SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy
Authors: Roshandel Delnaz , Sanders Eric J. , Shakeshaft Amy , Panjwani Naim , Lin Fan , Collingwood Amber , Hall Anna , Keenan Katherine , Deneubourg Celine , Mirabella Filippo , Topp Simon , Zarubova Jana , Thomas Rhys H. , Talvik Inga , Syvertsen Marte , Striano Pasquale , Smith Anna B. , Selmer Kaja K. , Rubboli Guido , Orsini Alessandro , Ng Ching Ching , Møller Rikke S. , Lim Kheng Seang , Hamandi Khalid , Greenberg David A. , Gesche Joanna , Gardella Elena , Fong Choong Yi , Beier Christoph P. , Andrade Danielle M. , Jungbluth Heinz , Richardson Mark P. , Pastore Annalisa , Fanto Manolis , Pal Deb K. , Strug Lisa J. ,   the BIOJUME Consortium, Šobíšková Zuzana , Pracoviste Cechovaz , Kajsova Michaela , Møller Rikke S. , Gardella Elena , Miranda Maria , Striano Pasquale , Orsini Alessandro , Bala Pronab , Kitching Amy , Irwin Kate , Walding Lorna , Adams Lynsey , Jegathasan Uma , Swingler Rachel , Wane Rachel , Aram Julia , Sudarsan Nikil , Mullan Dee , Ramsay Rebecca , Richmond Vivien , Sargent Mark , Frattaroli Paul , Taylor Matthew , Home Marie , Uka Sal , Kilroy Susan , Nortcliffe Tonicha , Salim Halima , Holroyd Kelly , McQueen Alison , Mcaleer Dympna , Jayachandran Dina , Egginton Dawn , MacDonald Bridget , Chang Michael , Deekollu David , Gaurav Alok , Hamilton Caroline , Natarajan Jaya , Takon Inyan , Cotta Janet , Moran Nick , Bland Jeremy , Belderbos Rosemary , Collier Heather , Henry Joanne , Milner Matthew , White Sam , Koutroumanidis Michalis , Stern William , Quirk Jennifer , Ceballos Javier Peña , Papathanasiou Anastasia , Stavropoulos Ioannis , Lozsadi Dora , Swain Andrew , Quamina Charlotte , Crooks Jennifer , Majeed Tahir , Raj Sonia , Patel Shakeelah , Young Michael , Maguire Melissa , Ray Munni , Peacey Caroline , Makawa Linetty , Chhibda Asyah , Sacre Eve , Begum Shanaz , O’ Malley Martin , Yeung Lap , Holliday Claire , Woodhead Louise , Rhodes Karen , Ellawela Shan , Glenton Joanne , Calder Verity , Davis John , McAlinden Paul , Francis Sarah , Robson Lisa , Lanyon Karen , Mackay Graham , Stephen Elma , Thow Coleen , Connon Margaret , Kirkpatrick Martin , MacFarlane Susan , Macleod Anne , Rice Debbie , Kumar Siva , Campbell Carolyn , Collins Vicky , Whitehouse William , Giavasi Christina , Petrova Boyanka , Brown Thomas , Picton Catie , O’Donoghue Michael , West Charlotte , Navarra Helen , Slaght Seán J. , Edwards Catherine , Gribbin Andrew , Nelson Liz , Warriner Stephen , Angus-Leppan Heather , Ehiorobo Loveth , Camara Bintou , Samakomva Tinashe , Mohanraj Rajiv , Parker Vicky , Pandey Rajesh , Charles Lisa , Cotter Catherine , Desurkar Archana , Hyde Alison , Harrison Rachel , Reuber Markus , Clegg Rosie , Sidebottom Jo , Recto Mayeth , Easton Patrick , Waite Charlotte , Howell Alice , Smith Jacqueline , Mariguddi Shyam , Haslam Zena , Galizia Elizabeth , Cock Hannah , Mencias Mark , Truscott Samantha , Daly Deirdre , Mhandu Hilda , Said Nooria , Rees Mark , Chung Seo-Kyung , Pickrell Owen , Fonferko-Shadrach Beata , Baker Mark , Scott Fraser , Ghaus Naveed , Castle Gail , Bartholomew Jacqui , Needle Ann , Ball Julie , Clough Andrea , Sastry Shashikiran , Busby Charlotte , Agrawal Amit , Dickerson Debbie , Duran Almu , Khan Muhammad , Thrasyvoulou Laura , Irvine Eve , Tittensor Sarah , Daglish Jacqueline , Kumar Sumant , Backhouse Claire , Mewies Claire , Aram Julia , Sudarsan Nikil , Mullan Dee , Ramsay Rebecca , Richmond Vivien , Skinner Denise , Sargent Mark , Bharat Rahul , Sharman Sarah-Jane , Saraswatula Arun , Cockerill Helen 
Published: September 2023

AbstractElevated 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.