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Lookup NU author(s): Dr Rhys ThomasORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023, Springer Nature Limited and Centre of Excellence in Genomic Medicine Research, King Abdulaziz University.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.
Author(s): Roshandel D, Sanders EJ, Shakeshaft A, Panjwani N, Lin F, Collingwood A, Hall A, Keenan K, Deneubourg C, Mirabella F, Topp S, Zarubova J, Thomas RH, Talvik I, Syvertsen M, Striano P, Smith AB, Selmer KK, Rubboli G, Orsini A, Ng CC, Moller RS, Lim KS, Hamandi K, Greenberg DA, Gesche J, Gardella E, Fong CY, Beier CP, Andrade DM, Jungbluth H, Richardson MP, Pastore A, Fanto M, Pal DK, Strug LJ, Sobiskova Z, Pracoviste C, Kajsova M, Moller RS, Gardella E, Miranda M, Striano P, Orsini A, Bala P, Kitching A, Irwin K, Walding L, Adams L, Jegathasan U, Swingler R, Wane R, Aram J, Mullan D, Ramsay R, Richmond V, Sargent M, Frattaroli P, Taylor M, Home M, Uka S, Kilroy S, Nortcliffe T, Salim H, Holroyd K, McQueen A, Mcaleer D, Jayachandran D, Egginton D, MacDonald B, Chang M, Deekollu D, Gaurav A, Hamilton C, Natarajan J, Takon I, Cotta J, Moran N, Bland J, Belderbos R, Collier H, Henry J, Milner M, White S, Koutroumanidis M, Stern W, Quirk J, Ceballos JP, Papathanasiou A, Stavropoulos I, Lozsadi D, Swain A, Quamina C, Crooks J, Majeed T, Raj S, Patel S, Young M, Maguire M, Ray M, Peacey C, Makawa L, Chhibda A, Sacre E, Begum S, O' Malley M, Yeung L, Holliday C, Woodhead L, Rhodes K, Ellawela S, Glenton J, Calder V, Davis J, McAlinden P, Francis S, Robson L, Lanyon K, Mackay G, Stephen E, Thow C, Connon M, Kirkpatrick M, MacFarlane S, Macleod A, Rice D, Kumar S, Campbell C, Collins V, Whitehouse W, Giavasi C, Petrova B, Brown T, Picton C, O'Donoghue M, West C, Navarra H, Slaght SJ, Edwards C, Gribbin A, Nelson L, Warriner S, Angus-Leppan H, Ehiorobo L, Camara B, Samakomva T, Mohanraj R, Parker V, Pandey R, Charles L, Cotter C, Desurkar A, Hyde A, Harrison R, Reuber M, Clegg R, Sidebottom J, Recto M, Easton P, Waite C, Howell A, Smith J, Mariguddi S, Haslam Z, Galizia E, Cock H, Mencias M, Truscott S, Daly D, Mhandu H, Said N, Rees M, Chung S-K, Pickrell O, Fonferko-Shadrach B, Baker M, Scott F, Ghaus N, Castle G, Bartholomew J, Needle A, Ball J, Clough A, Sastry S, Busby C, Agrawal A, Dickerson D, Duran A, Khan M, Thrasyvoulou L, Irvine E, Tittensor S, Daglish J, Kumar S, Backhouse C, Mewies C, Aram J, Sudarsan N, Sudarsan N, Mullan D, Ramsay R, Richmond V, Skinner D, Sargent M, Bharat R, Sharman S-J, Saraswatula A, Cockerill H
Publication type: Article
Publication status: Published
Journal: npj Genomic Medicine
Year: 2023
Volume: 8
Issue: 1
Online publication date: 28/09/2023
Acceptance date: 29/08/2023
Date deposited: 26/10/2023
ISSN (electronic): 2056-7944
Publisher: Nature Research
URL: https://doi.org/10.1038/s41525-023-00370-z
DOI: 10.1038/s41525-023-00370-z
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