisa [NORA names: Italy; Europe, EU; OECD];
- [14] University of Malaya [NORA names: Malaysia; Asia, South];
- [15] University of Southern Denmark [NORA names: SDU University of Southern Denmark; University; Denmark; Europe, EU; Nordic; OECD];
- [16] University of Malaya [NORA names: Malaysia; Asia, South];
- [17] Cardiff University [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [18] Cardiff and Vale University Health Board [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [19] Nationwide Children's Hospital [NORA names: United States; America, North; OECD];
- [20] Odense University Hospital [NORA names: Region of Southern Denmark; Hospital; Denmark; Europe, EU; Nordic; OECD];
- [21] King's College London [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [22] Guy's and St Thomas' NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [23] King's College Hospital [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [24] Hospital for Sick Children [NORA names: Canada; America, North; OECD];
- [25] Airedale NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [26] Ashford and St Peter’s Hospitals NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [27] Bradford Teaching Hospital [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [28] Brighton and Sussex University Hospitals [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [29] Calderdale and Huddersfield NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [30] County Durham and Darlington NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [31] Croydon Health Services NHS Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [32] Cwm Taf Morgannwg University Health Board [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [33] Mount Vernon Cancer Centre [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [34] East Kent Hospitals University NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [35] East Lancashire Hospitals NHS Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [36] Kingston Hospital [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [37] Lancashire Teaching Hospitals NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [38] Leeds Teaching Hospitals NHS Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [39] Manchester University NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [40] NHS Grampian [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [41] NHS Tayside [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [42] North Tees and Hartlepool NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [43] Nottingham University Hospitals NHS Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [44] Portsmouth Hospitals NHS Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [45] Royal Free London NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [46] Salford Royal NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [47] Sandwell and West Birmingham Hospitals NHS Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [48] Sheffield Children's NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [49] Sheffield Teaching Hospitals NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [50] Southport and Formby District General Hospital [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [51] St George's University Hospitals NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [52] Department of Dermatology [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [53] Mid Yorkshire Hospitals NHS Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [54] Royal Wolverhampton NHS Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [55] Walton Centre NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [56] University Hospitals Birmingham NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [57] Derby Teaching Hospitals NHS Foundation Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [58] University Hospitals Plymouth NHS Trust [NORA names: United Kingdom; Europe, Non-EU; OECD];
- [59] West Suffolk Hospital [NORA names: United Kingdom; Europe, Non-EU; OECD]
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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) and 10p11.21 (P = 3.6 × 10). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10). 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) and increased seizure-like events (P = 6.8 × 10). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.
Funders
- Llywodraeth Cymru
- Epilepsy Research UK
- RHT
- Medical Research Council Canada
- Abertawe Bro Morgannwg University NHS R&D
- Medical Research Council Centre for Neurodevelopmental Disorders
- Odense Universitetshospital
- ERN-Epicare
- Health and Care Research Wales
- Syddansk Universitet
- Horizon 2020 Framework Programme
- NGEU
- DINOGMI Department of Excellence of MIUR
- NIHR Specialist Biomedical Research Centre for Mental Health of South London and Maudsley National Health Service Foundation Trust
- Biomarin srl
- Sackler Institute, King's College London
- Nationwide Children's Hospital
- Eisai Canada
- Canadian Institutes of Health Research
- National Centre for the Replacement Refinement and Reduction of Animals in Research
- Canada Research Chairs
- UCB
- National Recovery and Resilience Plan
- Helse Sør-Øst RHF
- Engineering and Physical Sciences Research Council
- Norges Forskningsråd
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Action Medical Research
- Parc Geneteg Cymru