SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy

作者：Delnaz Roshandel, Eric J. Sanders, Amy Shakeshaft, Naim Panjwani, Lin Fan, Amber Collingwood, Anna Hall, Katherine Lisa Keenan, Celine Deneubourg, Filippo Mirabella, Simon D. Topp, Jana Zárubová, Rhys Huw Thomas, Inga Talvik, Marte Roa Syvertsen, Pasquale Striano, Anna B Smith, Kaja Kristine Selmer, Guido Rubboli, Alessandro Ascani Orsini, Ching Ching Ng, Rikke Steensbjerre Møller, Kheng Seang Lim, Khalid Hamandi, David A. Greenberg, Joanna Gesche, Elena Gardella, Choong Yi Fong, Christoph Patrick Beier, Danielle Molinari Andrade, Heinz Jungbluth, Mark Philip Richardson, Annalisa Pastore, Manolis Fanto, Deb Kumar Pal, Lisa J. Strug, Zuzana Šobíšková, Cechovaz Pracoviste, Michaela Kajšová, Rikke Steensbjerre Møller, Elena Gardella, M Miranda, Pasquale Striano, Alessandro Ascani Orsini, Paulina Bala, Amy Kitching, Kate Irwin, Lorna Walding, Lynsey Adams, Uma Jegathasan, Rachel Swingler, Rachel Wane, Julia A. Aram, Nikil Sudarsan, Dee Mullan, Rebecca Ramsay, Vivien Richmond, M. Sargent, Paul Frattaroli, Matthew D. Taylor, Marie Home, Sal Uka, Susan M. Kilroy, Tonicha Nortcliffe, Halima Salim, Kelly Holroyd, Alison McQueen, Dympna Mcaleer, Dina Jayachandran, Dawn Egginton, Bridget MacDonald, Michael Chang, David Deekollu, Alok Gaurav, Caroline D. Hamilton, Jaya Natarajan, Inyang Takon, Janet Cotta, Nick Moran, Jeremy D.P. Bland, Rosemary Belderbos, Heather Collier, Joanne Henry, Matthew J. Milner, Sam White, Michalis Koutroumanidis, William Stern, Jennifer M. Quirk, Javier Peña‐Ceballos, Anastasia Papathanasiou, Ioannis Stavropoulos, Dora A. Lozsádi, Andrew Swain, Charlotte Quamina, Jennifer Crooks, Tahir Majeed, Sonia Raj, Shakeelah Patel, Michael C. Young, Melissa Maguire, Munni Ray, Caroline Peacey, Linetty Makawa, Asyah Chhibda, Eve Sacre, Shanaz Begum, Martin O’ Malley, Lap Yeung, Claire Holliday, Louise Woodhead, Karen Helton Rhodes, Shan Ellawela, Joanne Glenton, Verity Calder, John M. Davis, Paul McAlinden, Sarah L Francis, Lisa G. Robson, Karen Lanyon, Graham A. Mackay, Elma Stephen, Coleen Thow, Margaret Connon, Martin Kirkpatrick, Susan MacFarlane, Anne Scott MacLeod, Debbie Rice, Siva Kumar, Carolyn Campbell, Vicky Collins, William Patrick Whitehouse, Christina Giavasi, Boyanka Petrova, Thomas David Brown, Catie Picton, Michael O’Donoghue, Charlotte West, Helen Navarra, Sean Slaght, Catherine Edwards, Andrew Gribbin, Liz Nelson, Stephen Warriner, Heather Angus‐Leppan, Loveth Ehiorobo, Bintou Camara, Tinashe Samakomva, Rajiv Mohanraj, Vicky Parker, Rajesh K. Pandey, Lisa Charles, Catherine Cotter, Archana Desurkar, Alison Hyde, Rachel Harrison, Markus Reuber, R. T. Clegg, Joanne Sidebottom, Mayeth Recto, Patrick Easton, Charlotte Waite, Alice Howell, Jacqueline Smith, Shyam Mariguddi, Zena Haslam, Elizabeth Caruana Galizia, Hannah R. Cock, Mark Mencias, Samantha Truscott, Déirdre Daly, Hilda Mhandu, Nooria Said, Mark I. Rees, Seo‐Kyung Chung, Owen Pickrell, Beata Fonferko‐Shadrach, Mark D. Baker, Fraser Scott, Naveed Ghaus, Gail Castle, Jacqui Bartholomew, Ann Needle, Julie Ball, Andrea Clough, Shashikiran Sastry, Charlotte Busby, Amit D. Agrawal, Debbie Dickerson, Almu Duran, Muhammad Shamim Khan, Laura Thrasyvoulou, Eve Irvine, Sarah Tittensor, Jacqueline Daglish, Sumant Kumar, Claire Backhouse, Claire Mewies, Julia A. Aram, Nikil Sudarsan, Dee Mullan, Rebecca Ramsay, Vivien Richmond, Denise Skinner, M. Sargent, Rahul Bharat, Sarah-Jane Sharman, Arun Saraswatula, Helen Cockerill · 发表于：npj Genomic Medicine · 年份：2023 · DOI：10.1038/s41525-023-00370-z · 被引用次数：16 · 研究领域：Genetics and Neurodevelopmental Disorders、Glycogen Storage Diseases and Myoclonus、Epilepsy research and treatment

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 −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.