TY - JOUR
T1 - SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy
AU - Fanto, Manolis
N1 - Funding Information:
This work was supported by the Canadian Institutes of Health Research (CIHR) Operating Grant, FRN: 142405 (D.K.P., L.J.S.) and CIHR Foundation Grant, FRN: 167282 (L.J.S.); UK Medical Research Council, Centre for Neurodevelopmental Disorders MR/N026063/1 (D.K.P., M.P.R.); UK Medical Research Council, Programme Grant MR/K013998/1, (M.P.R.); PhD stipend from UK Medical Research Council and the Sackler Institute for Translational Neurodevelopment (A.S.); NIHR Specialist Biomedical Research Centre for Mental Health of South London and Maudsley National Health Service Foundation Trust (D.K.P., M.P.R.); UK Engineering and Physical Sciences Research Council, Centre for Predictive Modelling in Healthcare (EP/N014391/1 (M.P.R.)); DINOGMI Department of Excellence of MIUR 2018–2022 (legge 232 del 2016 (P.S.)); Wales BRAIN Unit and Research Delivery Staff funded by Welsh Government through Health and Care Research Wales (K.H.); Biomarin srl, ENECTA srl, GW Pharmaceuticals, Kolfarma srl. and Eisai (P.S.); South-Eastern Regional Health Authority, Norway (Project Number 2016129 (K.K.S.)); The Research Council of Norway (Project Number 299266 (M.S.)); Epilepsy Research UK (RHT, M.P.R.); Health & Care Research Wales (M.P.R.), Wales Gene Park (M.P.R.), Abertawe Bro Morgannwg University NHS R&D (M.P.R.); UCB (G.R.); Nationwide Children’s Hospital (D.A.G.); Odense University Hospital (J.G.); University of Southern Denmark (17/18517 (C.P.B.)); Grants NC/V001051/1 from the NC3Rs (M.F.), European Union’s Horizon 2020 Research and Innovation Programme (765912 - DRIVE - H2020-MSCA-ITN-2017 (H.J.)) and Action Medical Research (GN2446 (H.J., M.F.)). L.J.S. is a Canada Research Chair and this research was undertaken, in part, thanks to funding from the Canada Research Chairs Programme. Work supported by #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006)–A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022)- IRCCS ‘G. Gaslini’ is a meber of ERN-Epicare.
Funding Information:
This work was supported by the Canadian Institutes of Health Research (CIHR) Operating Grant, FRN: 142405 (D.K.P., L.J.S.) and CIHR Foundation Grant, FRN: 167282 (L.J.S.); UK Medical Research Council, Centre for Neurodevelopmental Disorders MR/N026063/1 (D.K.P., M.P.R.); UK Medical Research Council, Programme Grant MR/K013998/1, (M.P.R.); PhD stipend from UK Medical Research Council and the Sackler Institute for Translational Neurodevelopment (A.S.); NIHR Specialist Biomedical Research Centre for Mental Health of South London and Maudsley National Health Service Foundation Trust (D.K.P., M.P.R.); UK Engineering and Physical Sciences Research Council, Centre for Predictive Modelling in Healthcare (EP/N014391/1 (M.P.R.)); DINOGMI Department of Excellence of MIUR 2018–2022 (legge 232 del 2016 (P.S.)); Wales BRAIN Unit and Research Delivery Staff funded by Welsh Government through Health and Care Research Wales (K.H.); Biomarin srl, ENECTA srl, GW Pharmaceuticals, Kolfarma srl. and Eisai (P.S.); South-Eastern Regional Health Authority, Norway (Project Number 2016129 (K.K.S.)); The Research Council of Norway (Project Number 299266 (M.S.)); Epilepsy Research UK (RHT, M.P.R.); Health & Care Research Wales (M.P.R.), Wales Gene Park (M.P.R.), Abertawe Bro Morgannwg University NHS R&D (M.P.R.); UCB (G.R.); Nationwide Children’s Hospital (D.A.G.); Odense University Hospital (J.G.); University of Southern Denmark (17/18517 (C.P.B.)); Grants NC/V001051/1 from the NC3Rs (M.F.), European Union’s Horizon 2020 Research and Innovation Programme (765912 - DRIVE - H2020-MSCA-ITN-2017 (H.J.)) and Action Medical Research (GN2446 (H.J., M.F.)). L.J.S. is a Canada Research Chair and this research was undertaken, in part, thanks to funding from the Canada Research Chairs Programme. Work supported by #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006)–A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022)- IRCCS ‘G. Gaslini’ is a meber of ERN-Epicare.
Publisher Copyright:
© 2023, Springer Nature Limited and Centre of Excellence in Genomic Medicine Research, King Abdulaziz University.
PY - 2023/9/28
Y1 - 2023/9/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85173085534&partnerID=8YFLogxK
U2 - 10.1038/s41525-023-00370-z
DO - 10.1038/s41525-023-00370-z
M3 - Article
SN - 2056-7944
VL - 8
JO - NPJ Genomic medicine
JF - NPJ Genomic medicine
IS - 1
M1 - 28
ER -