open access publication

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. 0000-0002-4902-8587 [1] Sanders E.J. [1] [2] Shakeshaft A. 0000-0003-1412-5413 [3] Panjwani N. [1] Lin F. [1] Collingwood A. [3] Hall A. [3] Keenan K. [1] Deneubourg C. [3] Mirabella F. [3] Topp S. 0000-0002-5200-3284 [3] Zarubova J. 0000-0001-8437-8091 [4] Thomas R.H. 0000-0003-2062-8623 [5] [6] Talvik I. [7] Syvertsen M. 0000-0003-2182-4247 Striano P. 0000-0002-6065-1476 [8] [9] Smith A.B. [3] Selmer K.K. 0000-0003-4871-112X [10] Rubboli G. 0000-0002-5309-2514 [11] [12] Orsini A. [13] Ng C.C. [14] Moller R.S. 0000-0002-9664-1448 [12] [15] Lim K.S. 0000-0002-2787-2365 [16] Hamandi K. [17] [18] Greenberg D.A. [19] Gesche J. 0000-0002-0546-4619 [20] Gardella E. 0000-0002-7138-6022 [12] [15] Fong C.Y. [16] Beier C.P. 0000-0001-8268-1492 [20] Andrade D.M. [2] Jungbluth H. 0000-0002-7159-3427 [21] [22] Richardson M.P. 0000-0001-8925-3140 [3] [23] Pastore A. [3] Fanto M. 0000-0001-7807-2563 [3] Pal D.K. 0000-0003-2655-0564 (Corresponding author) [3] [23] Strug L.J. 0000-0003-0503-9740 (Corresponding author) [1] [2] [24] Sobiskova Z. [4] Pracoviste C. [4] Kajsova M. [4] Moller R.S. 0000-0002-9664-1448 [12] Miranda M.J. [20] Orsini A. [9] Bala P. [25] Kitching A. [25] Irwin K. [26] Walding L. [26] Adams L. [26] Jegathasan U. [27] Swingler R. [27] Wane R. [27] Aram J. [28] Sudarsan N. [28] Mullan D. [28] Ramsay R. [28] Richmond V. [28] Sargent M. [28] Frattaroli P. [28] Taylor M. [29] Home M. [29] Uka S. [29] Kilroy S. [29] Nortcliffe T. [29] Salim H. [29] Holroyd K. [29] McQueen A. [18] McAleer D. [18] Jayachandran D. [30] Egginton D. [30] MacDonald B. [31] Chang M. [31] Deekollu D. [32] Gaurav A. [32] Hamilton C. [32] Natarajan J. [32] Takon I. [33] Cotta J. [33] Moran N. [34] Bland J. [34] Belderbos R. [35] Collier H. [35] Henry J. [35] Milner M. [35] White S. [35] Koutroumanidis M. [22] Stern W. [22] Quirk J. [23] Ceballos J.P. [23] Papathanasiou A. [23] Stavropoulos I. [23] Lozsadi D. [36] Swain A. [36] Quamina C. [36] Crooks J. [36] Majeed T. [37] Raj S. [37] Patel S. [37] Young M. [37] Maguire M. [38] Ray M. [38] Peacey C. [38] Makawa L. [38] Chhibda A. [38] Sacre E. [38] Begum S. [38] O' Malley M. [38] Yeung L. [39] Holliday C. [39] Woodhead L. [39] Rhodes K. [39] Ellawela S. [6] Glenton J. [6] Calder V. [6] Davis J. [6] McAlinden P. [6] Francis S. [6] Robson L. [6] Lanyon K. [40] Mackay G. [40] Stephen E. [40] Thow C. [40] Connon M. [40] Kirkpatrick M. [41] MacFarlane S. [41] Macleod A. [41] Rice D. [41] Kumar S. [42] Campbell C. [42] Collins V. [42] Whitehouse W. [43] Giavasi C. [43] Petrova B. [43] Brown T. [43] Picton C. [43] O'Donoghue M. [43] West C. [43] Navarra H. [43] Slaght S.J. [44] Edwards C. [44] Gribbin A. [44] Nelson L. [44] Warriner S. [44] Angus-Leppan H. [45] Ehiorobo L. [45] Camara B. [45] Samakomva T. [45] Mohanraj R. [46] Parker V. [46] Pandey R. [47] Charles L. [47] Cotter C. [47] Desurkar A. [48] Hyde A. [48] Harrison R. [48] Reuber M. 0000-0002-4104-6705 [49] Clegg R. [49] Sidebottom J. [49] Recto M. [49] Easton P. [49] Waite C. [49] Howell A. [49] Smith J. [49] Mariguddi S. [50] Haslam Z. [50] Galizia E. [51] Cock H. 0000-0002-5656-0141 [51] Mencias M. [51] Truscott S. [51] Daly D. [51] Mhandu H. [51] Said N. [51] Rees M.I. [52] Chung S.-K. [52] Pickrell O. [52] Fonferko-Shadrach B. [52] Baker M. [52] Scott F. [53] Ghaus N. [53] Castle G. [53] Bartholomew J. [53] Needle A. [53] Ball J. [53] Clough A. [53] Sastry S. [54] Busby C. [54] Agrawal A. [55] Dickerson D. [55] Duran A. [55] Khan M. [56] Thrasyvoulou L. [56] Irvine E. [56] Tittensor S. [56] Daglish J. [56] Kumar S. [57] Backhouse C. [57] Mewies C. [57] Aram J. [28] Sudarsan N. [28] Mullan D. [28] Ramsay R. [28] Richmond V. [28] Skinner D. [28] Sargent M. [28] Bharat R. [58] Sharman S.-J. [58] Saraswatula A. [59] Cockerill H. [59]

Affiliations

  1. [1] Hospital for Sick Children
    2. [NORA names: Canada; America, North; OECD];
  2. [2] University of Toronto
    3. [NORA names: Canada; America, North; OECD];
  3. [3] King's College London
    4. [NORA names: United Kingdom; Europe, Non-EU; OECD];
  4. [4] University Hospital Motol
    5. [NORA names: Czechia; Europe, EU; OECD];
  5. [5] Newcastle University
    6. [NORA names: United Kingdom; Europe, Non-EU; OECD];

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

Data Provider: Elsevier

LINKS
-

Matching Records in NORA

SUBJECTS
+

METRICS
+