Scopus list of publications for September 10, 2023
Probing the drivers of Staphylococcus aureus biofilm protein amyloidogenesis and disrupting biofilms with engineered protein disaggregases
(2023) mBio, 14 (4), p. e0058723.
Howard, M.K., Miller, K.R., Sohn, B.S., Ryan, J.J., Xu, A., Jackrel, M.E.
Department of Chemistry, Washington University, St. Louis, MO, United States
Abstract
Phenol-soluble modulins (PSMs) are the primary proteinaceous component of Staphylococcus aureus biofilms. Residence in the protective environment of biofilms allows bacteria to rapidly evolve and acquire antimicrobial resistance, which can lead to persistent infections such as those caused by methicillin-resistant S. aureus (MRSA). In their soluble form, PSMs hinder the immune response of the host and can increase the virulence potential of MRSA. PSMs also self-assemble into insoluble functional amyloids that contribute to the structural scaffold of biofilms. The specific roles of PSM peptides in biofilms remain poorly understood. Here, we report the development of a genetically tractable yeast model system for studying the properties of PSMα peptides. Expression of PSMα peptides in yeast drives the formation of toxic insoluble aggregates that adopt vesicle-like structures. Using this system, we probed the molecular drivers of PSMα aggregation to delineate key similarities and differences among the PSMs and identified a crucial residue that drives PSM features. Biofilms are a major public health threat; thus, biofilm disruption is a key goal. To solubilize aggregates comprised of a diverse range of amyloid and amyloid-like species, we have developed engineered variants of Hsp104, a hexameric AAA+ protein disaggregase from yeast. Here, we demonstrate that potentiated Hsp104 variants counter the toxicity and aggregation of PSMα peptides. Further, we demonstrate that a potentiated Hsp104 variant can drive the disassembly of preformed S. aureus biofilms. We suggest that this new yeast model can be a powerful platform for screening for agents that disrupt PSM aggregation and that Hsp104 disaggregases could be a promising tool for the safe enzymatic disruption of biofilms. IMPORTANCE Biofilms are complex mixtures secreted by bacteria that form a material in which the bacteria can become embedded. This process transforms the properties of the bacteria, and they become more resistant to removal, which can give rise to multidrug-resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA). Here, we study phenol-soluble modulins (PSMs), which are amyloidogenic proteins secreted by S. aureus, that become incorporated into biofilms. Biofilms are challenging to study, so we have developed a new genetically tractable yeast model to study the PSMs. We used our system to learn about several key features of the PSMs. We also demonstrate that variants of an amyloid disaggregase, Hsp104, can disrupt the PSMs and, more importantly, dissolve preformed S. aureus biofilms. We propose that our system can be a powerful screening tool and that Hsp104 disaggregases may be a new avenue to explore for biofilm disruption agents.
Author Keywords
amyloid; biofilm; disaggregase; MRSA; phenol-soluble modulins
Document Type: Article
Publication Stage: Final
Source: Scopus
Timing of Alzheimer’s Disease by Intellectual Disability Level in Down Syndrome
(2023) Journal of Alzheimer’s Disease: JAD, 95 (1), pp. 213-225.
Hartley, S.L.a b , Fleming, V.a b , Schworer, E.K.a , Peven, J.c , Handen, B.L.c , Krinsky-McHale, S.d , Hom, C.e , Lee, L.c , Tudorascu, D.L.c , Laymon, C.f , Minhas, D.f , Luo, W.f , Cohen, A.c , Zaman, S.g h , Ances, B.M.i , Mapstone, M.j , Head, E.k , Lai, F.l , Rosas, H.D.l m , Klunk, W.c , Christian, B.a , Alzheimer Biomarker Consortium-Down Syndromen
a Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
b School of Human Ecology, University of Wisconsin-Madison, Madison, WI, United States
c Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Psychology, New York Institute for Basic Research in Developmental Disabilities, Staten IslandNY, United States
e Department of Psychiatry and Human Behavior, University of California, Irvine, CA, United States
f Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
g Cambridgeshire & Peterborough NHS Foundation Trust (CPFT), Elizabeth House, Fulbourn Hospital, Cambridge, United Kingdom
h Department of Psychiatry, Cambridge Intellectual & Developmental Disabilities Research Group (CIDDRG), University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom
i Department of Neurology, Washington University St. Louis, St. Louis, MO, United States
j Clinical Neurology, University of California, Irvine, CA, United States
k Department of Pathology and Laboratory Medicine, University of California, Irvine, CA, United States
l Department of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, United States
m Massachusetts General Hospital, Center for Neuro-imaging of Aging and Neurodegenerative Diseases, Charlestown, MA, United States
Abstract
BACKGROUND: Trisomy 21 causes Down syndrome (DS) and is a recognized cause of early-onset Alzheimer’s disease (AD). OBJECTIVE: The current study sought to determine if premorbid intellectual disability level (ID) was associated with variability in age-trajectories of AD biomarkers and cognitive impairments. General linear mixed models compared the age-trajectory of the AD biomarkers PET Aβ and tau and cognitive decline across premorbid ID levels (mild, moderate, and severe/profound), in models controlling trisomy type, APOE status, biological sex, and site. METHODS: Analyses involved adults with DS from the Alzheimer’s Biomarkers Consortium-Down Syndrome. Participants completed measures of memory, mental status, and visuospatial ability. Premorbid ID level was based on IQ or mental age scores prior to dementia concerns. PET was acquired using [11C] PiB for Aβ, and [18F] AV-1451 for tau. RESULTS: Cognitive data was available for 361 participants with a mean age of 45.22 (SD = 9.92) and PET biomarker data was available for 154 participants. There was not a significant effect of premorbid ID level by age on cognitive outcomes. There was not a significant effect of premorbid ID by age on PET Aβ or on tau PET. There was not a significant difference in age at time of study visit of those with mild cognitive impairment-DS or dementia by premorbid ID level. CONCLUSION: Findings provide robust evidence of a similar time course in AD trajectory across premorbid ID levels, laying the groundwork for the inclusion of individuals with DS with a variety of IQ levels in clinical AD trials.
Author Keywords
Alzheimer’s disease; amyloid; cognitive; dementia; Down syndrome; imaging; intellectual; memory; tau
Document Type: Article
Publication Stage: Final
Source: Scopus
Antibody response to SARS-CoV-2 vaccines in patients with relapsing multiple sclerosis treated with evobrutinib: A Bruton’s tyrosine kinase inhibitor
(2023) Multiple Sclerosis Journal, .
Bar-Or, A.a , Cross, A.H.b , Cunningham, A.L.c , Hyvert, Y.d , Seitzinger, A.d , Gühring, H.d , Drouin, E.E.e , Alexandri, N.d , Tomic, D.f , Montalban, X.g
a Center for Neuroinflammation and Experimental Therapeutics, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
b Department of Neurology, Center for Neuroimmunology and Neuroinfectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
c Centre for Virus Research, The Westmead Institute for Medical Research, The University of Sydney, WestmeadNSW, Australia
d Merck Healthcare KGaA, Darmstadt, Germany
e EMD Serono Research & Development Institute, Inc, an affiliate of Merck KGaA, Billerica, MA, United States
f Ares Trading SA, an affiliate of Merck KGaA, Eysins, Switzerland
g Department of Neurology-Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, Barcelona, Spain
Abstract
Background: Evobrutinib is an oral, central nervous system (CNS)-penetrant and highly selective covalent Bruton’s tyrosine kinase inhibitor under clinical development for patients with relapsing multiple sclerosis (RMS). Objective: To investigate the effect of evobrutinib on immune responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinated patients with RMS from a Phase II trial (NCT02975349). Methods: A post hoc analysis of patients with RMS who received evobrutinib 75 mg twice daily and SARS-CoV-2 vaccines during the open-label extension (n = 45) was conducted. Immunoglobulin (Ig)G anti-S1/S2-specific SARS-CoV-2 antibodies were measured using an indirect chemiluminescence immunoassay. Results: In the vaccinated subgroup, mean/minimum evobrutinib exposure pre-vaccination was 105.2/88.7 weeks. In total, 43 of 45 patients developed/increased S1/S2 IgG antibody levels post-vaccination; one patient’s antibody response remained negative post-vaccination and the other had antibody levels above the upper limit of detection, both pre- and post-vaccination. Most patients (n = 36/45), regardless of pre-vaccination serostatus, had a 10–100-fold increase of antibody levels pre- to post-vaccination. Antibody levels post-booster were higher versus post-vaccination. Conclusion: These results suggest evobrutinib, an investigational drug with therapeutic potential for patients with RMS, acts as an immunomodulator, that is, it inhibits aberrant immune cell responses in patients with RMS, while responsiveness to foreign de novo and recall antigens is maintained. © The Author(s), 2023.
Author Keywords
Bruton’s tyrosine kinase; COVID-19; Evobrutinib; multiple sclerosis; SARS-CoV-2; vaccines
Funding details
Merck Healthcare KGaA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Intrusive Traumatic Re-Experiencing Domain: Functional Connectivity Feature Classification by the ENIGMA PTSD Consortium
(2023) Biological Psychiatry Global Open Science, .
Suarez-Jimenez, B.a , Lazarov, A.b c , Zhu, X.c , Zilcha-Mano, S.d , Kim, Y.e , Marino, C.E.a , Rjabtsenkov, P.a , Bavdekar, S.Y.a , Pine, D.S.f , Bar-Haim, Y.b g , Larson, C.L.i , Huggins, A.A.h , Terri deRoon-Cassinij , Tomas, C.j , Fitzgerald, J.k , Kennis, M.l m , Varkevisser, T.l m , Geuze, E.l m , Quidé, Y.n o , El Hage, W.p q , Wang, X.r , O’Leary, E.N.r , Cotton, A.S.r , Xie, H.r , Shih, C.r , Disner, S.G.s , Davenport, N.D.s , Sponheim, S.R.s , Koch, S.B.J.t , Frijling, J.L.u , Nawijn, L.u v , van Zuiden, M.u , Olff, M.u w , Veltman, D.J.v , Gordon, E.M.x , May, G.y , Nelson, S.M.z , Jia-Richards, M.aa , Neria, Y.c , Morey, R.A.h
a Del Monte Institute for Neuroscience, Department of Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, New York
b Department of Clinical Psychology, School of Psychological Sciences, Tel-Aviv University, Tel-Aviv, Israel
c Department of Psychiatry, Columbia University Irving Medical Center and New York State Psychiatric Institute, New York, New York
d Department of Psychology, University of Haifa, Mount Carmel, Haifa, Israel
e Department of Psychiatry, New York State Psychiatric Institute, New York, New York
f Section on Developmental Affective Neuroscience, National Institute of Mental Health, Bethesda, MD, United States
g Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
h Duke University, Durham, NC, United States
i University of Wisconsin–Milwaukee, Milwaukee, WI, United States
j Medical College of Wisconsin, Milwaukee, WI, United States
k Marquette University, Milwaukee, WI, United States
l Brain Research and Innovation Centre, Ministry of Defence, Utrecht, Netherlands
m Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands
n School of Psychology, University of New South Wales Sydney, Sydney, NSW, Australia
o Neuroscience Research Australia, Randwick, NSW, Australia
p Unité Mixte de Recherche 1253, Institut National de la Santé et de la Recherche Médicale, Université de Tours, Tours, France
q Centre d’investigation Clinique 1415, Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Régional Universitaire de Tours, Tours, France
r University of Toledo, Toledo, OH, United States
s Minneapolis VA Health Care System, Minneapolis, MN, United States
t Centre for Cognitive Neuroimaging, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, Netherlands
u Department of Psychiatry, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands
v Department of Psychiatry, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
w ARQ National Psychotrauma Centre, Diemen, Netherlands
x Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
y VISN 17 Center of Excellence for Research on Returning War Veterans, U.S. Department of Veterans Affairs, Waco, TX, United States
z Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
aa Department of Psychology and Neuroscience, Baylor University, Waco, TX, United States
Abstract
Background: Intrusive traumatic re-experiencing domain (ITRED) was recently introduced as a novel perspective on posttraumatic psychopathology, proposing to focus research of posttraumatic stress disorder (PTSD) on the unique symptoms of intrusive and involuntary re-experiencing of the trauma, namely, intrusive memories, nightmares, and flashbacks. The aim of the present study was to explore ITRED from a neural network connectivity perspective. Methods: Data were collected from 9 sites taking part in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) PTSD Consortium (n = 584) and included itemized PTSD symptom scores and resting-state functional connectivity (rsFC) data. We assessed the utility of rsFC in classifying PTSD, ITRED-only (no PTSD diagnosis), and trauma-exposed (TE)–only (no PTSD or ITRED) groups using a machine learning approach, examining well-known networks implicated in PTSD. A random forest classification model was built on a training set using cross-validation, and the averaged cross-validation model performance for classification was evaluated using the area under the curve. The model was tested using a fully independent portion of the data (test dataset), and the test area under the curve was evaluated. Results: rsFC signatures differentiated TE-only participants from PTSD and ITRED-only participants at about 60% accuracy. Conversely, rsFC signatures did not differentiate PTSD from ITRED-only individuals (45% accuracy). Common features differentiating TE-only participants from PTSD and ITRED-only participants mainly involved default mode network–related pathways. Some unique features, such as connectivity within the frontoparietal network, differentiated TE-only participants from one group (PTSD or ITRED-only) but to a lesser extent from the other group. Conclusions: Neural network connectivity supports ITRED as a novel neurobiologically based approach to classifying posttrauma psychopathology. © 2023 The Authors
Author Keywords
ITRED; Machine learning; PTSD; Re-experiencing; Resting-state functional connectivity; Trauma exposure
Funding details
110614
1IK2RX000709, 1K1RX002325, 1K2RX002922, I01RX000622
National Institute of Mental HealthNIMH1R01MH106574, 1R01MH110483, 1R21MH098198, 1R21MH125277, K01MH118428, K01MH122774, R01MH105355, R01MH131532, TdR-C
National Eye InstituteNEIP30 EY001319
Congressionally Directed Medical Research ProgramsCDMRPW81XWH-08-2-0038
Brain and Behavior Research FoundationBBRF
UCB
Clinical Science Research and DevelopmentCSRD1IK2CX001680
ZonMw40-00812-98-10041
Israel Science FoundationISF374/20, ZIA-MH-002782
Fondation Pierre Deniker pour la Recherche et la Prévention en Santé MentaleFED4226
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture
(2023) Nature Genetics, .
Stevelink, R.a , Campbell, C.b c , Chen, S.d e , Abou-Khalil, B.f , Adesoji, O.M.g , Afawi, Z.h , Amadori, E.i j , Anderson, A.k l , Anderson, J.m , Andrade, D.M.n , Annesi, G.o , Auce, P.p , Avbersek, A.q , Bahlo, M.r s t , Baker, M.D.u , Balagura, G.i j , Balestrini, S.q v , Barba, C.w , Barboza, K.x , Bartolomei, F.y , Bast, T.z aa , Baum, L.ab ac , Baumgartner, T.ad , Baykan, B.ae af , Bebek, N.ae af , Becker, A.J.ag , Becker, F.ah , Bennett, C.A.hl , Berghuis, B.ai , Berkovic, S.F.hl , Beydoun, A.aj , Bianchini, C.w , Bisulli, F.ak al , Blatt, I.h am , Bobbili, D.R.an , Borggraefe, I.ao ap , Bosselmann, C.aq , Braatz, V.q v , Bradfield, J.P.ar as , Brockmann, K.at , Brody, L.C.au , Buono, R.J.ar av aw , Busch, R.M.ax ay az , Caglayan, H.ba , Campbell, E.bb , Canafoglia, L.bc , Canavati, C.bd , Cascino, G.D.be , Castellotti, B.bf , Catarino, C.B.q , Cavalleri, G.L.b c , Cerrato, F.bg , Chassoux, F.bh , Cherny, S.S.ab bi , Cheung, C.-L.bj , Chinthapalli, K.q , Chou, I.-J.bk , Chung, S.-K.bl bm , Churchhouse, C.d e bg , Clark, P.O.bn , Cole, A.J.bo , Compston, A.bp , Coppola, A.bq , Cosico, M.br bs , Cossette, P.bt , Craig, J.J.bu , Cusick, C.bg , Daly, M.J.d e bg bv , Davis, L.K.bw bx by bz , de Haan, G.-J.ca , Delanty, N.b c cb , Depondt, C.cc , Derambure, P.cd , Devinsky, O.ce , Di Vito, L.ak , Dlugos, D.J.br , Doccini, V.w , Doherty, C.P.c cf , El-Naggar, H.b c cb , Elger, C.E.ad , Ellis, C.A.cg , Eriksson, J.G.ch , Faucon, A.ci , Feng, Y.-C.A.d e bg cj ck , Ferguson, L.ay , Ferraro, T.N.av cl , Ferri, L.ak al , Feucht, M.cm , Fitzgerald, M.br bs cg , Fonferko-Shadrach, B.u , Fortunato, F.cn , Franceschetti, S.co , Franke, A.cp , French, J.A.cq , Freri, E.cr , Gagliardi, M.cs , Gambardella, A.cn , Geller, E.B.ct , Giangregorio, T.ak , Gjerstad, L.cu , Glauser, T.bn , Goldberg, E.br bs , Goldman, A.cv , Granata, T.cr , Greenberg, D.A.cw , Guerrini, R.w , Gupta, N.e , Haas, K.F.f , Hakonarson, H.ar cx , Hallmann, K.ad cy , Hassanin, E.an cz , Hegde, M.da , Heinzen, E.L.db dc , Helbig, I.br bs cg cp dd de , Hengsbach, C.aq , Heyne, H.O.e bv df dg , Hirose, S.dh , Hirsch, E.di , Hjalgrim, H.dj dk , Howrigan, D.P.d e bg , Hucks, D.bw bz , Hung, P.-C.bk , Iacomino, M.j , Imbach, L.L.dl , Inoue, Y.dm , Ishii, A.dn , Jamnadas-Khoda, J.q do , Jehi, L.ay az , Johnson, M.R.dp , Kälviäinen, R.dq dr , Kamatani, Y.ds , Kanaan, M.bd , Kanai, M.dt du , Kantanen, A.-M.dq , Kara, B.dv , Kariuki, S.M.dw dx dy , Kasperavičiūte, D.q , Kasteleijn-Nolst Trenite, D.a , Kato, M.dz , Kegele, J.aq , Kesim, Y.ae , Khoueiry-Zgheib, N.ea , King, C.eb , Kirsch, H.E.da , Klein, K.M.ec ed ee ef , Kluger, G.eg eh , Knake, S.ec ef , Knowlton, R.C.da , Koeleman, B.P.C.a , Korczyn, A.D.h , Koupparis, A.ei , Kousiappa, I.ei , Krause, R.an , Krenn, M.ej , Krestel, H.ed ef ek el , Krey, I.em , Kunz, W.S.ad en , Kurki, M.I.d e bg bv , Kurlemann, G.eo , Kuzniecky, R.ep , Kwan, P.k l eq , Labate, A.er , Lacey, A.b c cb , Lal, D.ax ay bg , Landoulsi, Z.an , Lau, Y.-L.es , Lauxmann, S.aq , Leech, S.L.hl , Lehesjoki, A.-E.et , Lemke, J.R.em , Lerche, H.aq , Lesca, G.eu , Leu, C.q ax bg , Lewin, N.br bs , Lewis-Smith, D.br de ev ew , Li, G.H.-Y.bj ex , Li, Q.S.ey , Licchetta, L.ak , Lin, K.-L.bk , Lindhout, D.a ca , Linnankivi, T.ez fa fb , Lopes-Cendes, I.fc , Lowenstein, D.H.da , Lui, C.H.T.fd , Madia, F.j , Magnusson, S.fe , Marson, A.G.ff , May, P.an , McGraw, C.M.bo , Mei, D.w , Mills, J.L.fg , Minardi, R.ak , Mirza, N.ff , Møller, R.S.dj dk , Molloy, A.M.fh , Montomoli, M.w , Mostacci, B.ak , Muccioli, L.al , Muhle, H.dd , Müller-Schlüter, K.fi , Najm, I.M.ay az , Nasreddine, W.aj , Neale, B.M.d e bg , Neubauer, B.fj , Newton, C.R.J.C.dw dx dy , Nöthen, M.M.fk , Nothnagel, M.g fl , Nürnberg, P.g , O’Brien, T.J.k l , Okada, Y.du fm , Ólafsson, E.fn , Oliver, K.L.r hl s hl , Özkara, C.fo , Palotie, A.d e bg bv , Pangilinan, F.au , Papacostas, S.S.ei , Parrini, E.w , Pato, C.N.fp , Pato, M.T.fp , Pendziwiat, M.cp dd , Petrovski, S.k fq , Pickrell, W.O.u fr , Pinsky, R.fs , Pippucci, T.ft , Poduri, A.fs , Pondrelli, F.al , Powell, R.H.W.fr , Privitera, M.fu , Rademacher, A.dd , Radtke, R.fv , Ragona, F.cr , Rau, S.aq , Rees, M.I.bm fw , Regan, B.M.hl , Reif, P.S.ec ed ef , Rhelms, S.fx fy , Riva, A.i j , Rosenow, F.ec ed ef , Ryvlin, P.fz , Saarela, A.dq dr , Sadleir, L.G.eb , Sander, J.W.q v ca , Sander, T.g ga , Scala, M.i j , Scattergood, T.gb , Schachter, S.C.gc , Schankin, C.J.ek gd , Scheffer, I.E.ge hl hl , Schmitz, B.ga , Schoch, S.ag , Schubert-Bast, S.ed ef , Schulze-Bonhage, A.gf , Scudieri, P.i j , Sham, P.ab , Sheidley, B.R.fs , Shih, J.J.gg , Sills, G.J.gh , Sisodiya, S.M.q v , Smith, M.C.gi , Smith, P.E.gj , Sonsma, A.C.M.a , Speed, D.gk gl , Sperling, M.R.gm , Stefansson, H.fe , Stefansson, K.fe , Steinhoff, B.J.z aa , Stephani, U.dd , Stewart, W.C.gn go , Stipa, C.ak , Striano, P.i j , Stroink, H.gp , Strzelczyk, A.ec ed ef , Surges, R.ad , Suzuki, T.gq gr , Tan, K.M.k , Taneja, R.S.f , Tanteles, G.A.ei , Taubøll, E.cu , Thio, L.L.gs , Thomas, G.N.gt , Thomas, R.H.ev ew , Timonen, O.dr , Tinuper, P.ak al , Todaro, M.k l , Topaloğlu, P.gu , Tozzi, R.gv , Tsai, M.-H.gw , Tumiene, B.gx gy , Turkdogan, D.gz , Unnsteinsdóttir, U.fe , Utkus, A.gy , Vaidiswaran, P.br bs , Valton, L.ha , van Baalen, A.dd , Vetro, A.w , Vining, E.P.G.hb , Visscher, F.hc , von Brauchitsch, S.ed ef , von Wrede, R.ad , Wagner, R.G.hd , Weber, Y.G.aq he , Weckhuysen, S.hf hg hh , Weisenberg, J.gs , Weller, M.hi , Widdess-Walsh, P.b c cb , Wolff, M.hj , Wolking, S.he , Wu, D.ci , Yamakawa, K.gq gr , Yang, W.es , Yapıcı, Z.gu , Yücesan, E.hk , Zagaglia, S.q v , Zahnert, F.ec , Zara, F.i j , Zhou, W.d e bg , Zimprich, F.ej , Zsurka, G.ad en , Zulfiqar Ali, Q.n , International League Against Epilepsy Consortium on Complex Epilepsieshl
a Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
b School of Pharmacy and Biomolecular Sciences, The Royal College of Surgeons in Ireland, Dublin, Ireland
c The FutureNeuro Research Centre, Dublin, Ireland
d Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
e Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
f Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States
g Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
h Tel-Aviv University Sackler Faculty of Medicine, Ramat Aviv, Israel
i Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy
j IRCCS Istituto Giannina Gaslini, Genova, Italy
k Department of Medicine, University of Melbourne, Royal Melbourne Hospital, Parkville, VIC, Australia
l Department of Neuroscience, Central Clinical School, Alfred Health, Monash University, Melbourne, VIC, Australia
m Neurology Department, Aneurin Bevan University Health Board, Newport, United Kingdom
n Adult Genetic Epilepsy Program, University of Toronto, Toronto, ON, Canada
o Institute for Biomedical Research and Innovation, National Research Council, Cosenza, Italy
p St. George’s University Hospital NHS Foundation Trust, London, United Kingdom
q Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom
r Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
s Department of Biology, University of Melbourne, Parkville, VIC, Australia
t School of Mathematics and Statistics, University of Melbourne, Parkville, VIC, Australia
u Swansea University Medical School, Swansea University, Swansea, United Kingdom
v Chalfont Centre for Epilepsy, Chalfont-St-Peter, United Kingdom
w Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Children’s Hospital A. Meyer, University of Florence, Florence, Italy
x University Health Network, University of Toronto, Toronto, ON, Canada
y APHM, Timone Hospital, Epileptology and Cerebral Rhythmology, Aix Marseille Univ, INSERM, INS, Inst Neurosci Syst, Marseille, France
z Epilepsy Center Kork, Kehl-Kork, Germany
aa Medical Faculty of the University of Freiburg, Freiburg, Germany
ab Department of Psychiatry, The University of Hong Kong, Pokulam, Hong Kong
ac The State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Hong Kong
ad Department of Epileptology, University of Bonn Medical Centre, Bonn, Germany
ae Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
af Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
ag Section for Translational Epilepsy Research, Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany
ah Department of Neurology, University of Ulm, Ulm, Germany
ai Stichting Epilepsie Instellingen Nederland (SEIN), Zwolle, Netherlands
aj Department of Neurology, American University of Beirut Medical Center, Beirut, Lebanon
ak IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
al Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
am Department of Neurology, Sheba Medical Center, Ramat Gan, Israel
an Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
ao Department of Pediatric Neurology, Dr von Hauner Children’s Hospital, Ludwig Maximilians University, Munich, Germany
ap Epilepsy Center Munich, Munich, Germany
aq Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
ar Center for Applied Genomics, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
as Quantinuum Research LLC, Wayne, PA, United States
at Children’s Hospital, Department of Pediatric Neurology, University Medical Center Göttingen, Göttingen, Germany
au National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
av Department of Biomedical Sciences, Cooper Medical School of Rowan University, Camden, NJ, United States
aw Department of Neurology, Thomas Jefferson University Hospital, Philadelphia, PA, United States
ax Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
ay Cleveland Clinic Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
az Department of Neurology, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
ba Department of Molecular Biology and Genetics, Bogaziçi University, Istanbul, Turkey
bb Belfast Health and Social Care Trust, Belfast, United Kingdom
bc Integrated Diagnostics for Epilepsy, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy
bd Hereditary Research Lab, Bethlehem University, Bethlehem, Palestine
be Division of Epilepsy, Department of Neurology, Mayo Clinic, Rochester, MN, United States
bf Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
bg Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, Cambridge, MA, United States
bh Hôpital Lariboisière, Dept of Neurosurgery-Paris-Cité University, Paris, France
bi Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
bj Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong
bk Department of Pediatric Neurology, Chang Gung Memorial Hospital, Linkou Branch, and College of Medicine, Chang Gung University, Taoyuan, Taiwan
bl Kids Research, Children’s Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
bm Neurology Research Group, Swansea University Medical School, Faculty of Medicine, Health & Life Science, Swansea University, Swansea, United Kingdom
bn Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
bo Neurology, Massachusetts General Hospital, Boston, MA, United States
bp Department of Clinical Neurosciences, Cambridge Biomedical Campus, Cambridge, United Kingdom
bq Department of Neuroscience, Reproductive and Odontostomatological Sciences, University Federico II, Naples, Italy
br Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
bs The Epilepsy NeuroGenetics Initiative (ENGIN), Children’s Hospital of Philadelphia, Philadelphia, PA, United States
bt Department of Neurosciences, Université de Montréal, Montréal, QC, Canada
bu Department of Neurology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, United Kingdom
bv Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
bw Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
bx Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, United States
by Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, United States
bz Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States
ca Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands
cb Department of Neurology, Beaumont Hospital, Dublin, Ireland
cc Department of Neurology, Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium
cd Department of Clinical Neurophysiology, Lille University Medical Center, University of Lille, Lille, France
ce Department of Neurology, New York University/Langone Health, New York City, NY, United States
cf Department of Neurology, St. James’s Hospital, Dublin, Ireland
cg Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
ch Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
ci Human Genetics Training Program, Vanderbilt University, Nashville, TN, United States
cj Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
ck Division of Biostatistics, Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
cl Department of Pharmacology and Psychiatry, University of Pennsylvania Perlman School of Medicine, Philadelphia, PA, United States
cm Department of Pediatrics and Neonatology, Medical University of Vienna, Vienna, Austria
cn Institute of Neurology, Department of Medical and Surgical Sciences, University ‘Magna Graecia’, Catanzaro, Italy
co Neurophysiology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
cp Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, University Hospital Schleswig Holstein, Kiel, Germany
cq Department of Neurology, NYU School of Medicine, New York City, NY, United States
cr Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
cs Department of Medical and Surgical Sciences, Neuroscience Research Center, Magna Graecia University, Catanzaro, Italy
ct Institute of Neurology and Neurosurgery at St. Barnabas, Livingston, NJ, United States
cu Department of Neurology, Division of Clinical Neuroscience, Rikshospitalet Medical Centre, University of Oslo, Oslo, Norway
cv Department of Neurology, Baylor College of Medicine, Houston, TX, United States
cw Department of Pediatrics, Nationwide Children’s Hospital, Columbia, OH, United States
cx Division of Human Genetics, Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
cy Life and Brain Center, University of Bonn Medical Center, Bonn, Germany
cz Institute for Genomic Statistics and Bioinformatics, University of Bonn, Bonn, Germany
da Department of Neurology, University of California, San Francisco, CA, United States
db Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
dc Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
dd Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany
de Department of Biomedical and Health Informatics (DBHi), Children’s Hospital of Philadelphia, Philadelphia, PA, United States
df Hasso Plattner Institute, Digital Health Center, University of Potsdam, Potsdam, Germany
dg Hasso Plattner Institute, Mount Sinai School of Medicine, New York City, NY, United States
dh General Medical Research Center, School of Medicine, Fukuoka University, Fukuoka, Japan
di Department of Neurology, University Hospital of Strasbourg, Strasbourg, France
dj Danish Epilepsy Centre, Dianalund, Denmark
dk Institute of Regional Health Services Research, University of Southern Denmark, Odense, Denmark
dl Swiss Epilepsy Center, Klinik Lengg, Zurich, Switzerland
dm National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorder, Shizuoka, Japan
dn Department of Pediatrics, Fukuoka Sanno Hospital, Fukuoka, Japan
do Department of Psychiatry and Applied Psychology, Institute of Mental Health University of Nottingham, Nottingham, United Kingdom
dp Division of Brain Sciences, Imperial College London, London, United Kingdom
dq Kuopio Epilepsy Center, Neurocenter, Kuopio University Hospital, Kuopio, Finland
dr Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
ds Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
dt The Broad Institute of M.I.T. and Harvard, Cambridge, MA, United States
du Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
dv Department of Child Neurology, Medical School, Kocaeli University, Kocaeli, Turkey
dw Neuroscience Unit, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya
dx Department of Public Health, Pwani University, Kilifi, Kenya
dy Department of Psychiatry, University of Oxford, Oxford, United Kingdom
dz Department of Pediatrics, Showa University School of Medicine, Epilepsy Medical Center, Showa University Hospital, Tokyo, Japan
ea Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon
eb Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand
ec Epilepsy Center Hessen-Marburg, Department of Neurology, Philipps University Marburg, Marburg, Germany
ed Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, Goethe University Frankfurt, Frankfurt, Germany
ee Departments of Clinical Neurosciences, Medical Genetics and Community Health Sciences, Hotchkiss Brain Institute & Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
ef LOEWE Center for Personalized Translational Epilepsy Research (CePTER), Goethe University Frankfurt, Frankfurt, Germany
eg Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents, Vogtareuth, Germany
eh Research Institute for Rehabilitation, Transition, and Palliation, Paracelsus Medical University, Salzburg, Austria
ei Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
ej Department of Neurology, Medical University of Vienna, Vienna, Austria
ek Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
el Yale School of Medicine, New Haven, CT, United States
em Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
en Institute of Experimental Epileptology and Cognition Research, Medical Faculty, University of Bonn, Bonn, Germany
eo Neuropediatrics Department, Bonifatius Hospital Lingen, Lingen, Germany
ep Department of Neurology, Hofstra-Northwell Medical School, New York City, NY, United States
eq Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong
er Department of Biomedical and Dental Sciences, Morphological and Functional Images (BIOMORF), University of Messina, Messina, Italy
es Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong
et Folkhälsan Research Center and Medical Faculty, University of Helsinki, Helsinki, Finland
eu Department of Medical Genetics, Hospices Civils de Lyon and University of Lyon, Lyon, France
ev Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom
ew Department of Clinical Neurosciences, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom
ex Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hum, Hong Kong
ey Neuroscience Department, Janssen Research & Development, LLC, Titusville, NJ, United States
ez Child Neurology, New Children’s Hospital, Helsinki, Finland
fa Pediatric Research Center, University of Helsinki, Helsinki, Finland
fb Helsinki University Hospital, Helsinki, Finland
fc Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), and the Brazilian Institute of Neuroscience and Neurotecnology, Campinas, Brazil
fd Department of Medicine, Tseung Kwan O Hospital, Tseung Kwan O, Hong Kong
fe deCODE genetics, Reykjavík, Iceland
ff Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
fg Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
fh School of Medicine, Trinity College Dublin, Dublin, Ireland
fi Epilepsy Center for Children, University Hospital Ruppin-Brandenburg, Brandenburg Medical School, Neuruppin, Germany
fj Pediatric Neurology, University of Giessen, Giessen, Germany
fk Institute of Human Genetics, University of Bonn Medical Center, Bonn, Germany
fl University Hospital Cologne, Cologne, Germany
fm Laboratory for Systems Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
fn Department of Neurology, Landspitalinn University Hospital, Reykjavik, Iceland
fo Istanbul University-Cerrahpaşa, Cerrahpaşa Medical Faculty, Department of Neurology, Istanbul, Turkey
fp Department of Psychiatry, Robert Wood Johnson Medical School and New Jersey Medical School, Rutgers University, Newark, NJ, United States
fq Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
fr Department of Neurology, Morriston Hospital, Swansea Bay University Bay Health Board, Swansea, United Kingdom
fs Epilepsy Genetics Program, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
ft IRCCS Azienda Ospedaliero-Universitaria di Bologna, Medical Genetics Unit, Bologna, Italy
fu Department of Neurology, Gardner Neuroscience Institute, University of Cincinnati Medical Center, Cincinnati, OH, United States
fv Department of Neurology, Duke University School of Medicine, Durham, NC, United States
fw Faculty of Medicine & Health, University of Sydney, Sydney, NSW, Australia
fx Department of Functional Neurology and Epileptology, Hospices Civils de Lyon and University of Lyon, Lyon, France
fy Lyon Neuroscience Research Center, INSERM, Lyon, France
fz Department of Clinical Neurosciences, Centre Hospitalo-Universitaire Vaudois, Lausanne, Switzerland
ga Department of Neurology, Charité Universitaetsmedizin Berlin, Campus Virchow-Clinic, Berlin, Germany
gb Department of Endocrinology, Hospital of The University of Pennsylvania, Philadelphia, PA, United States
gc Departments of Neurology, Beth Israel Deaconess Medical Center, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, United States
gd Department of Neurology, Ludwig Maximilians University, Munchen, Germany
ge Department of Neurology, Royal Children’s Hospital, Parkville, VIC, Australia
gf Department of Epileptology, University Hospital Freiburg, Freiburg, Germany
gg Department of Neurosciences, University of California, San Diego, CA, United States
gh School of Life Sciences, University of Glasgow, Glasgow, United Kingdom
gi Rush University Medical Center, Chicago, IL, United States
gj Department of Neurology, Alan Richens Epilepsy Unit, University Hospital of Wales, Cardiff, United Kingdom
gk UCL Genetics Institute, University College London, London, United Kingdom
gl Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus, Denmark
gm Department of Neurology and Comprehensive Epilepsy Center, Thomas Jefferson University, Philadelphia, PA, United States
gn Department of Pediatrics, Ohio State University, Columbus, OH, United States
go The Research Institute, Nationwide Children’s Hospital, Columbus, OH, United States
gp CWZ Hospital, Nijmegen, Netherlands
gq Department of Neurodevelopmental Disorder Genetics, Institute of Brain Science, Nagoya City University Graduate School of Medical Science, Nagoya, Japan
gr Laboratory for Neurogenetics, RIKEN Center for Brain Science, Wako, Japan
gs Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
gt Institute for Applied Health Research, University of Birmingham, Birmingham, United Kingdom
gu Department of Child Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
gv C. Mondino National Neurological Institute, Pavia, Italy
gw Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
gx Centre for Medical Genetics, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania
gy Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
gz Department of Child Neurology, Medical School, Marmara University, Istanbul, Turkey
ha Epilepsy Unit, Department of Neurology, Brain and Cognition Research Center, University Hospital and University of Toulouse, Paul Sabatier University, Toulouse, France
hb Departments of Neurology and Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
hc Department of Neurology, Admiraal De Ruyter Hospital, Goes, Netherlands
hd MRC/Wits Rural Public Health & Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
he Department of Neurology and Epileptology, University of Aachen, Aachen, Germany
hf Applied & Translational Neurogenomics Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
hg Department of Neurology, Antwerp University Hospital, Edegem, Belgium
hh Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium
hi Department of Neurology, University Hospital and University of Zurich, Zürich, Switzerland
hj Department of Pediatric Neurology, Vivantes Hospital Neukölln, Berlin, Germany
hk Bezmialem Vakif University, Institute of Life Sciences and Biotechnology, Istanbul, Turkey
hl Epilepsy Research Centre, University of Melbourne, Austin Health, Heidelberg, VIC, Australia
Abstract
Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment. © 2023, The Author(s).
Funding details
27100416
National Institutes of HealthNIHU01MH105641
National Heart, Lung, and Blood InstituteNHLBI
National Human Genome Research InstituteNHGRI
Harvard University
Janssen Pharmaceuticals
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Wellcome TrustWT084730
Seventh Framework ProgrammeFP7279062
Broad Institute5U01HG009088-02, UM1 HG008895
UK Research and InnovationUKRIMR/S02638X/1
European CommissionEC
National Health and Medical Research CouncilNHMRC1091593, APP1195236, APP533086
Science Foundation IrelandSFI16/RC/3948
Deutsche ForschungsgemeinschaftDFGNO755/13-1, NO755/6-1
University of MelbourneUNIMELB203914/Z/16/Z
Fundação de Amparo à Pesquisa do Estado de São PauloFAPESP2013/07559-3
Fonds National de la Recherche LuxembourgFNRINTER/DFG/21/16394868 MechEPI2
Academy of FinlandAKA
European Regional Development FundERDF
NIHR Imperial Biomedical Research CentreBRC
NIHR Great Ormond Street Hospital Biomedical Research CentreNIHR GOSH BRC1616091
Muir Maxwell TrustMMT
Document Type: Article
Publication Stage: Article in Press
Source: Scopus