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2. mGlu3 metabotropic glutamate receptors as a target for the treatment of absence epilepsy: Preclinical and human genetics data

Author

Celli, R., Striano, P., Citraro, R., Di Menna, L., Cannella, M., Imbriglio, T., Koko, M., De Sarro, G., Monn, J. A., Battaglia, G., van Luijtelaar, G., Nicoletti, F., Russo, E., Leo, A., Palotie, A., Folkhalsan, A. -E. L., Ruppert, A. -K., Lal, D., Thiele, H., Altmuller, J., Jabbari, K., Nurnberg, P., Sander, T., Siren, A., Becker, F., Lerche, H., Weber, Y., Koeleman, B., Caglayan, H., Hjalgrim, H., Moller, R., Muhle, H., Helbig, I., Everett, K., May, P., Krause, R., Balling, R., Nabbout, R., Zara, F., Scala, M., Iacomino, M., Scudieri, P., Bocciardi, R., Balagura, G., Minetti, C., Riva, A., Vari, M. S., Amadori, E., Perinelli, M., Verrotti, A., Baulac, S., and Kunz, W.

Subjects
gaba, Pharmacology, cortico-thalamo-cortical network, Action, intention, and motor control, human genetics, glutamate, General Medicine, absence epilepsy, eeg, mglu3 receptors, Psychiatry and Mental health, Neurology, Pharmacology (medical), Neurology (clinical)
Abstract

Background: Previous studies suggest that different metabotropic glutamate (mGlu) receptor subtypes are potential drug targets for the treatment of absence epilepsy. However, no information is available on mGlu3 receptors. Objective: To examine whether (i) abnormalities changes of mGlu3 receptor expression/signaling are found in the somatosensory cortex and thalamus of WAG/Rij rats developing spontaneous absence seizures; (ii) selective activation of mGlu3 receptors with LY2794193 affects the number and duration of spike-wave discharges (SWDs) in WAG/Rij rats; and (iii) a genetic variant of GRM3 (encoding the mGlu3 receptor) is associated with absence epilepsy. Methods: Animals: immunoblot analysis of mGlu3 receptors, GAT-1, GLAST, and GLT-1; real-time PCR analysis of mGlu3 mRNA levels; assessment of mGlu3 receptor signaling; EEG analysis of SWDs; assessment of depressive-like behavior. Humans: search for GRM3 and GRM5 missense variants in 196 patients with absence epilepsy or other IGE/GGE Idiopathic Generalized Epilepsy (IGE)/ Genetic Generalized Epilepsy (GGE) and 125,748 controls. Results: mGlu3 protein levels and mGlu3-mediated inhibition of cAMP formation were reduced in the thalamus and somatosensory cortex of pre-symptomatic (25-27 days old) and symptomatic (6-7 months old) WAG/Rij rats compared to age-matched controls. Treatment with LY2794193 (1 or 10 mg/kg, i.p.) reduced absence seizures and depressive-like behavior in WAG/Rij rats. LY2794193 also enhanced GAT1, GLAST, and GLT-1 protein levels in the thalamus and somatosensory cortex. GRM3 and GRM5 gene variants did not differ between epileptic patients and controls. Conclusions: We suggest that mGlu3 receptors modulate the activity of the cortico-thalamo-cortical circuit underlying SWDs and that selective mGlu3 receptor agonists are promising candidate drugs for absence epilepsy treatment.

Published
2023

3. Additional file 1 of Increased prime edit rates in KCNQ2 and SCN1A via single nicking all-in-one plasmids

Author

Dirkx, N., Weuring, Wout J., De Vriendt, E., Smal, N., van de Vondervoort, J., van ’t Slot, Ruben, Koetsier, M., Zonnekein, N., De Pooter, Tim, Weckhuysen, S., and Koeleman, B. P. C.

Abstract

Additional file 1: Fig. S1. Graphical overview on protospacer-adjacent motif removal and the four possible outcome scenarios. Fig. S2. Integrative Genomics Viewer output file from WES data generated for the KCNQ2 R201H-P knock-in experiment in HEK293T cells. Fig. S3. Representative sanger sequencing files for KCNQ2 R201H-P knock-in in HEK293T using PE2max, PE4max and PE3. Fig. S4. Lentiviral vector and integrase-deficient lentiviral vector titering, expression in time, and edit rates. Fig. S5. pAIO-PE4max based removal of R201C in hiPSC over time. Fig. S6. Quality Control 1, Multiplex amplicon quantification for chromosome 20 duplication in hiPSC. Fig. S7. Quality Control 2, RT-qPCR based expression analysis of pluripotency markers in hiPSC. Fig. S8. Primers, pegRNAs and gBlocks used in study. Fig. S9. Visual representation of pegRNAs and their interacting sequences used in this study.

Published
2023
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5. Male patients affected by mosaic PCDH19 mutations: five new cases

Author

de Lange, I. M., Rump, P., Neuteboom, R. F., Augustijn, P. B., Hodges, K., Kistemaker, A. I., Brouwer, O. F., Mancini, G. M. S., Newman, H. A., Vos, Y. J., Helbig, K. L., Peeters-Scholte, C., Kriek, M., Knoers, N. V., Lindhout, D., Koeleman, B. P. C., van Kempen, M. J. A., and Brilstra, E. H.

Published
2017
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8. KBTBD13 is a novel cardiomyopathy gene

Author

Winter, J.M., Bouman, K., Strom, J., Methawasin, M., Jongbloed, J.D., Roest, W., Wijngaarden, J.V., Timmermans, J., Nijveldt, R., Heuvel, F.M.A. van den, Kamsteeg, E.J., Engelen, B.G.M. van, Galli, R., Bogaards, S.J.P., Boon, R.A., Pijl, R.J. van der, Granzier, H., Koeleman, B., Amin, A.S., Velden, J. van der, Tintelen, J.P. van, Berg, M.P., Spaendonck-Zwarts, K.Y. van, Voermans, N.C., Ottenheijm, C.A.C., Winter, J.M., Bouman, K., Strom, J., Methawasin, M., Jongbloed, J.D., Roest, W., Wijngaarden, J.V., Timmermans, J., Nijveldt, R., Heuvel, F.M.A. van den, Kamsteeg, E.J., Engelen, B.G.M. van, Galli, R., Bogaards, S.J.P., Boon, R.A., Pijl, R.J. van der, Granzier, H., Koeleman, B., Amin, A.S., Velden, J. van der, Tintelen, J.P. van, Berg, M.P., Spaendonck-Zwarts, K.Y. van, Voermans, N.C., and Ottenheijm, C.A.C.

Abstract

Item does not contain fulltext, KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.Arg408Cys (KBTBD13 p.R408C). Although KBTBD13 is expressed in cardiac muscle, cardiac involvement in NEM6 is unknown. Here, we constructed pedigrees of three families with the KBTBD13 p.R408C variant. In 65 evaluated patients, 12% presented with left ventricle dilatation, 29% with left ventricular ejection fraction< 50%, 8% with atrial fibrillation, 9% with ventricular tachycardia, and 20% with repolarization abnormalities. Five patients received an implantable cardioverter defibrillator, three cases of sudden cardiac death were reported. Linkage analysis confirmed cosegregation of the KBTBD13 p.R408C variant with the cardiac phenotype. Mouse studies revealed that (1) mice harboring the Kbtbd13 p.R408C variant display mild diastolic dysfunction; (2) Kbtbd13-deficient mice have systolic dysfunction. Hence, (1) KBTBD13 is associated with cardiac dysfunction and cardiomyopathy; (2) KBTBD13 should be added to the cardiomyopathy gene panel; (3) NEM6 patients should be referred to the cardiologist.

Published
2022

9. Comparative effectiveness of antiepileptic drugs in juvenile myoclonic epilepsy

Author

Silvennoinen K., de Lange N., Zagaglia S., Balestrini S., Androsova G., Wassenaar M., Auce P., Avbersek A., Becker F., Berghuis B., Campbell E., Coppola A., Francis B., Wolking S., Cavalleri G. L., Craig J., Delanty N., Johnson M. R., Koeleman B. P. C., Kunz W. S., Lerche H., Marson A. G., O'Brien T. J., Sander J. W., Sills G. J., Striano P., Zara F., van der Palen J., Krause R., Depondt C., Sisodiya S. M., Brodie M. J., Chinthapalli K., de Haan G. -J., Doherty C. P., Heavin S., McCormack M., Petrovski S., Sargsyan N., Slattery L., Willis J., National Institute for Health Research, Silvennoinen, K., de Lange, N., Zagaglia, S., Balestrini, S., Androsova, G., Wassenaar, M., Auce, P., Avbersek, A., Becker, F., Berghuis, B., Campbell, E., Coppola, A., Francis, B., Wolking, S., Cavalleri, G. L., Craig, J., Delanty, N., Johnson, M. R., Koeleman, B. P. C., Kunz, W. S., Lerche, H., Marson, A. G., O'Brien, T. J., Sander, J. W., Sills, G. J., Striano, P., Zara, F., van der Palen, J., Krause, R., Depondt, C., Sisodiya, S. M., Brodie, M. J., Chinthapalli, K., de Haan, G. -J., Doherty, C. P., Heavin, S., Mccormack, M., Petrovski, S., Sargsyan, N., Slattery, L., and Willis, J.

Subjects
Topiramate, Pediatrics, medicine.medical_specialty, Neurology [D14] [Human health sciences], seizure, adverse drug reaction, Clinical Neurology, Lamotrigine, lcsh:RC346-429, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Journal Article, medicine, 030212 general & internal medicine, EpiPGX Consortium, tolerability, lcsh:Neurology. Diseases of the nervous system, seizures, adverse drug reactions, Neurologie [D14] [Sciences de la santé humaine], business.industry, Weight change, Généralités, Carbamazepine, medicine.disease, 3. Good health, valproate, Neurology, Tolerability, Full‐length Original Research, Neurology (clinical), Levetiracetam, Juvenile myoclonic epilepsy, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

Objective: To study the effectiveness and tolerability of antiepileptic drugs (AEDs) commonly used in juvenile myoclonic epilepsy (JME). Methods: People with JME were identified from a large database of individuals with epilepsy, which includes detailed retrospective information on AED use. We assessed secular changes in AED use and calculated rates of response (12-month seizure freedom) and adverse drug reactions (ADRs) for the five most common AEDs. Retention was modeled with a Cox proportional hazards model. We compared valproate use between males and females. Results: We included 305 people with 688 AED trials of valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate and carbamazepine were most often prescribed as the first AED. The response rate to valproate was highest among the five AEDs (42.7%), and significantly higher than response rates for lamotrigine, carbamazepine, and topiramate; the difference to the response rate to levetiracetam (37.1%) was not significant. The rates of ADRs were highest for topiramate (45.5%) and valproate (37.5%). Commonest ADRs included weight change, lethargy, and tremor. In the Cox proportional hazards model, later start year (1.10 [1.08-1.13], P, SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2019

10. Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study

Author

Koko, M., Motelow, J. E., Stanley, K. E., Bobbili, D. R., Dhindsa, R. S., May, P., Alldredge, B. K., Allen, A. S., Altmuller, J., Amrom, D., Andermann, E., Auce, P., Avbersek, A., Baulac, S., Bautista, J. F., Becker, F., Bellows, S. T., Berghuis, B., Berkovic, S. F., Bluvstein, J., Boro, A., Bridgers, J., Burgess, R., Caglayan, H., Cascino, G. D., Cavalleri, G. L., Chung, S. -K., Cieuta-Walti, C., Cloutier, V., Consalvo, D., Cossette, P., Crumrine, P., Delanty, N., Depondt, C., Desbiens, R., Devinsky, O., Dlugos, D., Epstein, M. P., Everett, K., Fiol, M., Fountain, N. B., Francis, B., French, J., Freyer, C., Friedman, D., Gambardella, A., Geller, E. B., Girard, S., Glauser, T., Glynn, S., Goldstein, D. B., Gravel, M., Haas, K., Haut, S. R., Heinzen, E. L., Helbig, I., Hildebrand, M. S., Johnson, M. R., Jorgensen, A., Joshi, S., Kanner, A., Kirsch, H. E., Klein, K. M., Knowlton, R. C., Koeleman, B. P. C., Kossoff, E. H., Krause, R., Krenn, M., Kunz, W. S., Kuzniecky, R., Langley, S. R., Leguern, E., Lehesjoki, A. -E., Lerche, H., Leu, C., Lortie, A., Lowenstein, D. H., Marson, A. G., Mebane, C., Mefford, H. C., Meloche, C., Moreau, C., Motika, P. V., Muhle, H., Moller, R. S., Nabbout, R., Nguyen, D. K., Nikanorova, M., Novotny, E. J., Nurnberg, P., Ottman, R., O'Brien, T. J., Paolicchi, J. M., Parent, J. M., Park, K., Peter, S., Petrou, S., Petrovski, S., Pickrell, W. O., Poduri, A., Radtke, R. A., Rees, M. I., Regan, B. M., Ren, Z., Sadleir, L. G., Sander, J. W., Sander, T., Scheffer, I. E., Schubert, J., Shellhaas, R. A., Sherr, E. H., Shih, J. J., Shinnar, S., Sills, G. J., Singh, R. K., Siren, A., Sirven, J., Sisodiya, S. M., Smith, M. C., Sonsma, A. C. M., Striano, P., Sullivan, J., Thio, L. L., Thomas, R. H., Venkat, A., Vining, E. P. G., Von Allmen, G. K., Wang, Q., Weber, Y. G., Weckhuysen, S., Weisenberg, J. L., Widdess-Walsh, P., Winawer, M. R., Wolking, S., Zara, F., Zimprich, F., Canadian Epilepsy Network, Epi4K Consortium, Epilepsy Phenome/Genome Project, EpiPGX Consortium, EuroEPINOMICS-CoGIE Consortium, Department of Medical and Clinical Genetics, Medicum, Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Peter, Sarah, Petrou, Steven, Petrovski, Slavé, Pickrell, William O., Poduri, Annapurna, Radtke, Rodney A., Rees, Mark I., Regan, Brigid M., Ren, Zhong, Sadleir, Lynette G., Alldredge, Brian K., Sander, Josemir W., Sander, Thomas, Scheffer, Ingrid E., Schubert, Julian, Shellhaas, Renée A., Sherr, Elliott H., Shih, Jerry J., Shinnar, Shlomo, Sills, Graeme J., Singh, Rani K., Allen, Andrew S., Siren, Auli, Sirven, Joseph, Sisodiya, Sanjay M., Smith, Michael C., Sonsma, Anja C. M., Striano, Pasquale, Sullivan, Joseph, Thio, Liu Lin, Thomas, Rhys H., Venkat, Anu, Altmüller, Janine, Vining, Eileen P. G., Von Allmen, Gretchen K., Wang, Quanli, Weber, Yvonne G., Weckhuysen, Sarah, Weisenberg, Judith L., Widdess-Walsh, Peter, Winawer, Melodie R., Wolking, Stefan, Zara, Federico, Amrom, Dina, Zimprich, Fritz, Andermann, Eva, Auce, Pauls, Avbersek, Andreja, Baulac, Stéphanie, Bautista, Jocelyn F., Becker, Felicitas, Bellows, Susannah T., Berghuis, Bianca, Berkovic, Samuel F., Bluvstein, Judith, Boro, Alex, Bridgers, Joshua, Burgess, Rosemary, Caglayan, Hande, Cascino, Gregory D., Cavalleri, Gianpiero L., Chung, Seo-Kyung, Cieuta-Walti, Cécile, Cloutier, Véronique, Consalvo, Damian, Cossette, Patrick, Crumrine, Patricia, Delanty, Norman, Depondt, Chantal, Desbiens, Richard, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P., Everett, Kate, Fiol, Miguel, Fountain, Nathan B., Francis, Ben, French, Jacqueline, Freyer, Catharine, Friedman, Daniel, Gambardella, Antonio, Geller, Eric B., Girard, Simon, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gravel, Micheline, Haas, Kevin, Haut, Sheryl R., Heinzen, Erin L., Helbig, Ingo, Hildebrand, Michael S., Johnson, Michael R., Jorgensen, Andrea, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E., Klein, Karl M., Knowlton, Robert C., Koeleman, Bobby P. C., Kossoff, Eric H., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Langley, Sarah R., LeGuern, Eric, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lortie, Anne, Lowenstein, Daniel H., Marson, Anthony G., Mebane, Caroline, Mefford, Heather C., Meloche, Caroline, Moreau, Claudia, Motika, Paul V., Muhle, Hiltrud, Møller, Rikke S., Nabbout, Rima, Nguyen, Dang K., Nikanorova, Marina, Novotny, Edward J., Nürnberg, Peter, Ottman, Ruth, O'Brien, Terence J., Paolicchi, Juliann M., Parent, Jack M., and Park, Kristen

Subjects
GABA receptors, Neurology [D14] [Human health sciences], Clinical Sciences, GABA(A) receptors, GABRG2, familial epilepsy, Article, Clinical Research, Receptors, Exome Sequencing, Genetics, 2.1 Biological and endogenous factors, Humans, GGE, Genetic Predisposition to Disease, sporadic epilepsy, EpiPGX Consortium, Aetiology, gamma-Aminobutyric Acid, GABAA receptors, Epi4K Consortium, Epilepsy, Neurology & Neurosurgery, Neurologie [D14] [Sciences de la santé humaine], Generalized, GABA-A, Prevention, Human Genome, Neurosciences, 1184 Genetics, developmental biology, physiology, 3112 Neurosciences, Receptors, GABA-A, EuroEPINOMICS-CoGIE Consortium, Neurology, Case-Control Studies, Epilepsy, Generalized, Canadian Epilepsy Network, Neurology (clinical), Genetics & genetic processes [F10] [Life sciences], 3111 Biomedicine, Human medicine, Génétique & processus génétiques [F10] [Sciences du vivant], Epilepsy Phenome/Genome Project
Abstract

ObjectiveWe aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE.MethodsWe performed a case-control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19genes encoding γ-aminobutyric acid type A [GABAA ] receptors, 113genes representing the GABAergic pathway).ResultsGABRG2 was associated with GGE (p=1.8×10-5 ), approaching study-wide significance in familial GGE (p=3.0×10-6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR]=3.9, 95% confidence interval [CI]=1.9-7.8, false discovery rate [FDR]-adjusted p=.0024), whereas their association with sporadic GGE had marginally lower odds (OR=3.1, 95% CI=1.3-6.7, FDR-adjusted p=.022). URVs in GABAergic pathway genes were associated with familial GGE (OR=1.8, 95% CI=1.3-2.5, FDR-adjusted p=.0024) but not with sporadic GGE (OR=1.3, 95% CI=.9-1.9, FDR-adjusted p=.19).SignificanceURVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.

Published
2022

11. A genome-wide association study of anorexia nervosa

Author

Boraska, V, Franklin, C S, Floyd, J A B, Thornton, L M, Huckins, L M, Southam, L, Rayner, N W, Tachmazidou, I, Klump, K L, Treasure, J, Lewis, C M, Schmidt, U, Tozzi, F, Kiezebrink, K, Hebebrand, J, Gorwood, P, Adan, R A H, Kas, M J H, Favaro, A, Santonastaso, P, Fernández-Aranda, F, Gratacos, M, Rybakowski, F, Dmitrzak-Weglarz, M, Kaprio, J, Keski-Rahkonen, A, Raevuori, A, Van Furth, E F, Slof-Op 't Landt, M C T, Hudson, J I, Reichborn-Kjennerud, T, Knudsen, G P S, Monteleone, P, Kaplan, A S, Karwautz, A, Hakonarson, H, Berrettini, W H, Guo, Y, Li, D, Schork, N J, Komaki, G, Ando, T, Inoko, H, Esko, T, Fischer, K, Männik, K, Metspalu, A, Baker, J H, Cone, R D, Dackor, J, DeSocio, J E, Hilliard, C E, O'Toole, J K, Pantel, J, Szatkiewicz, J P, Taico, C, Zerwas, S, Trace, S E, Davis, O S P, Helder, S, Bühren, K, Burghardt, R, de Zwaan, M, Egberts, K, Ehrlich, S, Herpertz-Dahlmann, B, Herzog, W, Imgart, H, Scherag, A, Scherag, S, Zipfel, S, Boni, C, Ramoz, N, Versini, A, Brandys, M K, Danner, U N, de Kovel, C, Hendriks, J, Koeleman, B P C, Ophoff, R A, Strengman, E, van Elburg, A A, Bruson, A, Clementi, M, Degortes, D, Forzan, M, Tenconi, E, Docampo, E, Escaramís, G, Jiménez-Murcia, S, Lissowska, J, Rajewski, A, Szeszenia-Dabrowska, N, Slopien, A, Hauser, J, Karhunen, L, Meulenbelt, I, Slagboom, P E, Tortorella, A, Maj, M, Dedoussis, G, Dikeos, D, Gonidakis, F, Tziouvas, K, Tsitsika, A, Papezova, H, Slachtova, L, Martaskova, D, Kennedy, J L, Levitan, R D, Yilmaz, Z, Huemer, J, Koubek, D, Merl, E, Wagner, G, Lichtenstein, P, Breen, G, Cohen-Woods, S, Farmer, A, McGuffin, P, Cichon, S, Giegling, I, Herms, S, Rujescu, D, Schreiber, S, Wichmann, H-E, Dina, C, Sladek, R, Gambaro, G, Soranzo, N, Julia, A, Marsal, S, Rabionet, R, Gaborieau, V, Dick, D M, Palotie, A, Ripatti, S, Widén, E, Andreassen, O A, Espeseth, T, Lundervold, A, Reinvang, I, Steen, V M, Le Hellard, S, Mattingsdal, M, Ntalla, I, Bencko, V, Foretova, L, Janout, V, Navratilova, M, Gallinger, S, Pinto, D, Scherer, S W, Aschauer, H, Carlberg, L, Schosser, A, Alfredsson, L, Ding, B, Klareskog, L, Padyukov, L, Courtet, P, Guillaume, S, Jaussent, I, Finan, C, Kalsi, G, Roberts, M, Logan, D W, Peltonen, L, Ritchie, G R S, Barrett, J C, Estivill, X, Hinney, A, Sullivan, P F, Collier, D A, Zeggini, E, and Bulik, C M

Published
2014
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14. A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides

Author

Bossini-Castillo, L, de Kovel, C, Kallberg, H, van ‘t Slot, R, Italiaander, A, Coenen, M, Tak, P P, Posthumus, M D, Wijmenga, C, Huizinga, T, van der Helm-van Mil, A H M, Stoeken-Rijsbergen, G, Rodriguez-Rodriguez, Luis, Balsa, Alejandro, González-Álvaro, Isidoro, González-Gay, Miguel Ángel, Gómez-Vaquero, Carmen, Franke, B, Vermeulen, S, van der Horst-Bruinsma, I E, Dijkmans, B A C, Wolbink, G J, Ophoff, R A, Maehlen, M T, van Riel, P, Merriman, M, Klareskog, L, Lie, B A, Merriman, T, Crusius, J B A, Brouwer, E, Martin, J, de Vries, N, Toes, R, Padyukov, L, and Koeleman, B P C

Published
2015
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15. Clinical and genetic aspects of PCDH19-related epilepsy syndromes and the possible role of PCDH19 mutations in males with autism spectrum disorders

Author

van Harssel, J. J. T., Weckhuysen, S., van Kempen, M. J. A., Hardies, K., Verbeek, N. E., de Kovel, C. G. F., Gunning, W. B., van Daalen, E., de Jonge, M. V., Jansen, A. C., Vermeulen, R. J., Arts, W. F. M., Verhelst, H., Fogarasi, A., de Rijk-van Andel, J. F., Kelemen, A., Lindhout, D., De Jonghe, P., Koeleman, B. P. C., Suls, A., and Brilstra, E. H.

Published
2013
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17. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy

Author

Wolking, S., Moreau, C., Mccormack, M., Krause, R., Krenn, M., Berkovic, S., Cavalleri, G. L., Delanty, N., Depondt, C., Johnson, M. R., Koeleman, B. P. C., Kunz, W. S., Lerche, H., Marson, A. G., O'Brien, T. J., Petrovski, S., Sander, J. W., Sills, G. J., Striano, P., Zara, F., Zimprich, F., Sisodiya, S. M., Girard, S. L., Cossette, P., Avbersek, A., Leu, C., Heggeli, K., Demurtas, R., Willis, J., Speed, D., Sargsyan, N., Chinthapalli, K., Borghei, M., Coppola, A., Gambardella, A., Becker, F., Rau, S., Hengsbach, C., Weber, Y. G., Berghuis, B., Campbell, E., Gudmundsson, L. J., Ingason, A., Stefansson, K., Schneider, R., Balling, R., Auce, P., Francis, B., Jorgensen, A., Morris, A., Langley, S., Srivastava, P., Brodie, M., Todaro, M., Hutton, J., Muhle, H., Klein, K. M., Moller, R. S., Nikanorova, M., Weckhuysen, S., Rener-Primec, Z., Craig, J., and Stefansson, H.

Subjects
0301 basic medicine, Male, Candidate gene, Drug Resistant Epilepsy, Neurology [D14] [Human health sciences], Neurosciences. Biological psychiatry. Neuropsychiatry, Drug resistance, Bioinformatics, Polymorphism, Single Nucleotide, Whole Exome Sequencing, Cohort Studies, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Exome Sequencing, medicine, Humans, Polymorphism, RC346-429, Gene, Exome sequencing, Research Articles, Genetic Association Studies, Neurologie [D14] [Sciences de la santé humaine], business.industry, General Neuroscience, Genetic variants, Genetic Variation, Single Nucleotide, medicine.disease, DEPDC5, Female, 030104 developmental biology, Cohort, Neurology (clinical), Neurology. Diseases of the nervous system, business, 030217 neurology & neurosurgery, RC321-571, Research Article
Abstract

Annals of Clinical and Translational Neurology 8(7), 1376-1387 (2021). doi:10.1002/acn3.51374, Published by Wiley, Chichester [u.a.]

Published
2021

18. The autoimmune disease-associated IL2RA locus is involved in the clinical manifestations of systemic sclerosis

Author

Martin, J-E, Carmona, F D, Broen, J C A, Simeón, C P, Vonk, M C, Carreira, P, Ríos-Fernández, R, Espinosa, G, Vicente-Rabaneda, E, Tolosa, C, García-Hernández, F J, Castellví, I, Fonollosa, V, González-Gay, M A, Sáez-Comet, L, Portales, R García, de la Peña, P García, Fernández-Castro, M, Díaz, B, Martínez-Estupiñán, L, Coenen, M, Voskuyl, A E, Schuerwegh, A J, Vanthuyne, M, Houssiau, F, Smith, V, de Keyser, F, De Langhe, E, Riemekasten, G, Witte, T, Hunzelmann, N, Kreuter, A, Palm, Ø, Chee, M M, van Laar, J M, Denton, C, Herrick, A, Worthington, J, Koeleman, B P C, Radstake, T R D J, Fonseca, C, and Martín, J

Published
2012
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20. Associations Between Attention-Deficit/Hyperactivity Disorder and Various Eating Disorders: A Swedish Nationwide Population Study Using Multiple Genetically Informative Approaches

Author

Yao, S., Kuja-Halkola, R., Martin, J., Lu, Y., Lichtenstein, P., Hubel, C., Almqvist, C., Magnusson, P. K., Bulik, C. M., Larsson, H., Norring, C., Birgegard, A., Yilmaz, Z., Watson, H., Baker, J., Thornton, L. M., Adan, R., Ando, T., Bergen, A., Berrettini, W., Boni, C., Boraska Perica, V., Brandt, H., Burghardt, R., Cassina, M., Cesta, C., Clementi, M., Coleman, J., Cone, R., Courtet, P., Crawford, S., Crow, S., Crowley, J., Danner, U., Davis, O., de Zwaan, M., Dedoussis, G., Degortes, D., Desocio, J., Dick, D., Dikeos, D., Dmitrzak-Weglarz, M., Docampo, E., Egberts, K., Ehrlich, S., Escaramis, G., Esko, T., Estivill, X., Favaro, A., Fernandez-Aranda, F., Fichter, M., Finan, C., Fischer, K., Focker, M., Foretova, L., Forzan, M., Franklin, C., Gaspar, H., Gonidakis, F., Gorwood, P., Gratacos, M., Guillaume, S., Guo, Y., Hakonarson, H., Halmi, K., Hatzikotoulas, K., Hauser, J., Hebebrand, J., Helder, S., Hendriks, J., Herpertz-Dahlmann, B., Herzog, W., Hilliard, C., Hinney, A., Huckins, L., Hudson, J., Huemer, J., Imgart, H., Inoko, H., Jimenez-Murcia, S., Johnson, C., Jordan, J., Jureus, A., Kalsi, G., Kaminska, D., Kaplan, A., Kaprio, J., Karhunen, L., Karwautz, A., Kas, M., Kaye, W., Kennedy, J., Kennedy, M., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y. -R., Klump, K., Knudsen, G. P., Koeleman, B., Koubek, D., La Via, M., Landen, M., Levitan, R., Li, D., Lilenfeld, L., Lissowska, J., Magistretti, P., Maj, M., Mannik, K., Martin, N., Mcdevitt, S., Mcguffin, P., Merl, E., Metspalu, A., Meulenbelt, I., Micali, N., Mitchell, J., Mitchell, K., Monteleone, P., Monteleone, A. M., Mortensen, P., Munn-Chernoff, M., Nacmias, B., Nilsson, I., Ntalla, I., O'Toole, J., Pantel, J., Papezova, H., Parker, R., Rabionet, R., Raevuori, A., Rajewski, A., Ramoz, N., Rayner, N. W., Reichborn-Kjennerud, T., Ricca, V., Ripke, S., Ritschel, F., Roberts, M., Rotondo, A., Rybakowski, F., Santonastaso, P., Scherag, A., Schmidt, U., Schork, N., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op't Landt, M., Slopien, A., Smith, T., Sorbi, S., Strengman, E., Strober, M., Sullivan, P., Szatkiewicz, J., Szeszenia-Dabrowska, N., Tachmazidou, I., Tenconi, E., Thornton, L., Tortorella, A., Tozzi, F., Treasure, J., Tsitsika, A., Tziouvas, K., van Elburg, A., van Furth, E., Wade, T., Wagner, G., Walton, E., Woodside, D. B., Zeggini, E., Zerwas, S., Zipfel, S., Alfredsson, L., Andreassen, O., Aschauer, H., Barrett, J., Bencko, V., Carlberg, L., Cichon, S., Cohen-Woods, S., Dina, C., Ding, B., Espeseth, T., Floyd, J., Gallinger, S., Gambaro, G., Giegling, I., Herms, S., Janout, V., Julia, A., Klareskog, L., Le Hellard, S., Leboyer, M., Lundervold, A., Marsal, S., Mattingsdal, M., Navratilova, M., Ophoff, R., Palotie, A., Pinto, D., Ripatti, S., Rujescu, D., Scherer, S., Scott, L., Sladek, R., Soranzo, N., Southam, L., Steen, V., Wichmann, H. -E., Widen, E., Breen, G., Bulik, C., Yao, S., Kuja-Halkola, R., Martin, J., Lu, Y., Lichtenstein, P., Hubel, C., Almqvist, C., Magnusson, P. K., Bulik, C. M., Larsson, H., Norring, C., Birgegard, A., Yilmaz, Z., Watson, H., Baker, J., Thornton, L. M., Adan, R., Ando, T., Bergen, A., Berrettini, W., Boni, C., Boraska Perica, V., Brandt, H., Burghardt, R., Cassina, M., Cesta, C., Clementi, M., Coleman, J., Cone, R., Courtet, P., Crawford, S., Crow, S., Crowley, J., Danner, U., Davis, O., de Zwaan, M., Dedoussis, G., Degortes, D., Desocio, J., Dick, D., Dikeos, D., Dmitrzak-Weglarz, M., Docampo, E., Egberts, K., Ehrlich, S., Escaramis, G., Esko, T., Estivill, X., Favaro, A., Fernandez-Aranda, F., Fichter, M., Finan, C., Fischer, K., Focker, M., Foretova, L., Forzan, M., Franklin, C., Gaspar, H., Gonidakis, F., Gorwood, P., Gratacos, M., Guillaume, S., Guo, Y., Hakonarson, H., Halmi, K., Hatzikotoulas, K., Hauser, J., Hebebrand, J., Helder, S., Hendriks, J., Herpertz-Dahlmann, B., Herzog, W., Hilliard, C., Hinney, A., Huckins, L., Hudson, J., Huemer, J., Imgart, H., Inoko, H., Jimenez-Murcia, S., Johnson, C., Jordan, J., Jureus, A., Kalsi, G., Kaminska, D., Kaplan, A., Kaprio, J., Karhunen, L., Karwautz, A., Kas, M., Kaye, W., Kennedy, J., Kennedy, M., Keski-Rahkonen, A., Kiezebrink, K., Kim, Y. -R., Klump, K., Knudsen, G. P., Koeleman, B., Koubek, D., La Via, M., Landen, M., Levitan, R., Li, D., Lilenfeld, L., Lissowska, J., Magistretti, P., Maj, M., Mannik, K., Martin, N., Mcdevitt, S., Mcguffin, P., Merl, E., Metspalu, A., Meulenbelt, I., Micali, N., Mitchell, J., Mitchell, K., Monteleone, P., Monteleone, A. M., Mortensen, P., Munn-Chernoff, M., Nacmias, B., Nilsson, I., Ntalla, I., O'Toole, J., Pantel, J., Papezova, H., Parker, R., Rabionet, R., Raevuori, A., Rajewski, A., Ramoz, N., Rayner, N. W., Reichborn-Kjennerud, T., Ricca, V., Ripke, S., Ritschel, F., Roberts, M., Rotondo, A., Rybakowski, F., Santonastaso, P., Scherag, A., Schmidt, U., Schork, N., Schosser, A., Seitz, J., Slachtova, L., Slagboom, P. E., Slof-Op't Landt, M., Slopien, A., Smith, T., Sorbi, S., Strengman, E., Strober, M., Sullivan, P., Szatkiewicz, J., Szeszenia-Dabrowska, N., Tachmazidou, I., Tenconi, E., Thornton, L., Tortorella, A., Tozzi, F., Treasure, J., Tsitsika, A., Tziouvas, K., van Elburg, A., van Furth, E., Wade, T., Wagner, G., Walton, E., Woodside, D. B., Zeggini, E., Zerwas, S., Zipfel, S., Alfredsson, L., Andreassen, O., Aschauer, H., Barrett, J., Bencko, V., Carlberg, L., Cichon, S., Cohen-Woods, S., Dina, C., Ding, B., Espeseth, T., Floyd, J., Gallinger, S., Gambaro, G., Giegling, I., Herms, S., Janout, V., Julia, A., Klareskog, L., Le Hellard, S., Leboyer, M., Lundervold, A., Marsal, S., Mattingsdal, M., Navratilova, M., Ophoff, R., Palotie, A., Pinto, D., Ripatti, S., Rujescu, D., Scherer, S., Scott, L., Sladek, R., Soranzo, N., Southam, L., Steen, V., Wichmann, H. -E., Widen, E., Breen, G., Bulik, C., Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Department Psychiatry [Chapel Hill], University of North Carolina System (UNC)-University of North Carolina System (UNC), Oregon Research Institute (ORI), Department of Psychiatry [Philadelphia], University of Pennsylvania [Philadelphia], Stockholm County Council, Analyse Phenotypique, Developpementale et Genetique des Comportements Addictifs, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Diderot - Paris 7 (UPD7), University of Split, Azienda Ospedaliera di Padova, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Nutrition-Dietetics, Harokopio University of Athens, University of Athens Medical School [Athens], MetaGenoPolis, Institut National de la Recherche Agronomique (INRA), Medstar Research Institute, Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), Department of Psychiatry (IDIBELL), CIBERobn Fisiopatología de la Obesidad y Nutrición-University Hospital of Bellvitge, Infectious diseases division, Department of internal medicine, Washington University in Saint Louis (WUSTL), Masaryk Memorial Cancer Institute and Medical Faculty of Masaryk University, National and Kapodistrian University of Athens (NKUA), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Weill Medical College of Cornell University [New York], Department of Genomics, Department of Child and Adolescent Psychiatry and Psychotherapy, LVR-Klinikum Essen, Universität Duisburg-Essen [Essen], Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Icahn School of Medicine at Mount Sinai [New York] (MSSM), School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, 4072, Australia., Tokai University, Institute for Marine and Antarctic Studies [Horbat] (IMAS), University of Tasmania [Hobart, Australia] (UTAS), National Institute for Health and Welfare [Helsinki], Medizinische Universität Wien = Medical University of Vienna, University of California [San Diego] (UC San Diego), University of California, Psychiatric Neurogenetics Section, Centre for Addiction and Mental Health, School of Computing [Dublin], Dublin City University [Dublin] (DCU), University of Helsinki, University Medical Center [Utrecht], Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Oak Ridge National Laboratory [Oak Ridge] (ORNL), UT-Battelle, LLC, The M Sklodowska-Curie Cancer Center and Institute of Oncology, Brain and Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Università degli studi della Campania 'Luigi Vanvitelli', Center for Integrative Genomics - Institute of Bioinformatics, Génopode (CIG), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL)-Université de Lausanne (UNIL), Queensland Institute of Medical Research, MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, Estonian Genome and Medicine, University of Tartu, Section Molecular Epidemiology, Leiden University Medical Center (LUMC), Institute of Psychiatry, King's College, Università degli Studi di Salerno (UNISA), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Vanderbilt University School of Medicine [Nashville], Charles University [Prague] (CU), Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K, Norwegian Institute of Public Health [Oslo] (NIPH), Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Institute of Medical Informatics, Biometry and Epidemiology, The Scripps Translational Science Institute and The Scripps Research Institute, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, Leiden University Medical Center (LUMC), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, The Jackson Laboratory [Bar Harbor] (JAX), The Nofer Institute of Occupational Medicine, Università degli Studi di Perugia (UNIPG), Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Utrecht University [Utrecht], SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department Biostatistics University of North Carolina, Human Genetics, The Wellcome Trust Sanger Institute [Cambridge], Institute of Environmental Medicine, Karolinska Institutet [Stockholm]-Sachs' Children's Hospital, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Institute of Hygiene and Epidemiology, Charles University and General University Hospital-First Faculty of Medicine, Life & Brain Center - Department of Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oslo (UiO), Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), Centre for Epidemiology and Biostatistics, Faculty of Medicine and Health Leeds, University of Leeds, Department of Optics [Univ Palacký], Faculty of Science [Univ Palacký], Palacky University Olomouc-Palacky University Olomouc, Vall d'Hebron University Hospital [Barcelona], Rheumatology Unit, University of Bergen (UiB), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Masaryk Memorial Cancer Institute (RECAMO), Department of Psychiatry, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Department of Biostatistics and Center for Statistical Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München (LMU)-Chair of Epidemiology, Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Institute of Psychiatry-King‘s College London, Cardiff University-Medical Research Council, and Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)

Subjects
Adult, Male, Multifactorial Inheritance, Adolescent, behavioral disciplines and activities, Article, Feeding and Eating Disorders, Young Adult, [SCCO]Cognitive science, Polygenic risk score, Risk Factors, mental disorders, Humans, ADHD, Genetic epidemiology, Registries, Child, Sweden, [SDV.GEN]Life Sciences [q-bio]/Genetics, Eating disorder, Anorexia nervosa, Bulimia nervosa, Eating disorders, Attention Deficit Disorder with Hyperactivity, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

International audience; BACKGROUND:Although attention-deficit/hyperactivity disorder (ADHD) and eating disorders (EDs) frequently co-occur, little is known about the shared etiology. In this study, we comprehensively investigated the genetic association between ADHD and various EDs, including anorexia nervosa (AN) and other EDs such as bulimia nervosa.METHODS:We applied different genetically informative designs to register-based information of a Swedish nationwide population (N = 3,550,118). We first examined the familial coaggregation of clinically diagnosed ADHD and EDs across multiple types of relatives. We then applied quantitative genetic modeling in full-sisters and maternal half-sisters to estimate the genetic correlations between ADHD and EDs. We further tested the associations between ADHD polygenic risk scores and ED symptoms, and between AN polygenic risk scores and ADHD symptoms, in a genotyped population-based sample (N = 13,472).RESULTS:Increased risk of all types of EDs was found in individuals with ADHD (any ED: odds ratio [OR] = 3.97, 95% confidence interval [CI] = 3.81, 4.14; AN: OR = 2.68, 95% CI = 2.15, 2.86; other EDs: OR = 4.66, 95% CI = 4.47, 4.87; bulimia nervosa: OR = 5.01, 95% CI = 4.63, 5.41) and their relatives compared with individuals without ADHD and their relatives. The magnitude of the associations decreased as the degree of relatedness decreased, suggesting shared familial liability between ADHD and EDs. Quantitative genetic models revealed stronger genetic correlation of ADHD with other EDs (.37, 95% CI = .31, .42) than with AN (.14, 95% CI = .05, .22). ADHD polygenic risk scores correlated positively with ED symptom measures overall and with the subscales Drive for Thinness and Body Dissatisfaction despite small effect sizes.CONCLUSIONS:We observed stronger genetic association with ADHD for non-AN EDs than for AN, highlighting specific genetic correlation beyond a general genetic factor across psychiatric disorders.

Published
2019

22. Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Author

Schijven, D., Stevelink, R., Mccormack, M., van Rheenen, W., Luykx, J. J., Koeleman, B. P. C., Veldink, J. H., Aleksey, Shatunov, Mclaughlin, Russell L., van der Spek, Rick A. A., Alfredo, Iacoangeli, Kenna, Kevin P., van Eijk, Kristel R., Nicola, Ticozzi, Boris, Rogelj, Katarina, Vrabec, Metka, Ravnik-Glavač, Blaž, Koritnik, Janez, Zidar, Lea, Leonardis, Leja Dolenc Grošelj, Stéphanie, Millecamps, François, Salachas, Vincent, Meininger, Mamede de Carvalho, Susana, Pinto, Marta, Gromicho, Ana, Pronto-Laborinho, Mora, Jesus S., Ricardo, Rojas-García, Meraida, Polak, Siddharthan, Chandran, Shuna, Colville, Robert, Swingler, Morrison, Karen E., Shaw, Pamela J., John, Hardy, Orrell, Richard W., Alan, Pittman, Katie, Sidle, Pietro, Fratta, Andrea, Malaspina, Simon, Topp, Susanne, Petri, Susanna, Abdulla, Carsten, Drepper, Michael, Sendtner, Thomas, Meyer, Ophoff, Roel A., Staats, Kim A., Martina, Wiedau-Pazos, Catherine, Lomen-Hoerth, Van Deerlin, Vivianna M., Trojanowski, John Q., Lauren, Elman, Leo, Mccluskey, Nazli Basak, A., Thomas, Meitinger, Peter, Lichtner, Milena, Blagojevic-Radivojkov, Andres, Christian R., Gilbert, Bensimon, Bernhard, Landwehrmeyer, Alexis, Brice, Payan, Christine A. M., Safaa, Saker-Delye, Alexandra, Dürr, Wood, Nicholas W., Lukas, Tittmann, Wolfgang, Lieb, Andre, Franke, Marcella, Rietschel, Sven, Cichon, Nöthen, Markus M., Philippe, Amouyel, Christophe, Tzourio, Jean-François, Dartigues, Uitterlinden, Andre G., Fernando, Rivadeneira, Karol, Estrada, Albert, Hofman, Charles, Curtis, van der Kooi, Anneke J., Markus, Weber, Shaw, Christopher E., Smith, Bradley N., Daisy, Sproviero, Cristina, Cereda, Mauro, Ceroni, Luca, Diamanti, Roberto Del Bo, Stefania, Corti, Comi, Giacomo P., Sandra, D'Alfonso, Lucia, Corrado, Bertolin, Cinzia, Soraru', Gianni, Letizia, Mazzini, Viviana, Pensato, Cinzia, Gellera, Cinzia, Tiloca, Antonia, Ratti, Andrea, Calvo, Cristina, Moglia, Maura, Brunetti, Simona, Arcuti, Rosa, Capozzo, Chiara, Zecca, Christian, Lunetta, Silvana, Penco, Nilo, Riva, Alessandro, Padovani, Massimiliano, Filosto, Ian, Blair, Nicholson, Garth A., Rowe, Dominic B., Roger, Pamphlett, Kiernan, Matthew C., Julian, Grosskreutz, Witte, Otto W., Robert, Steinbach, Tino, Prell, Beatrice, Stubendorff, Ingo, Kurth, Hübner, Christian A., Nigel Leigh, P., Federico, Casale, Adriano, Chio, Ettore, Beghi, Elisabetta, Pupillo, Rosanna, Tortelli, Giancarlo, Logroscino, John, Powell, Ludolph, Albert C., Weishaupt, Jochen H., Wim, Robberecht, Philip Van Damme, Brown, Robert H., Glass, Jonathan D., Landers, John E., Orla, Hardiman, Andersen, Peter M., Philippe, Corcia, Patrick, Vourc'H, Vincenzo, Silani, van Es, Michael A., Jeroen Pasterkamp, R., Lewis, Cathryn M., Gerome, Breen, Ammar, Al-Chalabi, van den Berg, Leonard H., Veldink, Jan H., Daniela, Calini, Isabella, Fogh, Barbara, Castellotti, Franco, Taroni, Stella, Gagliardi, Giacomo, Comi, Sandra, D’Alfonso, Pegoraro, Elena, Giorgia, Querin, Francesca, Gerardi, Fabrizio, Rinaldi, Maria Sofia Cotelli, Luca, Chiveri, Maria Cristina Guaita, Patrizia, Perrone, Giancarlo, Comi, Carlo, Ferrarese, Lucio, Tremolizzo, Marialuisa, Delodovici, Giorgio, Bono, Stefania, Cammarosano, Antonio, Canosa, Dario, Cocito, Leonardo, Lopiano, Luca, Durelli, Bruno, Ferrero, Antonio, Bertolotto, Alessandro, Mauro, Luca, Pradotto, Roberto, Cantello, Enrica, Bersano, Dario, Giobbe, Maurizio, Gionco, Daniela, Leotta, Lucia, Appendino, Cavallo, Cavallo, Enrico, Odddenino, Claudio, Geda, Fabio, Poglio, Paola, Santimaria, Umberto, Massazza, Antonio, Villani, Roberto, Conti, Fabrizio, Pisano, Mario, Palermo, Franco, Vergnano, Paolo, Provera, Maria Teresa Penza, Marco, Aguggia, Nicoletta Di Vito, Piero, Meineri, Ilaria, Pastore, Paolo, Ghiglione, Danilo, Seliak, Nicola, Launaro, Giovanni, Astegiano, Bottacchi, Edo, Isabella Laura Simone, Stefano, Zoccolella, Michele, Zarrelli, Franco, Apollo, William, Camu, Jean Sebastien Hulot, Francois, Viallet, Philippe, Couratier, David, Maltete, Christine, Tranchant, Marie, Vidailhet, Bassel, Abou-Khalil, Pauls, Auce, Andreja, Avbersek, Melanie, Bahlo, David, J Balding, Thomas, Bast, Larry, Baum, Albert, J Becker, Felicitas, Becker, Bianca, Berghuis, Samuel, F Berkovic, Katja, E Boysen, Jonathan, P Bradfield, Lawrence, C Brody, Russell, J Buono, Ellen, Campbell, Gregory, D Cascino, Claudia, B Catarino, Gianpiero, L Cavalleri, Stacey, S Cherny, Krishna, Chinthapalli, Alison, J Coffey, Alastair, Compston, Antonietta, Coppola, Patrick, Cossette, John, J Craig, Gerrit-Jan de Haan, Peter De Jonghe, Carolien G, F de Kovel, Norman, Delanty, Chantal, Depondt, Orrin, Devinsky, Dennis, J Dlugos, Colin, P Doherty, Christian, E Elger, Johan, G Eriksson, Thomas, N Ferraro, Martha, Feucht, Ben, Francis, Jacqueline, A French, Saskia, Freytag, Verena, Gaus, Eric, B Geller, Christian, Gieger, Tracy, Glauser, Simon, Glynn, David, B Goldstein, Hongsheng, Gui, Youling, Guo, Kevin, F Haas, Hakon, Hakonarson, Kerstin, Hallmann, Sheryl, Haut, Erin, L Heinzen, Ingo, Helbig, Christian, Hengsbach, Helle, Hjalgrim, Michele, Iacomino, Andrés, Ingason, Michael, R Johnson, Reetta, Kälviäinen, Anne-Mari, Kantanen, Dalia, Kasperavičiūte, Dorothee Kasteleijn-Nolst Trenite, Heidi, E Kirsch, Robert, C Knowlton, Bobby P, C Koeleman, Roland, Krause, Martin, Krenn, Wolfram, S Kunz, Ruben, Kuzniecky, Patrick, Kwan, Dennis, Lal, Yu-Lung, Lau, Anna-Elina, Lehesjoki, Holger, Lerche, Costin, Leu, Dick, Lindhout, Warren, D Lo, Iscia, Lopes-Cendes, Daniel, H Lowenstein, Alberto, Malovini, Anthony, G Marson, Thomas, Mayer, Mark, Mccormack, James, L Mills, Nasir, Mirza, Martina, Moerzinger, Rikke, S Møller, Anne, M Molloy, Hiltrud, Muhle, Mark, Newton, Ping-Wing, Ng, Markus, M Nöthen, Peter, Nürnberg, Terence, J O’Brien, Karen, L Oliver, Aarno, Palotie, Faith, Pangilinan, Sarah, Peter, Slavé, Petrovski, Annapurna, Poduri, Michael, Privitera, Rodney, Radtke, Sarah, Rau, Philipp, S Reif, Eva, M Reinthaler, Felix, Rosenow, Josemir, W Sander, Thomas, Sander, Theresa, Scattergood, Steven, C Schachter, Christoph, J Schankin, Ingrid, E Scheffer, Bettina, Schmitz, Susanne, Schoch, Pak, C Sham, Jerry, J Shih, Graeme, J Sills, Sanjay, M Sisodiya, Lisa, Slattery, Alexander, Smith, David, F Smith, Michael, C Smith, Philip, E Smith, Anja C, M Sonsma, Doug, Speed, Michael, R Sperling, Bernhard, J Steinhoff, Ulrich, Stephani, Remi, Stevelink, Konstantin, Strauch, Pasquale, Striano, Hans, Stroink, Rainer, Surges, K Meng Tan, Liu Lin Thio, G Neil Thomas, Marian, Todaro, Rossana, Tozzi, Maria, S Vari, Eileen P, G Vining, Frank, Visscher, Sarah von Spiczak, Nicole, M Walley, Yvonne, G Weber, Zhi, Wei, Judith, Weisenberg, Christopher, D Whelan, Peter, Widdess-Walsh, Markus, Wolff, Stefan, Wolking, Wanling, Yang, Federico, Zara, Fritz, Zimprich, Project MinE ALS GWAS Consortium, International League Against Epilepsy Consortium on Complex Epilepsies, Department of Medical and Clinical Genetics, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Clinicum, Johan Eriksson / Principal Investigator, Department of General Practice and Primary Health Care, and HUS Helsinki and Uusimaa Hospital District

Subjects
Risk, 0301 basic medicine, Aging, Genetic correlation, Geriatrics & Gerontology, education, Genome-wide association study, Biology, ALS, Epilepsy, Amyotrophic Lateral Sclerosis, Gene Frequency, Humans, Genetic Variation, Genome-Wide Association Study, Negative Results, Article, 3124 Neurology and psychiatry, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, medicine, Amyotrophic lateral sclerosis, Allele frequency, Genetics, Science & Technology, Mechanism (biology), General Neuroscience, 3112 Neurosciences, Neurosciences, medicine.disease, 3. Good health, Minor allele frequency, 030104 developmental biology, Neurology (clinical), Neurosciences & Neurology, Geriatrics and Gerontology, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins. ispartof: NEUROBIOLOGY OF AGING vol:92 ispartof: location:United States status: published

Published
2020

23. Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Author

Lal, D., May, P., Perez-Palma, E., Samocha, K. E., Kosmicki, J. A., Robinson, E. B., Moller, R. S., Krause, R., Nurnberg, P., Weckhuysen, S., De Jonghe, P., Guerrini, R., Niestroj, L. M., Du, J., Marini, C., Balling, R., Barisic, N., Baulac, S., Caglayan, H., Craiu, D. C., Depienne, C., Helbig, I., Hjalgrim, H., Hoffman-Zacharska, D., Jahn, J., Klein, K. M., Koeleman, B. P. C., Komarek, V., Leguern, E., Lehesjoki, A. -E., Lemke, J. R., Lerche, H., Linnankivi, T., Muhle, H., Pal, D. K., Palotie, A., Rosenow, F., Schubert-Bast, S., Selmer, K., Serratosa, J. M., Stephani, U., Sterbova, K., Striano, P., Suls, A., Talvik, T., Von Spiczak, S., Weber, Y. G., Zara, F., Ware, J. S., Kurki, M., Gormley, P., Tang, S., Wu, S., Biskup, S., Poduri, A., Neubauer, B. A., Helbig, K. L., Majithia, A. R., Daly, M. J., EuroEPINOMICS-RES Consortium, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Department of Medical and Clinical Genetics, Medicum, HUS Helsinki and Uusimaa Hospital District, and Wellcome Trust

Subjects
Candidate gene, lcsh:QH426-470, Developmental Disabilities, Mutation, Missense, Sequence Homology, lcsh:Medicine, ORTHOLOGS, Computational biology, Conservation, Gene family, Missense variants, Neurodevelopmental disorders, Paralogs, Biology, 03 medical and health sciences, MULTIPLE SEQUENCE ALIGNMENT, PHYLOGENETIC TREES, Genetics, Missense mutation, Ensembl, Molecular Biology, Gene, Genetics (clinical), Phylogeny, 030304 developmental biology, 0303 health sciences, 0604 Genetics, Phylogenetic tree, Research, 030305 genetics & heredity, lcsh:R, 1184 Genetics, developmental biology, physiology, 1103 Clinical Sciences, EuroEPINOMICS-RES Consortium, Human genetics, lcsh:Genetics, Genetic Loci, DE-NOVO MUTATIONS, Multigene Family, Molecular Medicine, Human medicine, Orthologous Gene, Genome-Wide Association Study
Abstract

Background Classifying pathogenicity of missense variants represents a major challenge in clinical practice during the diagnoses of rare and genetic heterogeneous neurodevelopmental disorders (NDDs). While orthologous gene conservation is commonly employed in variant annotation, approximately 80% of known disease-associated genes belong to gene families. The use of gene family information for disease gene discovery and variant interpretation has not yet been investigated on a genome-wide scale. We empirically evaluate whether paralog-conserved or non-conserved sites in human gene families are important in NDDs. Methods Gene family information was collected from Ensembl. Paralog-conserved sites were defined based on paralog sequence alignments; 10,068 NDD patients and 2078 controls were statistically evaluated for de novo variant burden in gene families. Results We demonstrate that disease-associated missense variants are enriched at paralog-conserved sites across all disease groups and inheritance models tested. We developed a gene family de novo enrichment framework that identified 43 exome-wide enriched gene families including 98 de novo variant carrying genes in NDD patients of which 28 represent novel candidate genes for NDD which are brain expressed and under evolutionary constraint. Conclusion This study represents the first method to incorporate gene family information into a statistical framework to interpret variant data for NDDs and to discover new NDD-associated genes.

Published
2020

24. Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load

Author

Perucca, P., Anderson, A., Jazayeri, D., Hitchcock, A., Graham, J., Todaro, M., Tomson, T., Battino, D., Perucca, E., Ferri, M. M., Rochtus, A., Lagae, L., Canevini, M. P., Zambrelli, E., Campbell, E., Koeleman, B. P. C., Scheffer, I. E., Berkovic, S. F., Kwan, P., Sisodiya, S. M., Goldstein, D. B., Petrovski, S., Craig, J., Vajda, F. J. E., O'Brien, T. J., Leu, C., Wolking, S., Peter, S., Weber, Y. G., Weckhuysen, S., Moller, R. S., Nikanorova, M., Muhle, H., Avbersek, A., Heggeli, K., Striano, P., Gambardella, A., Langley, S. R., Krenn, M., Klein, K. M., Mccormack, M., Borghei, M., Willis, J., Berghuis, B., Jorgensen, A., Auce, P., Francis, B., Srivastava, P., Sonsma, A. C. M., Sander, Jw., Zimprich, F., Depondt, C., Johnson, M. M., Marson, A. G., Sills, G. J., Kunz, W. S., Cavalleri, G. L., Delanty, N., Zara, F., Krause, R., Lerche, H., Andrade, D., Sen, A., Bazil, C. W., Boland, M., Cavalleri, G., Choi, H., Colombo, S., Costello, D., Devinsky, O., Doherty, C. P., Dugan, P., Frankel, W., Heinzen, E., Johnson, M., Marson, T., Mikati, M., Ottman, R., Pandolfo, M., Radtke, R., Rees, M., Sadoway, T., Valley, N., Walley, N., Wood, N., and Zuberi, S.

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, DNA Copy Number Variations, Polymorphism, Single Nucleotide, Paternal Age, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Pregnancy, Polymorphism (computer science), medicine, Humans, Exome, Copy-number variation, Indel, business.industry, Confounding, Infant, Newborn, Abnormalities, Drug-Induced, Genetic Variation, DNA, medicine.disease, Genetic load, Exact test, Teratogens, 030104 developmental biology, Neurology, Anticonvulsants, Female, Neurology (clinical), Genetic Load, business, 030217 neurology & neurosurgery
Abstract

OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism which we investigated. METHODS: Whole-exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED-exposed children) vs children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs vs those without BDs, adjusting for confounders. Fisher's exact test was used to compare categorical data. RESULTS: 67 child-parent trios were included: 10 with AED-exposed children with BDs; 46 with AED-exposed unaffected children; 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children [median dnSNV/indel number/child (range): 3 (0-7) vs 3 (1-5), p = 0.50]. Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9/67 (13%) children, none of whom had BDs. The proportion of cases harbouring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counselling. This article is protected by copyright. All rights reserved.

Published
2020

27. Damaging de novo missense variants in EEF1A2 lead to a developmental and degenerative epileptic-dyskinetic encephalopathy

Author

Carvill, GL, Helbig, KL, Myers, CT, Scala, M, Huether, R, Lewis, S, Kruer, TN, Guida, BS, Bakhtiari, S, Sebe, J, Tang, S, Stickney, H, Oktay, SU, Bhandiwad, AA, Ramsey, K, Narayanan, V, Feyma, T, Rohena, LO, Accogli, A, Severino, M, Hollingsworth, G, Gill, D, Depienne, C, Nava, C, Sadleir, LG, Caruso, PA, Lin, AE, Jansen, FE, Koeleman, B, Brilstra, E, Willemsen, MH, Kleefstra, T, Sa, J, Mathieu, M-L, Perrin, L, Lesca, G, Striano, P, Casari, G, Scheffer, IE, Raible, D, Sattlegger, E, Capra, V, Padilla-Lopez, S, Mefford, HC, Kruer, MC, Carvill, GL, Helbig, KL, Myers, CT, Scala, M, Huether, R, Lewis, S, Kruer, TN, Guida, BS, Bakhtiari, S, Sebe, J, Tang, S, Stickney, H, Oktay, SU, Bhandiwad, AA, Ramsey, K, Narayanan, V, Feyma, T, Rohena, LO, Accogli, A, Severino, M, Hollingsworth, G, Gill, D, Depienne, C, Nava, C, Sadleir, LG, Caruso, PA, Lin, AE, Jansen, FE, Koeleman, B, Brilstra, E, Willemsen, MH, Kleefstra, T, Sa, J, Mathieu, M-L, Perrin, L, Lesca, G, Striano, P, Casari, G, Scheffer, IE, Raible, D, Sattlegger, E, Capra, V, Padilla-Lopez, S, Mefford, HC, and Kruer, MC

Abstract

Heterozygous de novo variants in the eukaryotic elongation factor EEF1A2 have previously been described in association with intellectual disability and epilepsy but never functionally validated. Here we report 14 new individuals with heterozygous EEF1A2 variants. We functionally validate multiple variants as protein-damaging using heterologous expression and complementation analysis. Our findings allow us to confirm multiple variants as pathogenic and broaden the phenotypic spectrum to include dystonia/choreoathetosis, and in some cases a degenerative course with cerebral and cerebellar atrophy. Pathogenic variants appear to act via a haploinsufficiency mechanism, disrupting both the protein synthesis and integrated stress response functions of EEF1A2. Our studies provide evidence that EEF1A2 is highly intolerant to variation and that de novo pathogenic variants lead to an epileptic-dyskinetic encephalopathy with both neurodevelopmental and neurodegenerative features. Developmental features may be driven by impaired synaptic protein synthesis during early brain development while progressive symptoms may be linked to an impaired ability to handle cytotoxic stressors.

Published
2020

28. De novo variants in neurodevelopmental disorders with epilepsy

Author

Heyne, H. O., Singh, T., Stamberger, H., Abou Jamra, R., Caglayan, H., Craiu, D., De Jonghe, P., Guerrini, R., Helbig, K. L., Koeleman, B. P. C., Kosmicki, J. A., Linnankivi, T., May, P., Muhle, H., Moller, R. S., Neubauer, B. A., Palotie, A., Pendziwiat, M., Striano, P., Tang, S., Wu, S., Afawi, Z., De Kovel, C., Dimova, P., Djemie, T., Endziniene, M., Hoffman-Zacharska, D., Jahn, J., Korff, C., Lehesjoki, A. -E., Marini, C., Muller, S. H., Pal, D., Schwarz, N., Selmer, K., Serratosa, J., Stephani, U., Sterbova, K., Suls, A., Syrbe, S., Talvik, I., Von Spiczak, S., Zara, F., Poduri, A., Weber, Y. G., Weckhuysen, S., Sisodiya, S. M., Daly, M. J., Helbig, I., Lal, D., Lemke, J. R., Children's Hospital, Lastenneurologian yksikkö, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Research Programme for Molecular Neurology, Neuroscience Center, HUS Children and Adolescents, Genomics of Neurological and Neuropsychiatric Disorders, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], University of Luxembourg: High Performance Computing - ULHPC [research center], Korff, Christian, and EuroEPINOMICS RES Consortium

Subjects
Exome/genetics, Male, 0301 basic medicine, ILAE COMMISSION, Joint analysis, Neurodevelopmental Disorders/genetics, Bioinformatics, Epilepsy/genetics, Epilepsy, 0302 clinical medicine, Intellectual disability, SEQUENCE VARIANTS, Missense mutation, Epilepsy is a frequent feature, Exome, TERMINOLOGY, Disease gene, 0303 health sciences, ddc:618, medicine.diagnostic_test, Genetic Predisposition to Disease/genetics, Neurodevelopmental disorders, 1184 Genetics, developmental biology, physiology, HUMAN-DISEASE, PREVALENCE, 3. Good health, Genetic Variation/genetics, De novo variants, Female, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Genetic Testing/methods, Disease Association, Biology, CLASSIFICATION, 03 medical and health sciences, Intellectual Disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Limited evidence, 030304 developmental biology, Genetic testing, business.industry, MUTATIONS, AUTISM SPECTRUM DISORDER, Genetic Variation, medicine.disease, Intellectual Disability/genetics, 030104 developmental biology, Neurodevelopmental Disorders, epilepsy, KCNQ2 ENCEPHALOPATHY, Human medicine, 3111 Biomedicine, business, Genetic diagnosis, 030217 neurology & neurosurgery
Abstract

Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.

Published
2018

31. A replication study confirms the association of TNFSF4 (OX40L) polymorphisms with Systemic Sclerosis in a large European cohort

Author

Airó P, Lie B A, Palm Ø, Nordin A, Padykov L, Claes K, Denton C, Fonseca C, Madhok R, Shiels P, Chee M M, Schuerwegh A J, Voskuyl A E, De Langhe E, Westhovens R, Smith V, De Keyser F, Houssiau F, Koeleman B P, Coenen MJH, Witte T, Riemekasten G, Hesselstrand R, González-Gay M A, Pros A, García de la Peña P, Follonosa V, Egurbide M V, Fernández-Nebro A, Gallego M, Castellví I, García-Hernández F J, Gómez-Gracia I, Román-Ivorra J A, Tolosa C, Rodríguez L, Vicente-Rabaneda E, González-Escribano M F, Navarrete N, Camps M T, Carreira P, Espinosa G, Ortego-Centeno N, Vonk M C, Beretta L, Simeon C P, Broen JCA, Bossini-Castillo L, Scorza R, van Laar J M, Hunzelmann N, Kreuter A, Herrick A, Worthington J, Radstake TRDJ, Martín J, and Rueda B

Subjects
Medicine
Published
2010
Full Text
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39. PHENOTYPING OF IGE PATIENTS WITH A PHOTOPAROXYSMAL EEG RESPONSE (PPR) FOR EUROPEAN GENETIC STUDIES: TWO MAIN PHENOTYPES APPEAR TO BE SIMILAR IN NORTHERN AND SOUTHERN EUROPEAN COUNTRIES: 002

Author

Kasteleijn-Nolst, Trenité D, de Kovel, C, Jocic-Jakubi, B, Baykan, B, Visscher, F, Janssen, A, Verrotti, A, Schippers, H, Sonsma, A, Koeleman, B, Lindhout, D, Elia, M, Stylianidou, G, Mikati, M, Cerminara, C, Incorpora, G, Augustijn, P, Latella, A, Bianchi, A, Carpay, J, and Stroink, H

Published
2010

43. Polygenic burden in focal and generalized epilepsies

Author

Leu C., Stevelink R., Smith A. W., Goleva S. B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S. M., Cavalleri G. L., Koeleman B. P. C., Lerche H., Jehi L., Davis L. K., Najm I. M., Palotie A., Daly M. J., Busch R. M., Lal D., Feng Y. -C. A., Howrigan D. P., Abbott L. E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B. M., Berkovic S. F., Goldstein D. B., Lowenstein D. H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E. L., Helbig I., Kwan P., Marson A. G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D. J., Scheffer I. E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B. M., Bellows S. T., Bennett C. A., Johns E. M. C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T. J., Todaro M., Stamberger H., Andrade D. M., Sadoway T. R., Mo K., Krestel H., Gallati S., Papacostas S. S., Kousiappa I., Tanteles G. A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K. M., Rosenow F., Reif P. S., Knake S., Kunz W. S., Zsurka G., Elger C. E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A. D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J. R., Krey I., Weber Y. G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A. F., Steinhoff B. J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C. J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A. -E., Rees M. I., Chung S. -K., Pickrell W. O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M. R., Auce P., Sills G. J., Baum L. W., Sham P. C., Cherny S. S., Lui C. H. T., Barisic N., Delanty N., Doherty C. P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M. S., Mancardi M. M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L. G., King C., Mountier E., Caglayan S. H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B. R., Shain C., Poduri A., Buono R. J., Ferraro T. N., Sperling M. R., Lo W., Privitera M., French J. A., Schachter S., Kuzniecky R. I., Devinsky O., Hegde M., Khankhanian P., Helbig K. L., Ellis C. A., Spalletta G., Piras F., Gili T., Ciullo V., Leu C., Stevelink R., Smith A.W., Goleva S.B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S.M., Cavalleri G.L., Koeleman B.P.C., Lerche H., Jehi L., Davis L.K., Najm I.M., Palotie A., Daly M.J., Busch R.M., Lal D., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B.M., Berkovic S.F., Goldstein D.B., Lowenstein D.H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bellows S.T., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B.R., Shain C., Poduri A., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Commission of the European Communities, Medical Research Council (MRC), Tumienė, Birutė, Mameniškienė, Rūta, Utkus, Algirdas, Praninskienė, Rūta, Grikinienė, Jurgita, Samaitienė-Aleknienė, Rūta, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Helsinki Institute of Life Science HiLIFE, and Department of Medical and Clinical Genetics

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, Epi25 Consortium, Databases, Factual, FEATURES, Genome-wide association study, Epilepsies, 3124 Neurology and psychiatry, Cohort Studies, Epilepsy, 0302 clinical medicine, Cost of Illness, 1ST SEIZURE, HISTORY, genetics, POPULATION, 11 Medical and Health Sciences, education.field_of_study, medicine.diagnostic_test, SCORES, Single Nucleotide, Biobank, 3. Good health, 17 Psychology and Cognitive Sciences, Genetic generalized epilepsy, Epilepsy, Generalized, Female, Partial, Cohort study, Human, medicine.medical_specialty, Population, European Continental Ancestry Group, Clinical Neurology, BIOBANK, Polymorphism, Single Nucleotide, epilepsy, genetic generalized epilepsy, common variant risk, Databases, 03 medical and health sciences, Genetic, Internal medicine, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Generalized epilepsy, education, SEIZURE RECURRENCE, Factual, METAANALYSIS, Genetic testing, Neurology & Neurosurgery, RISK PREDICTION, Generalized, business.industry, 3112 Neurosciences, Common variant risk, Genetic Variation, Original Articles, medicine.disease, Comorbidity, Cost of Illne, Epilepsies, Partial, Genome-Wide Association Study, 030104 developmental biology, Neurology (clinical), Cohort Studie, business, 030217 neurology & neurosurgery
Abstract

See Hansen and Møller (doi:10.1093/brain/awz318) for a scientific commentary on this article. Using polygenic risk scores from a genome-wide association study in generalized and focal epilepsy, Leu et al. reveal a significantly higher genetic burden for epilepsy in multiple cohorts of people with epilepsy compared to population controls. Quantification of common variant burden may be valuable for epilepsy prognosis and treatment., Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10−15; Cleveland: P = 2.85×10−4; Finnish-ancestry Epi25: P = 1.80×10−4) or population controls (Epi25: P = 2.35×10−70; Cleveland: P = 1.43×10−7; Finnish-ancestry Epi25: P = 3.11×10−4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10−4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10−19; Cleveland: P = 1.69×10−6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10−15; Cleveland: P = 1.39×10−2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls—in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

Published
2019

44. A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

Author

Berghuis, B., Stapleton, C., Sonsma, A. C. M., Hulst, J., de Haan, G. -J., Lindhout, D., Demurtas, R., Krause, R., Depondt, C., Kunz, W. S., Zara, F., Striano, P., Craig, J., Auce, P., Marson, A. G., Stefansson, H., O'Brien, T. J., Johnson, M. R., Sills, G. J., Wolking, S., Lerche, H., Sisodiya, S. M., Sander, J. W., Cavalleri, G. L., Koeleman, B. P. C., Mccormack, M., Avbersek, A., Leu, C., Heggeli, K., Willis, J., Speed, D., Sargsyan, N., Chinthapalli, K., Borghei, M., Coppola, A., Gambardella, A., Becker, F., Rau, S., Hengsbach, C., Weber, Y. G., Delanty, N., Campbell, E., Gudmundsson, L. J., Ingason, A., Stefansson, K., Schneider, R., Balling, R., Francis, B., Jorgensen, A., Morris, A., Langley, S., Srivastava, P., Brodie, M., Todaro, M., Petrovski, S., Hutton, J., Zimprich, F., Krenn, M., Muhle, H., Martin Klein, K., Moller, R., Nikanorova, M., Weckhuysen, S., Rener-Primec, Z., Berghuis, Bianca, Stapleton, Caragh, Sonsma, Anja C. M., Hulst, Janic, de Haan, Gerrit-Jan, Lindhout, Dick, Demurtas, Rita, Krause, Roland, Depondt, Chantal, Kunz, Wolfram S., Zara, Federico, Striano, Pasquale, Craig, John, Auce, Paul, Marson, Anthony G., Stefansson, Hreinn, O'Brien, Terence J., Johnson, Michael R., Sills, Graeme J., Wolking, Stefan, Lerche, Holger, Sisodiya, Sanjay M., Sander, Josemir W., Cavalleri, Gianpiero L., Koeleman, Bobby P. C., Mccormack, Mark, Weckhuysen, Sarah, EpiPGX Consortium, Imperial College Healthcare NHS Trust- BRC Funding, and Commission of the European Communities

Subjects
medicine.medical_specialty, hyponatremia, Clinical Neurology, Gastroenterology, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, adverse effects, antiepileptic drugs, EpiPGX Consortium, GWAS, antiepileptic drug, Internal medicine, adverse effect, medicine, Oxcarbazepine, Adverse effect, 030304 developmental biology, 0303 health sciences, business.industry, Généralités, Carbamazepine, medicine.disease, 3. Good health, Neurology, Cohort, Full‐length Original Research, Phenobarbital, Human medicine, Neurology (clinical), Hyponatremia, business, 030217 neurology & neurosurgery, Drug metabolism, medicine.drug
Abstract

Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2019

45. IDENTIFICATION OF FOUR NEW SHARED SUSCEPTIBILITY GENES IN SYSTEMIC SCLEROSIS AND CROHN¿S DISEASE THROUGH A CROSS-DISEASE META-GWAS

Author

González-Serna, David, Ochoa, Eguzkine, López-Isac, Elena, Julià, A, Degenhardt, Frauke, van Beelen Granlund, A, Carreira, PE, Simeon, CP, Ortego-Centeno, N., González-Gay, M. A., Vicente, Esther, Beltran, E, Alegre-Sancho, Juan-José, Spanish Scleroderma Group, Beretta, L., Santaniello, A, Lunardi, C., Hunzelmann, Nicolas, Riemekasten, G, Witte, T, Distler, J.H.W., Kreuter, A., Airó, P, Koeleman, B. P., Voskuyl, AE, de Vries-Bouwstra, Jeska, Radstake, TRDJ, Wijmenga, C, Assassi, S., Franke, Andre, Marsal, Sara, Mayes, Maureen D., Martín, J., and Márquez A

Published
2019

46. Genome-wide meta-analysis reveals shared new loci in systemic seropositive rheumatic diseases

Author

Acosta-Herrera, Marialbert, Kerick, Martin, González-Serna, David, Wijmenga, Cisca, Franke, Andre, Gregersen, Peter K., Padyukov, Leonid, Worthington, J., Vyse, T. J., Alarcón-Riquelme, M. E., Mayes, M. D., Martín, J., Miller, Frederick W., Chen, Wei, O'Hanlon, Terrance P., Cooper, Robert G., Vencovsky, Jiri, Rider, Lisa G, Danko, Katalin, Wedderburn, Lucy R., Lundberg, Ingrid E., Pachman, Lauren M., Reed, Ann M., Ytterberg, Steven R, Selva-O'Callaghan, Alber, Radstake, Timothy R., Isenberg, David A, Chinoy, Hector, Ollier, William E. R, Scheet, Paul, Peng, Bo, Lee, Annette, Lamb, Janine A., Amos, Christopher I., Denton, Christopher, Hilton-Jones, David, Plotz, Paul H., Varsani, Hemlata, Radstake, Timothy R. D. J., Gorlova, Olga, Rueda, B., Martín, J. E., Alizadeh, B. Z., Palomino-Morales, Rogelio, Coenen, Marieke J. H., Vonk, Madelon C., Voskuyl, Alexandre E., Scheurwegh, Annemie J., Broen, Jasper C., van Riel, Piet L. C. M., van 't Slot, Rubén, Italiaander, Annet, Ophoff, Roel A., Riemekasten, Gabriela, Hunzelmann, Nicolas, Simeon, Carmen P., Ortego-Centeno, N., González-Gay, M. A., González-Escribano, María Francisca, Airó, Paolo, van Laar, Jaap, Herrick, Ariane L., Hesselstrand, Roger, Smith, Vanessa, de Keyser, Filip, Houssiau, Fredric, Chee, Meng May, Madhok, Rajan, Shiels, Paul, Westhovens, Rene, Kreuter, A., Kiener, Hans, de Baere, Elfride, Witte, Torsten, Klareskog, Lars, Beretta, Lorenzo, Scorza, Rafaella, Lie, Benedicte A., Hoffman-Vold, A. M., Carreira, P., Varga, John, Hinchcliff, Monique, Lee, Annette T., Ying, Jun, Han, Younghun, Weng, Shih-Feng, Wigley, Fredrick M., Hummers, L. K., Nelson, J. Lee, Agarwal, Sandeep K., Assassi, S., Gourh, Pravitt, Tan, Filemon K., Koeleman, B. P., Arnett, Frank C., Myositis Genetics Consortium, Scleroderma Genetics Consortium., Innovative Medicines Initiative, Ministerio de Economía, Industria y Competitividad (España), Junta de Andalucía, National Institute of Environmental Health Sciences (US), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Polymer Chemistry and Bioengineering, Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Myositis Genetics Consortium, and Scleroderma Genetics Consortium

Subjects
0301 basic medicine, Male, Lydia Becker Institute, PATHOGENESIS, PROTEIN, Arthritis, VARIANTS, medicine.disease_cause, Myositis Genetics Consortium, Autoimmunity, Scleroderma, Arthritis, Rheumatoid, 0302 clinical medicine, Scleroderma Genetics Consortium, Rheumatoid, MULTIPLE, Lupus Erythematosus, Systemic, Immunology and Allergy, Medicine, 2.1 Biological and endogenous factors, Aetiology, Genetics, autoimmunity, Family aggregation, Lim Kinases, ASSOCIATION, Single Nucleotide, Public Health and Health Services, Female, ARTHRITIS, Life Sciences & Biomedicine, alpha Karyopherins, Adult, medicine.medical_specialty, GENETICS, gene polymorphism, Quantitative Trait Loci, Clinical Sciences, Immunology, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Autoimmune Disease, General Biochemistry, Genetics and Molecular Biology, White People, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], 03 medical and health sciences, Immune system, Rheumatology, Internal medicine, Rheumatic Diseases, ResearchInstitutes_Networks_Beacons/lydia_becker_institute_of_immunology_and_inflammation, Humans, Genetic Predisposition to Disease, autoimmune diseases, Polymorphism, SCLEROSIS, COMMON, 030203 arthritis & rheumatology, Science & Technology, Scleroderma, Systemic, COMPLEX, Myositis, Lupus Erythematosus, business.industry, Inflammatory and immune system, Systemic, Human Genome, Membrane Proteins, medicine.disease, Arthritis & Rheumatology, Repressor Proteins, 030104 developmental biology, Expression quantitative trait loci, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], Human medicine, Gene polymorphism, business, Genome-Wide Association Study
Abstract

ObjectiveImmune-mediated inflammatory diseases (IMIDs) are heterogeneous and complex conditions with overlapping clinical symptoms and elevated familial aggregation, which suggests the existence of a shared genetic component. In order to identify this genetic background in a systematic fashion, we performed the first cross-disease genome-wide meta-analysis in systemic seropositive rheumatic diseases, namely, systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and idiopathic inflammatory myopathies.MethodsWe meta-analysed ~6.5 million single nucleotide polymorphisms in 11 678 cases and 19 704 non-affected controls of European descent populations. The functional roles of the associated variants were interrogated using publicly available databases.ResultsOur analysis revealed five shared genome-wide significant independent loci that had not been previously associated with these diseases: NAB1, KPNA4-ARL14, DGQK, LIMK1 and PRR12. All of these loci are related with immune processes such as interferon and epidermal growth factor signalling, response to methotrexate, cytoskeleton dynamics and coagulation cascade. Remarkably, several of the associated loci are known key players in autoimmunity, which supports the validity of our results. All the associated variants showed significant functional enrichment in DNase hypersensitivity sites, chromatin states and histone marks in relevant immune cells, including shared expression quantitative trait loci. Additionally, our results were significantly enriched in drugs that are being tested for the treatment of the diseases under study.ConclusionsWe have identified shared new risk loci with functional value across diseases and pinpoint new potential candidate loci that could be further investigated. Our results highlight the potential of drug repositioning among related systemic seropositive rheumatic IMIDs.

Published
2019

49. Relative predispositional effects of HLA class II DRB1-DQB1 haplotypes and genotypes on type 1 diabetes: a meta-analysis

Author

Thomson, G., Valdes, A. M., Noble, J. A., Kockum, I., Grote, M. N., Najman, J., Erlich, H. A., Cucca, F., Pugliese, A., Steenkiste, A., Dorman, J. S., Caillat-Zucman, S., Hermann, R., Ilonen, J., Lambert, A. P., Bingley, P. J., Gillespie, K. M., Lernmark, Å., Sanjeevi, C. B., Rønningen, K. S., Undlien, D. E., Thorsby, E., Petrone, A., Buzzetti, R., Koeleman, B. P.C., Roep, B. O., Saruhan-Direskeneli, G., Uyar, F. A., Günoz, H., Gorodezky, C., Alaez, C., Boehm, B. O., Mlynarski, W., Ikegami, H., Berrino, M., Fasano, M. E., Dametto, E., Israel, S., Brautbar, C., Santiago-Cortes, A., de Llado, T. Frazer, She, J.-X., Bugawan, T. L., Rotter, J. I., Raffel, L., Zeidler, A., Leyva-Cobian, F., Hawkins, B. R., Chan, S. H., Castano, L., Pociot, F., and Nerup, J.

Published
2007

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