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.

Adult Epilepsy Genetics Program Krembil Research Institute University of Toronto Toronto Canada

Danish Epilepsy Centre Dianalund Denmark

Department of Basic and Clinical Neurosciences Institute of Psychiatry Psychology and Neuroscience King's College London London UK

Department of Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Neurology Drammen Hospital Vestre Viken Health Trust Oslo Norway

Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genova Genova Italy

Department of Paediatric Neurology Neuromuscular Service Evelina's Children Hospital Guy's and St Thomas' Hospital NHS Foundation Trust London UK

Department of Psychological Medicine and Clinical Neuroscience Cardiff University Cardiff UK

Department of Regional Health Research University of Southern Denmark Odense Denmark

Department of Research and Innovation Division of Clinical Neuroscience Oslo University Hospital Oslo Norway

Departments of Statistical Sciences and Computer Science The University of Toronto Toronto Canada

Division of Biostatistics Dalla Lana School of Public Health The University of Toronto Toronto Canada

Division of Neurology Department of Medicine Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Division of Paediatric Neurology Department of Pediatrics Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Genetics and Genome Biology Program The Hospital for Sick Children Toronto Canada

Institute of Biological Sciences Faculty of Science University of Malaya Kuala Lumpur Malaysia

IRCCS Istituto 'G Gaslini' Genova Italy

King's College Hospital London UK

MRC Centre for Neurodevelopmental Disorders King's College London London UK

National Centre for Epilepsy Oslo University Hospital Oslo Norway

Nationwide Children's Hospital Columbus OH USA

Newcastle upon Tyne NHS Foundation Trust Newcastle UK

Odense University Hospital Odense Denmark

Pediatric Neurology Azienda Ospedaliero Universitaria Pisana Pisa University Hospital Pisa Italy

Randall Centre for Cell and Molecular Biophysics Muscle Signalling Section Faculty of Life Sciences and Medicine King's College London London UK

Tallin Children's Hospital Tallin Estonia

The Centre for Applied Genomics The Hospital for Sick Children Toronto Canada

The Welsh Epilepsy Unit Department of Neurology Cardiff and Vale University Health Board Cardiff UK

Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Newcastle UK

University of Copenhagen Copenhagen Denmark

Zobrazit více v PubMed

Daruna, J. H. & Barnes, P. A. In: The impulsive client: theory, research and treatment (eds W. G. McCown, J. L. Johnson, & M. B. Shure) 23–37 (American Psychological Association, 1993).

Niv S, Tuvblad C, Raine A, Wang P, Baker LA. Heritability and longitudinal stability of impulsivity in adolescence. Behav. Genet. 2012;42:378–392. PubMed PMC

Dalley JW, Robbins TW. Fractionating impulsivity: neuropsychiatric implications. Nat. Rev. Neurosci. 2017;18:158–171. PubMed

Ramirez-Martin A, Ramos-Martin J, Mayoral-Cleries F, Moreno-Kustner B, Guzman-Parra J. Impulsivity, decision-making and risk-taking behaviour in bipolar disorder: a systematic review and meta-analysis. Psychol. Med. 2020;50:2141–2153. PubMed

Smith A, Syvertsen M, Pal DK. Meta-analysis of response inhibition in juvenile myoclonic epilepsy. Epilepsy Behav. 2020;106:107038. PubMed

Shakeshaft, A. et al. Trait impulsivity in juvenile myoclonic epilepsy. Ann Clin Transl Neurol, 10.1002/acn3.51255 (2020). PubMed PMC

Wandschneider B, et al. Risk-taking behavior in juvenile myoclonic epilepsy. Epilepsia. 2013;54:2158–2165. PubMed PMC

Malloy-Diniz L, Fuentes D, Leite WB, Correa H, Bechara A. Impulsive behavior in adults with attention deficit/ hyperactivity disorder: characterization of attentional, motor and cognitive impulsiveness. J. Int. Neuropsychol. Soc. 2007;13:693–698. PubMed

Sanchez-Roige S, et al. Genome-wide association studies of impulsive personality traits (BIS-11 and UPPS-P) and drug experimentation in up to 22,861 adult research participants identify loci in the CACNA1I and CADM2 genes. J. Neurosci. 2019;39:2562–2572. PubMed PMC

Barbeira AN, et al. Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics. Nat. Commun. 2018;9:1825. PubMed PMC

Schizophrenia Working Group of the Psychiatric Genomics, C. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511:421–427. PubMed PMC

GTEx Consortium. The genotype-tissue expression (GTEx) project. Nat. Genet. 2013;45:580–585. PubMed PMC

O’Muircheartaigh J, et al. Focal structural changes and cognitive dysfunction in juvenile myoclonic epilepsy. Neurology. 2011;76:34–40. PubMed PMC

Keller SS, et al. Microstructural and volumetric abnormalities of the putamen in juvenile myoclonic epilepsy. Epilepsia. 2011;52:1715–1724. PubMed

Landvogt C, Buchholz H-G, Bernedo V, Schreckenberger M, Werhahn KJ. Alteration of dopamine D2/D3 receptor binding in patients with juvenile myoclonic epilepsy: alteration of dopamine D2/D3 receptor binding in JME. Epilepsia. 2010;51:1699–1706. PubMed

Ciumas C, et al. Reduced dopamine transporter binding in patients with juvenile myoclonic epilepsy. Neurology. 2008;71:788–794. PubMed

Dalley JW, Everitt BJ, Robbins TW. Impulsivity, compulsivity, and top-down cognitive control. Neuron. 2011;69:680–694. PubMed

Dalley JW, Roiser JP. Dopamine, serotonin and impulsivity. Neuroscience. 2012;215:42–58. PubMed

Deransart C, Vercueil L, Marescaux C, Depaulis A. The role of basal ganglia in the control of generalized absence seizures. Epilepsy Res. 1998;32:213–223. PubMed

Cho SS, et al. Morphometric correlation of impulsivity in medial prefrontal cortex. Brain Topogr. 2013;26:479–487. PubMed PMC

Santos BPD, et al. Genetic susceptibility in juvenile myoclonic epilepsy: systematic review of genetic association studies. PLoS One. 2017;12:e0179629. PubMed PMC

International League Against Epilepsy Consortium on Complex Epilepsies. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat. Commun. 2018;9:5269. PubMed PMC

Bai D, et al. DNA variants in coding region of EFHC1: SNPs do not associate with juvenile myoclonic epilepsy. Epilepsia. 2008;50:1184–1190. PubMed PMC

Bailey JN, et al. Variant intestinal-cell kinase in juvenile myoclonic epilepsy. N. Engl. J. Med. 2018;378:1018–1028. PubMed

Shakeshaft A, et al. Sex-specific disease modifiers in juvenile myoclonic epilepsy. Sci. Rep. 2022;12:2785. PubMed PMC

Li M, et al. Antisense oligonucleotide therapy reduces seizures and extends life span in an SCN2A gain-of-function epilepsy model. J. Clin. Invest. 2021;131:e152079. PubMed PMC

Karalis V, Bateup HS. Current approaches and future directions for the treatment of mTORopathies. Dev. Neurosci. 2021;43:143–158. PubMed PMC

Hall M-H, Smoller JW. A new role for endophenotypes in the GWAS era: functional characterization of risk variants. Harv. Rev. Psychiatry. 2010;18:67–74. PubMed PMC

Manchia M, et al. The impact of phenotypic and genetic heterogeneity on results of genome wide association studies of complex diseases. PLoS One. 2013;8:e76295. PubMed PMC

Steinberg L, Sharp C, Stanford MS, Tharp AT. New tricks for an old measure: the development of the Barratt Impulsiveness Scale-Brief (BIS-Brief) Psychol. Assess. 2013;25:216–226. PubMed

Watanabe K, et al. A global overview of pleiotropy and genetic architecture in complex traits. Nat. Genet. 2019;51:1339–1348. PubMed

Neale’s Lab UK Biobank GWAS Results Round 2 (Imputed v3 - File Manifest Release 20180731), http://www.nealelab.is/uk-biobank.

Kinirons P, et al. A novel locus for idiopathic generalized epilepsy in French-Canadian families maps to 10p11. Am. J. Med. Genet. A. 2008;146A:578–584. PubMed

Wang, D. et al. Comprehensive functional genomic resource and integrative model for the human brain. Science362, 10.1126/science.aat8464 (2018). PubMed PMC

O’Brien HE, et al. Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders. Genome Biol. 2018;19:194. PubMed PMC

Wang F, Panjwani N, Wang C, Sun L, Strug LJ. A flexible summary statistics-based colocalization method with application to the mucin cystic fibrosis lung disease modifier locus. Am. J. Hum. Genet. 2022;109:253–269. PubMed PMC

BrainSpan Atlas of the Developing Human Brain [Internet], http://brainspan.org.

Sunkin SM, et al. Allen Brain Atlas: an integrated spatio-temporal portal for exploring the central nervous system. Nucleic Acids Res. 2013;41:D996–D1008. PubMed PMC

Sebastian K, et al. Characterization of SLCO5A1/OATP5A1, a solute carrier transport protein with non-classical function. PLoS One. 2013;8:e83257. PubMed PMC

Faville R, Kottler B, Goodhill GJ, Shaw PJ, van Swinderen B. How deeply does your mutant sleep? Probing arousal to better understand sleep defects in Drosophila. Sci. Rep. 2015;5:8454. PubMed PMC

Mazaud D, et al. Transcriptional regulation of the glutamate/GABA/glutamine cycle in adult glia controls motor activity and seizures in drosophila. J. Neurosci. 2019;39:5269–5283. PubMed PMC

Falcon S, Gentleman R. Using GOstats to test gene lists for GO term association. Bioinformatics. 2007;23:257–258. PubMed

Liberzon A, et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–425. PubMed PMC

Meissner A, et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature. 2008;454:766–770. PubMed PMC

Mikkelsen TS, et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007;448:553–560. PubMed PMC

Demontis D, et al. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat. Genet. 2019;51:63–75. PubMed PMC

Lawlor DA, Tilling K, Davey Smith G. Triangulation in aetiological epidemiology. Int. J. Epidemiol. 2016;45:1866–1886. PubMed PMC

Parker L, Howlett IC, Rusan ZM, Tanouye MA. Seizure and epilepsy: studies of seizure disorders in Drosophila. Int. Rev. Neurobiol. 2011;99:1–21. PubMed PMC

Uhl GR, Martinez MJ. PTPRD: neurobiology, genetics, and initial pharmacology of a pleiotropic contributor to brain phenotypes. Ann. N Y Acad. Sci. 2019;1451:112–129. PubMed PMC

Hu Z, Xiao X, Zhang Z, Li M. Genetic insights and neurobiological implications from NRXN1 in neuropsychiatric disorders. Mol. Psychiatry. 2019;24:1400–1414. PubMed

Sanes JR, Zipursky SL. Synaptic specificity, recognition molecules, and assembly of neural circuits. Cell. 2020;181:536–556. PubMed

Miyamoto H, et al. Impaired cortico-striatal excitatory transmission triggers epilepsy. Nat. Commun. 2019;10:1917. PubMed PMC

Purcell S, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 2007;81:559–575. PubMed PMC

Manichaikul A, et al. Robust relationship inference in genome-wide association studies. Bioinformatics. 2010;26:2867–2873. PubMed PMC

Wigginton JE, Abecasis GR. PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics. 2005;21:3445–3447. PubMed

Conomos MP, Miller MB, Thornton TA. Robust inference of population structure for ancestry prediction and correction of stratification in the presence of relatedness. Genet. Epidemiol. 2015;39:276–293. PubMed PMC

Das S, et al. Next-generation genotype imputation service and methods. Nat. Genet. 2016;48:1284–1287. PubMed PMC

Fuchsberger C, Abecasis GR, Hinds DA. minimac2: faster genotype imputation. Bioinformatics. 2015;31:782–784. PubMed PMC

Taliun D, et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature. 2021;590:290–299. PubMed PMC

Genomes Project Consortium, et al. A global reference for human genetic variation. Nature. 2015;526:68–74. PubMed PMC

Chen B, Craiu RV, Strug LJ, Sun L. The X factor: a robust and powerful approach to X-chromosome-inclusive whole-genome association studies. Genet. Epidemiol. 2021;45:694–709. PubMed PMC

McLaren W, et al. The ensembl variant effect predictor. Genome Biol. 2016;17:122. PubMed PMC

Ashburner M, et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 2000;25:25–29. PubMed PMC

Gene Ontology, C. The Gene Ontology resource: enriching a GOld mine. Nucleic Acids Res. 2021;49:D325–D334. PubMed PMC

Backes C, et al. Systematic permutation testing in GWAS pathway analyses: identification of genetic networks in dilated cardiomyopathy and ulcerative colitis. BMC Genomics. 2014;15:622. PubMed PMC

McInnes G, et al. Global Biobank Engine: enabling genotype-phenotype browsing for biobank summary statistics. Bioinformatics. 2019;35:2495–2497. PubMed PMC

Gagliano Taliun SA, et al. Exploring and visualizing large-scale genetic associations by using PheWeb. Nat. Genet. 2020;52:550–552. PubMed PMC

Canela-Xandri O, Rawlik K, Tenesa A. An atlas of genetic associations in UK Biobank. Nat. Genet. 2018;50:1593–1599. PubMed PMC

Dobbyn A, et al. Landscape of conditional eQTL in dorsolateral prefrontal cortex and co-localization with schizophrenia GWAS. Am. J. Hum. Genet. 2018;102:1169–1184. PubMed PMC

Panjwani N, et al. LocusFocus: web-based colocalization for the annotation and functional follow-up of GWAS. PLoS Comput. Biol. 2020;16:e1008336. PubMed PMC

Napoletano F, et al. Polyglutamine Atrophin provokes neurodegeneration in Drosophila by repressing fat. EMBO J. 2011;30:945–958. PubMed PMC

Pao SS, Paulsen IT, Saier MH., Jr Major facilitator superfamily. Microbiol. Mol. Biol. Rev. 1998;62:1–34. PubMed PMC

Walmsley AR, Barrett MP, Bringaud F, Gould GW. Sugar transporters from bacteria, parasites and mammals: structure-activity relationships. Trends Biochem. Sci. 1998;23:476–481. PubMed

Madej MG, Dang S, Yan N, Kaback HR. Evolutionary mix-and-match with MFS transporters. Proc. Natl Acad. Sci. USA. 2013;110:5870–5874. PubMed PMC