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87 results on '"De Kovel, C."'

1. A genome-wide association study of anorexia nervosa

Author

Boraska, V, Franklin, CS, Floyd, JAB, Thornton, LM, Huckins, LM, Southam, L, Rayner, NW, Tachmazidou, I, Klump, KL, Treasure, J, Lewis, CM, Schmidt, U, Tozzi, F, Kiezebrink, K, Hebebrand, J, Gorwood, P, Adan, RAH, Kas, MJH, Favaro, A, Santonastaso, P, Fernández-Aranda, F, Gratacos, M, Rybakowski, F, Dmitrzak-Weglarz, M, Kaprio, J, Keski-Rahkonen, A, Raevuori, A, Van Furth, EF, Slof-Op 't Landt, MCT, Hudson, JI, Reichborn-Kjennerud, T, Knudsen, GPS, Monteleone, P, Kaplan, AS, Karwautz, A, Hakonarson, H, Berrettini, WH, Guo, Y, Li, D, Schork, NJ, Komaki, G, Ando, T, Inoko, H, Esko, T, Fischer, K, Männik, K, Metspalu, A, Baker, JH, Cone, RD, Dackor, J, DeSocio, JE, Hilliard, CE, O'Toole, JK, Pantel, J, Szatkiewicz, JP, Taico, C, Zerwas, S, Trace, SE, Davis, OSP, 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, MK, Danner, UN, de Kovel, C, Hendriks, J, Koeleman, BPC, Ophoff, RA, Strengman, E, van Elburg, AA, 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, PE, Tortorella, A, and Maj, M

Subjects
Anorexia, Mental Health, Serious Mental Illness, Human Genome, Eating Disorders, Clinical Research, Genetics, Aetiology, 2.1 Biological and endogenous factors, Anorexia Nervosa, Asian People, Calcineurin, Carrier Proteins, Case-Control Studies, Cullin Proteins, Female, Genome-Wide Association Study, Guanine Nucleotide Exchange Factors, Humans, Japan, Male, Meta-Analysis as Topic, Nuclear Proteins, Polymorphism, Single Nucleotide, White People, anorexia nervosa, body mass index, eating disorders, genome-wide association study, GWAS, metabolic, Wellcome Trust Case Control Consortium 3, Biological Sciences, Medical and Health Sciences, Psychology and Cognitive Sciences, Psychiatry
Abstract

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

Published
2014

2. Mapping brain asymmetry in health and disease through the ENIGMA consortium

Author

Kong, X-Z, Postema, MC, Guadalupe, T, de Kovel, C, Boedhoe, PSW, Hoogman, M, Mathias, SR, van Rooij, D, Schijven, D, Glahn, DC, Medland, SE, Jahanshad, N, Thomopoulos, S, Turner, JA, Buitelaar, J, van Erp, TGM, Franke, B, Fisher, SE, van den Heuvel, OA, Schmaal, L, Thompson, PM, Francks, C, Kong, X-Z, Postema, MC, Guadalupe, T, de Kovel, C, Boedhoe, PSW, Hoogman, M, Mathias, SR, van Rooij, D, Schijven, D, Glahn, DC, Medland, SE, Jahanshad, N, Thomopoulos, S, Turner, JA, Buitelaar, J, van Erp, TGM, Franke, B, Fisher, SE, van den Heuvel, OA, Schmaal, L, Thompson, PM, and Francks, C

Abstract

Left-right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last 4 years, the ENIGMA-Laterality Working Group has published six studies of gray matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population-level mapping of average asymmetry was achieved, including an intriguing fronto-occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA's multi-dataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for gray matter asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders: autism spectrum disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; pediatric obsessive-compulsive disorder was associated with altered subcortical asymmetry; major depressive disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders.

Published
2022

5. 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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6. 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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7. Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-B signalling

Author

Trynka, G., Zhernakova, A., Romanos, J., Franke, L., Hunt, K.A., Turner, G., Bruinenberg, M., Heap, G.A., Platteel, M., Ryan, A.W., de Kovel, C., Holmes, G.K.T., Howdle, P.D., Walters, J.R.F., Sanders, D.S., Mulder, C.J.J., Mearin, M.L., Verbeek, W.H.M., Trimble, V., Stevens, F.M., Kelleher, D., Barisani, D., Bardella, M.T., McManus, R., van Heel, D.A., and Wijmenga, C.

Subjects
Cellular signal transduction -- Research, Celiac disease -- Genetic aspects, Celiac disease -- Risk factors, Celiac disease -- Research, Histocompatibility antigens -- Genetic aspects, Histocompatibility antigens -- Research, HLA histocompatibility antigens -- Genetic aspects, HLA histocompatibility antigens -- Research, Genetic variation -- Research, Health
Published
2009

8. 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
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10. 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

15. KCNB1 MUTATIONS ARE CAUSING A NEURODEVELOPMENTAL DISORDER INCLUDING EPILEPSY AND AUTISM

Author

Conlin, L., Krock, B., Thiffault, I., Pendziwiat, M., Desai, S., Schonewolf-Greulich, B., Syrbe, S., de Kovel, C. G. F., Bayat, A., Naidu, S., Bergqvist, C., Rajagopalan, R., Verbeek, N., Brilstra, E. H., Jayaraman, V., Srivastava, S., Caglayan, H., Dubbs, H., Plugge, S., van den Boogaardt, M-J., Lemke, J. R., Borggraefe, I., Polster, T., Moller, R. S., Helbig, I., Kerr, B., Kessler, S., Marsh, E., Goldberg, E., Saunders, C., Rook, M., Yis, U., Koeleman, B. P. C., Gardella, E., Larsen, L. H. G., Svaneby, D., and Rokkjaer, M.

Published
2017

16. Exon-disrupting deletions ofNRXN1in idiopathic generalized epilepsy

Author

Møller, R.S., Weber, Y.G., Klitten, L.L., Trucks, H., Muhle, H., Kunz, W.S., Mefford, H.C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I.M., Wichmann, H.E., Ernst, J.P., Schurmann, C., Grabe, H.J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D.B., Lehesjoki, A.E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M.R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C.E., Kleefuß Lie, A.A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K.M., Reif, P.S., Oertel, W.H., Hamer, H.M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M.T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B.P.C., De Kovel, C., Lindhout, D., De Haan, G.J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., R. S. Møller, Y. G. Weber, L. L. Klitten, H. Truck, H. Muhle, W. S. Kunz, H. C. Mefford, A. Franke, M. Kautza, P. Wolf, D. Dennig, S. Schreiber, I. Rückert, H. Wichmann, J. P. Ernst, C. Schurmann, H. J. Grabe, N. Tommerup, U. Stephani, H. Lerche, H. Hjalgrim, I. Helbig, T. Sander, P. Tinuper, F. Bisulli, EPICURE Consortium, Suls, Arvid, Weckhuysen, Sarah, Claes, Godelieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Jordanova, Albena, Møller, R, Weber, Yg, Klitten, Ll, Trucks, H, Muhle, H, Kunz, W, Mefford, Hc, Franke, A, Kautza, M, Wolf, P, Dennig, D, Schreiber, S, Rückert, Im, Wichmann, He, Ernst, Jp, Schurmann, C, Grabe, Hj, Tommerup, N, Stephani, U, Lerche, H, Hjalgrim, H, Helbig, I, Sander, T, Epicure, Consortium, DEL GIUDICE, Ennio, Coppola, Antonietta, and YÜCESAN, EMRAH

Subjects
Male, Idiopathic generalized epilepsy, Neuronal, Idiopathic Generalized Epilepsy, 1q21, 1 Microdeletion, Two-hit Hypothesis, Nrxn1, Neuropsychological Tests, Immunoglobulin E, Cell Adhesion Molecules, Neuronal/genetics, Adult, Age of Onset, Anticonvulsant, Exon, 1q21.1 microdeletion, Exons/genetics, Odds Ratio, Nerve Tissue Proteins/genetics, Copy-number variation, Valproic Acid/therapeutic use, Age of Onset, Neural Cell Adhesion Molecules, genetics, DNA Copy Number Variations, Electroencephalography, Epilepsy, Genetics, biology, Triazines, Anticonvulsants/therapeutic use, Electroencephalography, genetics, Family, Female, Fructose, Exons, Middle Aged, Settore MED/39 - Neuropsichiatria Infantile, Pedigree, therapeutic use, Valproic Acid, Neurology, Settore MED/26 - Neurologia, Anticonvulsants, Epilepsy, Generalized, Female, Adult, Case-Control Studies, Cell Adhesion Molecules, Neuronal, DNA Copy Number Variations, Family, Fructose, Gene Deletion, Genotype, Humans, Infant, Microarray Analysis, Nerve Tissue Proteins, Valproic Acid, analogs /&/ derivatives/therapeutic use, Gene Deletion, Genotype, Humans, Infant, Male, Microarray Analysis, Middle Aged, Nerve Tissue Protein, therapeutic use, Case-Control Studies, Cell Adhesion Molecule, drug therapy/genetics/psychology, Exon, genetics, Neuropsychological Tests, Odds Ratio, Pedigree, Triazine, Lamotrigine, NRXN1, Topiramate, Epilepsy, Generalized/drug therapy, medicine, Allele, Biology, Gene, Generalized, Point mutation, Calcium-Binding Proteins, Odds ratio, medicine.disease, Triazines/therapeutic use, Settore MED/03 - Genetica Medica, therapeutic use, biology.protein, Fructose/analogs & derivatives, Human medicine, Neurology (clinical), Two-hit hypothesis
Abstract

Summary Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92–51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

Published
2013
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17. 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, Angela, Santonastaso, Paolo, 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, Alice, Clementi, Maurizio, Degortes, Daniela, Forzan, Monica, Tenconi, Elena, 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., Anderson, Carl A., Barrett, Jeffrey C., Floyd, James A. B., Franklin, Christopher S., Ralph, Mcginnis, Nicole, Soranzo, Eleftheria, Zeggini, Jennifer, Sambrook, Jonathan, Stephens, Ouwehand, Willem H., Mcardle, Wendy L., Ring, Susan M., Strachan, David P., Graeme, Alexander, Bulik, Cynthia M., Collier, David A., Conlon, Peter J., Anna, Dominiczak, Audrey, Duncanson, Adrian, Hill, Cordelia, Langford, Graham, Lord, Maxwell, Alexander P., Linda, Morgan, Leena, Peltonen, Sandford, Richard N., Neil, Sheerin, Vannberg, Fredrik O., Hannah, Blackburn, Wei Min Chen, Sarah, Edkins, Mathew, Gillman, Emma, Gray, Hunt, Sarah E., Suna Onengut Gumuscu, Simon, Potter, Rich, Stephen S., Douglas, Simpkin, Pamela, Whittaker, Estivill, X., Hinney, A., Sullivan, P. F., Collier, D. A., Zeggini, E., Bulik, C. M., Boraska, V., Franklin, Christopher S., Floyd, James 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, Nicole, 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, Leena, Ritchie, G. R. S., Barrett, Jeffrey C., Anderson, Carl A., Mcginnis, Ralph, Zeggini, Eleftheria, Sambrook, Jennifer, Stephens, Jonathan, Ouwehand, Willem H., Mcardle, Wendy L., Ring, Susan M., Strachan, David P., Alexander, Graeme, Bulik, C. M., Collier, David A., Conlon, Peter J., Dominiczak, Anna, Duncanson, Audrey, Hill, Adrian, Langford, Cordelia, Lord, Graham, Maxwell, Alexander P., Morgan, Linda, Sandford, Richard N., Sheerin, Neil, Vannberg, Fredrik O., Blackburn, Hannah, Chen, Wei-Min, Edkins, Sarah, Gillman, Mathew, Gray, Emma, Hunt, Sarah E., Onengut-Gumuscu, Suna, Potter, Simon, Rich, Stephen S., Simpkin, Dougla, Whittaker, Pamela, Estivill, X., Hinney, A., Sullivan, P. F., Martaskova D., Wellcome Trust Case Control Consortium 3, Anderson, CA., Barrett, JC., Floyd, JA., Franklin, CS., McGinnis, R., Soranzo, N., Zeggini, E., Sambrook, J., Stephens, J., Ouwehand, WH., McArdle, WL., Ring, SM., Strachan, DP., Alexander, G., Bulik, CM., Collier, DA., Conlon, PJ., Dominiczak, A., Duncanson, A., Hill, A., Langford, C., Lord, G., Maxwell, AP., Morgan, L., Peltonen, L., Sandford, RN., Sheerin, N., Vannberg, FO., Blackburn, H., Chen, WM., Edkins, S., Gillman, M., Gray, E., Hunt, SE., Onengut-Gumuscu, S., Potter, S., Rich, SS., Simpkin, D., and Whittaker, P.

Subjects
Male, Candidate gene, Anorexia Nervosa, Medizin, Genome-wide association study, anorexia nervosa, body mass index, eating disorders, genome-wide association study, GWAS, metabolic, Japan, Settore MED/14 - NEFROLOGIA, Guanine Nucleotide Exchange Factors, genome wide association study, Nuclear Protein, Genetics, Calcineurin, Eating disorder, Anorèxia nerviosa, Nuclear Proteins, Genomics, Cullin Proteins, 3. Good health, Anorexia, VDP::Midical sciences: 700::Basic medical, dental and veterinary sciences: 710::Medical genetics: 714, Anorexia nervosa (differential diagnoses), Psychiatry and Mental Health, Female, Case-Control Studie, Human, Asian Continental Ancestry Group, European Continental Ancestry Group, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, White People, Cellular and Molecular Neuroscience, Asian People, Meta-Analysis as Topic, Genetic linkage, Humans, Genotyping, Molecular Biology, anorexia nervosa, body mass index, eating disorders, genome wide association study, GWAS, metabolic, Cullin Protein, Case-control study, Anorexia nervosa, VDP::Medisinske fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714, Guanine Nucleotide Exchange Factor, Genòmica, Case-Control Studies, Carrier Protein, Carrier Proteins, Body mass index, Genome-Wide Association Study
Abstract

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P = 3.01 x 10(-7)) in SOX2OT and rs17030795 (P = 5.84 x 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P = 5.76 x 10(-6)) between CUL3 and FAM124B and rs1886797 (P = 8.05 x 10(-6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4x10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

Published
2014

18. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia

Author

Hardies, K., De Kovel, C. G. F., Weckhuysen, S., Asselbergh, B., Geuens, T., Deconinck, T., Azmi, A., May, P., Brilstra, E., Becker, F., Barisic, N., Craiu, D., Braun, K. P. J., Lal, D., Thiele, H., Schubert, J., Weber, Y., Van 'T Slot, R., Nurnberg, P., Balling, R., Timmerman, V., Lerche, H., Maudsley, S., Helbig, I., Suls, A., Koeleman, B. P. C., De Jonghe, P., Afawi, Z., Baulac, S., Caglayan, H., Lopez, R. G., Guerrini, R., Hjalgrim, H., Jahn, J., Klein, K. M., Leguern, E., Lemke, J., Marini, C., Muhle, H., Rosenow, F., Serratosa, J., Sterbova, K., Moller, R. S., Striano, P., Zara, F., and EuroEPINOMICS RES Consortium

Subjects
Male, medicine.medical_specialty, Adolescent, anaplerosis, epileptic encephalopathy, NaCT, recessive disorder, SLC13A5, teeth hypoplasia, medicine.medical_treatment, Developmental Disabilities, Mutant, Genes, Recessive, Biology, medicine.disease_cause, Citric Acid, Epilepsy, Internal medicine, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Child, Gene, Anodontia, Genetics, Mutation, Brain Diseases, Symporters, Citrate transport, medicine.disease, Hypoplasia, Pedigree, Endocrinology, HEK293 Cells, Epilepsy syndromes, Female, Neurology (clinical), Human medicine, Ketogenic diet
Abstract

The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder.

Published
2015
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19. Erratum: Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy (Epilepsia (2013) 54 (256-264) DOI:10.1111/epi.12517)

Author

Møller, R. S., Weber, Y. G., Klitten, L. L., Trucks, H., Muhle, H., Kunz, W. S., Mefford, H. C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I. -M., Wichmann, H. -E., Ernst, J. P., Schurmann, C., Grabe, H. J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D. B., Lehesjoki, A. -E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M. R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C. E., Kleefuß-Lie, A. A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K. M., Reif, P. S., Oertel, W. H., Hamer, H. M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M. T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B. P. C., De Kovel, C., Lindhout, D., De Haan, G. -J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., Møller, R. S., Weber, Y. G., Klitten, L. L., Trucks, H., Muhle, H., Kunz, W. S., Mefford, H. C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I. -M., Wichmann, H. -E., Ernst, J. P., Schurmann, C., Grabe, H. J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D. B., Lehesjoki, A. -E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M. R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C. E., Kleefuß-Lie, A. A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K. M., Reif, P. S., Oertel, W. H., Hamer, H. M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M. T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B. P. C., De Kovel, C., Lindhout, D., De Haan, G. -J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., and Agan, K.

Published
2013

20. Erythematous nodes, urticarial rash and arthralgias in a large pedigree with NLRC4-related autoinflammatory disease, expansion of the phenotype

Author

Volker-Touw, C. M L, de Koning, H. D., Giltay, J. C., de Kovel, C. G F, van Kempen, T. S., Oberndorff, K. M E J, Boes, M. L., van Steensel, M. A M, van Well, G. T J, Blokx, W. A M, Schalkwijk, J., Simon, A., Frenkel, J., van Gijn, M. E., Volker-Touw, C. M L, de Koning, H. D., Giltay, J. C., de Kovel, C. G F, van Kempen, T. S., Oberndorff, K. M E J, Boes, M. L., van Steensel, M. A M, van Well, G. T J, Blokx, W. A M, Schalkwijk, J., Simon, A., Frenkel, J., and van Gijn, M. E.

Published
2017

21. Genetic and phenotypic dissection of 1q43q44 microdeletion syndrome and neurodevelopmental phenotypes associated with mutations in ZBTB18 and HNRNPU

Author

Depienne, C, Nava, C, Keren, B, Heide, S, Rastetter, A, Passemard, S, Chantot-Bastaraud, S, Moutard, M-L, Agrawal, PB, VanNoy, G, Stoler, JM, Amor, DJ, de Villemeur, TB, Doummar, D, Alby, C, Cormier-Daire, V, Garel, C, Marzin, P, Scheidecker, S, de Saint-Martin, A, Hirsch, E, Korff, C, Bottani, A, Faivre, L, Verloes, A, Orzechowski, C, Burglen, L, Leheup, B, Roume, J, Andrieux, J, Sheth, F, Datar, C, Parker, MJ, Pasquier, L, Odent, S, Naudion, S, Delrue, M-A, Le Caignec, C, Vincent, M, Isidor, B, Renaldo, F, Stewart, F, Toutain, A, Koehler, U, Hackl, B, von Stulpnagel, C, Kluger, G, Moller, RS, Pal, D, Jonson, T, Soller, M, Verbeek, NE, van Haelst, MM, de Kovel, C, Koeleman, B, Monroe, G, van Haaften, G, Study, DDD, Attie-Bitach, T, Boutaud, L, Heron, D, Mignot, C, Depienne, C, Nava, C, Keren, B, Heide, S, Rastetter, A, Passemard, S, Chantot-Bastaraud, S, Moutard, M-L, Agrawal, PB, VanNoy, G, Stoler, JM, Amor, DJ, de Villemeur, TB, Doummar, D, Alby, C, Cormier-Daire, V, Garel, C, Marzin, P, Scheidecker, S, de Saint-Martin, A, Hirsch, E, Korff, C, Bottani, A, Faivre, L, Verloes, A, Orzechowski, C, Burglen, L, Leheup, B, Roume, J, Andrieux, J, Sheth, F, Datar, C, Parker, MJ, Pasquier, L, Odent, S, Naudion, S, Delrue, M-A, Le Caignec, C, Vincent, M, Isidor, B, Renaldo, F, Stewart, F, Toutain, A, Koehler, U, Hackl, B, von Stulpnagel, C, Kluger, G, Moller, RS, Pal, D, Jonson, T, Soller, M, Verbeek, NE, van Haelst, MM, de Kovel, C, Koeleman, B, Monroe, G, van Haaften, G, Study, DDD, Attie-Bitach, T, Boutaud, L, Heron, D, and Mignot, C

Abstract

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.

Published
2017

22. Erythematous nodes, urticarial rash and arthralgias in a large pedigree with NLRC4-related autoinflammatory disease, expansion of the phenotype

Author

Genetica Klinische Genetica, Child Health, Genetica Groep Koeleman, Translationele immunologie, Infection & Immunity, Immuno/reuma onderzoek 2 (Boes), CTI Boes, Arts-assistenten Kinderen, Genetica Sectie Genoomdiagnostiek, Volker-Touw, C. M L, de Koning, H. D., Giltay, J. C., de Kovel, C. G F, van Kempen, T. S., Oberndorff, K. M E J, Boes, M. L., van Steensel, M. A M, van Well, G. T J, Blokx, W. A M, Schalkwijk, J., Simon, A., Frenkel, J., van Gijn, M. E., Genetica Klinische Genetica, Child Health, Genetica Groep Koeleman, Translationele immunologie, Infection & Immunity, Immuno/reuma onderzoek 2 (Boes), CTI Boes, Arts-assistenten Kinderen, Genetica Sectie Genoomdiagnostiek, Volker-Touw, C. M L, de Koning, H. D., Giltay, J. C., de Kovel, C. G F, van Kempen, T. S., Oberndorff, K. M E J, Boes, M. L., van Steensel, M. A M, van Well, G. T J, Blokx, W. A M, Schalkwijk, J., Simon, A., Frenkel, J., and van Gijn, M. E.

Published
2017

23. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

Author

Schubert, J., Siekierska, A., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J. R., de Kovel, C. G. F., Thiele, H., Konrad, K., Kawalia, A., Toliat, M. R., Sander, T., Ruschendorf, F., Caliebe, A., Nagel, I., Kohl, B., Kecskes, A., Jacmin, M., Hardies, K., Weckhuysen, S., Riesch, E., Dorn, T., Brilstra, E. H., Baulac, S., Moller, R. S., Hjalgrim, H., Koeleman, B. P. C., Jurkat-Rott, K., Lehman-Horn, F., Roach, J. C., Glusman, G., Hood, L., Galas, D. J., Martin, B., de Witte, P. A. M., Biskup, S., De Jonghe, P., Helbig, I., Balling, R., Nurnberg, P., Crawford, A. D., Esguerra, C. V., Weber, Y. G., Lerche, H., Euro, Epinomics R. E. S. Consortium, EuroEPINOMICS RES Consortium, [GIN] Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Institute for Systems Biology [Seattle] (ISB), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurogenetics Group, Institut für Humangenetik, Universität Heidelberg [Heidelberg], Cologne Center for Genomics (CCG), University of Cologne, Department of Molecular and Developmental Genetics (VIB11), Flanders institute of biotechnology, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Medical Genetics Laboratory, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratory of Pharmaceutical Biology, Faculty of Pharmaceutical Sciences Lueven Belgium, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Center for Genomics and Transcriptomics (CEGAT), Antwerp University Hospital [Edegem] (UZA), Children’s Hospital of Philadelphia (CHOP ), Cologne Center for Genomics, University of Cologne, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Heidelberg [Heidelberg] = Heidelberg University, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Genetic Linkage, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Syntaxin 1, medicine.disease_cause, Epilepsy/genetics, Cohort Studies, Epilepsy, 0302 clinical medicine, Syntaxin 1/genetics, Missense mutation, Exome, ComputingMilieux_MISCELLANEOUS, In Situ Hybridization, Fluorescence, Zebrafish, Genetics, 0303 health sciences, Mutation, Comparative Genomic Hybridization, Temperature, PAROXYSMAL KINESIGENIC DYSKINESIA SYNAPTIC VESICLE FUSION DE-NOVO MUTATIONS FEBRILE SEIZURES INFANTILE CONVULSIONS GENERALIZED EPILEPSY PRRT2 MUTATIONS GENERATION DISORDERS ZEBRAFISH, Pedigree, Phenotype, Codon, Nonsense, Female, Molecular Sequence Data, Biology, Polymorphism, Single Nucleotide, Seizures, Febrile, 03 medical and health sciences, SCN1B, medicine, Animals, Humans, Amino Acid Sequence, Seizures, Febrile/genetics, Generalized epilepsy, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Sequence Analysis, DNA, Paroxysmal dyskinesia, medicine.disease, Epilepsy syndromes, Human medicine, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Gene Deletion
Abstract

Febrile seizures affect 2-4% of all children(1) and have a strong genetic component(2). Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)(3-5) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B(6), that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees(7,8) identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.

Published
2014
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24. 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. Anderson, C.A. McGinnis, R. Zeggini, E. Sambrook, J. Stephens, J. Ouwehand, W.H. McArdle, W.L. Ring, S.M. Strachan, D.P. Alexander, G. Bulik, C.M. Collier, D.A. Conlon, P.J. Dominiczak, A. Duncanson, A. Hill, A. Langford, C. Lord, G. Maxwell, A.P. Morgan, L. Sandford, R.N. Sheerin, N. Vannberg, F.O. Blackburn, H. Chen, W.-M. Edkins, S. Gillman, M. Gray, E. Hunt, S.E. Onengut-Gumuscu, S. Potter, S. Rich, S.S. Simpkin, D. Whittaker, P. Estivill, X. Hinney, A. Sullivan, P.F. The Wellcome Trust Case Control Consortium 3

Abstract

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P = 3.01 × 10-7) in SOX2OT and rs17030795 (P = 5.84 × 10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P = 5.76 × 10-6) between CUL3 and FAM124B and rs1886797 (P = 8.05 × 10-6) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P = 4 × 10-6), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. © 2014 Macmillan Publishers Limited All rights reserved.

Published
2014

25. Using ancestry-informative markers to identify fine structure across 15 populations of European origin

Author

Huckins, L.M. Boraska, V. Franklin, C.S. Floyd, J.A.B. Southam, L. Sullivan, P.F. Bulik, C.M. Collier, D.A. Tyler-Smith, C. Zeggini, E. Tachmazidou, I. Thornton, L.M. William Rayner, N. Klump, K.L. Treasure, J. 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, 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. Finan, C. Kalsi, G. Roberts, M. Logan, D.W. Peltonen, L. Ritchie, G.R.S. Courtet, P. Guillame, S. Jaussent, I. Barrett, J.C. Estivill, X. Hinney, A. Bulik, C.M. McGinnis, R. Sambrook, J. Stephens, J. Ouwehand, W.H. McArdle, W.L. Ring, S.M. Strachan, D.P. Alexander, G. Conlon, P.J. Dominiczak, A. Anderson, C.A. Hill, A. Langford, C. Lord, G. Maxwell, A.P. Morgan, L. Sandford, R.N. Sheerin, N. Vannberg, F.O. Blackburn, H. Chen, W.-M. Edkins, S. Gillman, M. Gray, E. Hunt, S.E. Onengut-Gumuscu, S. Potter, S. Rich, S.S. Simpkin, D. Whittaker, P.

Abstract

The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify population structure in such studies using only common variants with minor allele frequency (MAF) >5%; we find that this may result in highly informative SNPs being discarded, and suggest that instead all SNPs with MAF >1% may be used. We established informative axes of variation identified via principal component analysis and highlight important features of the genetic structure of diverse European-descent populations, some studied for the first time at this scale. Finally, we investigated the substructure within each of these 15 populations and identified SNPs that help capture hidden stratification. This work can provide information regarding the designing and interpretation of association results in the International Consortia. © 2014 Macmillan Publishers Limited All rights reserved.

Published
2014

27. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies

Author

EPICURE Consortium, Leu C., de Kovel C. G., Zara F., Striano P., Pezzella M., Robbiano A., Bianchi A., Coppola A., Giallonardo A. T., Beccaria F., Trenité D. K., Lindhout D., Gaus V., Schmitz B., Janz D., Weber Y. G., Becker F., Lerche H., Kleefuss Lie A. A., Hallman K., Kunz W. S., Elger C. E., Muhle H., Stephani U., Møller R. S., Hjalgrim H., Mullen S., Scheffer I. E., Berkovic S. F., Everett K. V., Gardiner M. R., Marini C., Guerrini R., Lehesjoki A. E., Siren A., Nabbout R., Baulac S., Leguern E., Serratosa J. M., Rosenow F., Feucht M., Unterberger I., Covanis A., Suls A., Weckhuysen S., Kaneva R., Caglayan H., Turkdogan D., Baykan B., Bebek N., Ozbek U., Hempelmann A., Schulz H., Rüschendorf F., Trucks H., Nürnberg P., Avanzini G., Koeleman B. P., Sander T., BISULLI, FRANCESCA, TINUPER, PAOLO, YÜCESAN, EMRAH, EPICURE Consortium, Leu C., de Kovel C.G., Zara F., Striano P., Pezzella M., Robbiano A., Bianchi A., Bisulli F., Coppola A., Giallonardo A.T., Beccaria F., Trenité D.K., Lindhout D., Gaus V., Schmitz B., Janz D., Weber Y.G., Becker F., Lerche H., Kleefuss-Lie A.A., Hallman K., Kunz W.S., Elger C.E., Muhle H., Stephani U., Møller R.S., Hjalgrim H., Mullen S., Scheffer I.E., Berkovic S.F., Everett K.V., Gardiner M.R., Marini C., Guerrini R., Lehesjoki A.E., Siren A., Nabbout R., Baulac S., Leguern E., Serratosa J.M., Rosenow F., Feucht M., Unterberger I., Covanis A., Suls A., Weckhuysen S., Kaneva R., Caglayan H., Turkdogan D., Baykan B., Bebek N., Ozbek U., Hempelmann A., Schulz H., Rüschendorf F., Trucks H., Nürnberg P., Avanzini G., Koeleman B.P., Sander T., and Tinuper P.

Subjects
Male, Chromosomes, Human, Pair 13, Genotype, Genetic Linkage, Chromosome Mapping, complex inheritance, Pedigree, genetic generalized epilepsy, myoclonic seizure, Phenotype, Genetic Loci, Chromosomes, Human, Pair 2, Humans, Epilepsy, Generalized, Family, Female, Genetic Predisposition to Disease, linkage analysis, absence seizure, Genome-Wide Association Study
Abstract

PURPOSE: Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively. METHODS: Meta-analysis of three genome-wide linkage datasets was carried out in 379 GGE-multiplex families of European ancestry including 982 relatives with GGEs. To dissect out seizure type-related susceptibility genes, two family subgroups were stratified comprising 235 families with predominantly genetic absence epilepsies (GAEs) and 118 families with an aggregation of juvenile myoclonic epilepsy (JME). To map shared and seizure type-related susceptibility loci, both nonparametric loci (NPL) and parametric linkage analyses were performed for a broad trait model (GGEs) in the entire set of GGE-multiplex families and a narrow trait model (typical absence or myoclonic seizures) in the subgroups of JME and GAE families. KEY FINDINGS: For the entire set of 379 GGE-multiplex families, linkage analysis revealed six loci achieving suggestive evidence for linkage at 1p36.22, 3p14.2, 5q34, 13q12.12, 13q31.3, and 19q13.42. The linkage finding at 5q34 was consistently supported by both NPL and parametric linkage results across all three family groups. A genome-wide significant nonparametric logarithm of odds score of 3.43 was obtained at 2q34 in 118 JME families. Significant parametric linkage to 13q31.3 was found in 235 GAE families assuming recessive inheritance (heterogeneity logarithm of odds = 5.02). SIGNIFICANCE: Our linkage results support an oligogenic predisposition of familial GGE syndromes. The genetic risk factor at 5q34 confers risk to a broad spectrum of familial GGE syndromes, whereas susceptibility loci at 2q34 and 13q31.3 preferentially predispose to myoclonic seizures or absence seizures, respectively. Phenotype- genotype strategies applying narrow trait definitions in phenotypic homogeneous subgroups of families improve the prospects of disentangling the genetic basis of common familial GGE syndromes.

Published
2012

28. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1,2q22.3 and 17q21.32

Author

Steffens, M., Leu, C., Ruppert, A., Zara, F., Striano, P., Robbiano, A., Capovilla, G., Tinuper, P., Gambardella, A., Bianchi, A., La neve, A., Crichiutti, G., de kovel, C. G., Trenité, D. K. -N., de haan, G., Lindhout, D., Gaus, V., Schmitz, B., Janz, D., Weber, Y. G., Becker, F., Lerche, H., Steinhoff, B. J., Kleefuß-Lie, A. A., Kunz, W. S., Surges, R., Elger, C. E., Muhle, H., Von spiczak, S., Ostertag, P., Helbig, I., Stephani, U., Møller, R. S., Hjalgrim, H., Dibbens, L. M., Bellows, S., Oliver, K., Mullen, S., Scheffer, I. E., Berkovic, S. F., Everett, K. V., Gardiner, M. R., Marini, Chiara, Guerrini, R., Lehesjoki, A., Siren, A., Guipponi, M., Malafosse, A., Thomas, P., Nabbout, R., Baulac, S., Leguern, E., Guerrero, R., Serratosa, J. M., Reif, P. S., Rosenow, F., Mörzinger, M., Feucht, M., Zimprich, F., Kapser, C., Schankin, C. J., Suls, A., Smets, K., De jonghe, P., Jordanova, A., Caglayan, H., Yapici, Z., Yalcin, D. A., Baykan, B., Bebek, N., Ozbek, U., Gieger, C., Wichmann, H., Balschun, T., Ellinghaus, D., Franke, A., Meesters, C., Becker, T., Wienker, T. F., Hempelmann, A., Schulz, H., Rüschendorf, F., Leber, M., Pauck, S. M., Trucks, H., Toliat, M. R., Nürnberg, P., Avanzini, G., Koeleman, B. P., Sander, T., Weckhuysen, S., Claes, L., Deprez, L., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Lehesjoki, A. -E., von Spiczak, S., Martin Klein, K., Oertel, W. H., Hamer, H. M., Marini, C., Mei, D., Norci, V., Pezzella, M., La Neve, A., Vigliano, P., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Egeo, G., Teresa Giallonardo, M., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., de Haan, G. -J., Giraldez, B. G., Ozbeck, U., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Ozkara, C., Yalcin, O., Turkdogan, D., Dizdarer, G., Agan, K., Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Frederico, Dibbens, Leanne Michelle, Sander, Thomas, EPICURE Consortium, Epicure, Consortium, DEL GIUDICE, Ennio, Steffens, M, Leu, C, Ruppert, Ak, Zara, F, Striano, P, Robbiano, A., Coppola, Antonietta, E. P. I. C. U. R. E. Consortium, E. M. I.Net Consortium, M. Steffen, C. Leu, A. Ruppert, F. Zara, P. Striano, A. Robbiano, G. Capovilla, P. Tinuper, A. Gambardella, A. Bianchi, A. L. Neve, G. Crichiutti, C. G. F, D. K. Trenité, G. d. Haan, D. Lindhout, V. Gau, B. Schmitz, D. Janz, Y. G. Weber, F. Becker, H. Lerche, B. J. Steinhoff, A. A. Kleefuß-Lie, W. S. Kunz, R. Surge, C. E. Elger, H. Muhle, S. v. Spiczak, P. Ostertag, I. Helbig, U. Stephani, R. S. Møller, H. Hjalgrim, L. M. Dibben, S. Bellow, K. Oliver, S. Mullen, I. E. Scheffer, S. F. Berkovic, K. V. Everett, M. R. Gardiner, C. Marini, R. Guerrini, A. Lehesjoki, A. Siren, M. Guipponi, A. Malafosse, P. Thoma, R. Nabbout, S. Baulac, E. Leguern, R. Guerrero, J. M. Serratosa, P. S. Reif, F. Rosenow, M. Mörzinger, M. Feucht, F. Zimprich, C. Kapser, C. J. Schankin, A. Sul, K. Smet, P. D. Jonghe, A. Jordanova, H. Caglayan, Z. Yapici, D. A. Yalcin, B. Baykan, N. Bebek, U. Ozbek, C. Gieger, H. Wichmann, T. Balschun, D. Ellinghau, A. Franke, C. Meester, T. Becker, T. F. Wienker, A. Hempelmann, H. Schulz, F. Rüschendorf, M. Leber, S. M. Pauck, H. Truck, M. R. Toliat, P. Nürnberg, G. Avanzini, B. P. C, and T. Sander

Subjects
Candidate gene, Juvenile, Genome-wide association study, Alleles, Epilepsy, ZEB2 protein, human, VRK2 protein, human, 0302 clinical medicine, genetics [Genetic Predisposition to Disease], genetics, Humans, Myoclonic Epilepsy, genetics [Epilepsy, Generalized], SCN1A protein, human, Genetics (clinical), Genetics, 0303 health sciences, genetics [Epilepsy, Absence], Myoclonic Epilepsy, Juvenile, genetics, Genetic Predisposition to Disease, General Medicine, Protein-Serine-Threonine Kinases, 3. Good health, Chemistry, Absence, genetics, Epilepsy, genetics [Myoclonic Epilepsy, Juvenile], Epilepsy, Generalized, genetics [Receptor, Muscarinic M3], genetics, NAV1.1 Voltage-Gated Sodium Channel, genetics [Homeodomain Proteins], Single-nucleotide polymorphism, genetics [NAV1.1 Voltage-Gated Sodium Channel], Protein Serine-Threonine Kinases, Biology, genetics [Protein-Serine-Threonine Kinases], 03 medical and health sciences, ddc:570, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, genetics, Repressor Protein, Allele, Molecular Biology, Alleles, Zinc Finger E-box Binding Homeobox 2, 030304 developmental biology, Homeodomain Proteins, Receptor, Muscarinic M3, genetics, Protein-Serine-Threonine Kinase, genetics, Receptor, Generalized, genetics, Genome-Wide Association Study, Homeodomain Protein, Heritability, medicine.disease, NAV1.1 Voltage-Gated Sodium Channel, Repressor Proteins, genetics [Repressor Proteins], Muscarinic M3, Epilepsy, Absence, Myoclonic epilepsy, Human medicine, Juvenile myoclonic epilepsy, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3\% and account for 20-30\% of all epilepsies. Despite their high heritability of 80\%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Published
2012
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29. 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, Gonzalez-Alvaro, Isidoro, Angel Gonzalez-Gay, Miguel, Gomez-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., Koeleman, B. P. C., LifeLines Cohort Study, 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, Gonzalez-Alvaro, Isidoro, Angel Gonzalez-Gay, Miguel, Gomez-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., Koeleman, B. P. C., and LifeLines Cohort Study

Published
2015

30. MODELING OF FEVER-ASSOCIATED EPILEPSY SYNDROMES CAUSED BY MUTATIONS IN STX1B IN ZEBRAFISH

Author

Siekierska, A., Schubert, J., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J. R., De Kovel, C. G. F., Thiele, H., Kecskes, A., Jacmin, M., Koeleman, B., Martin, B., de Witte, P. A. M., Biskup, S., De Jonghe, P., Helbig, I., Balling, R., Nuernberg, P., Crawford, A. D., Weber, Y. G., Lerche, H., Esguerra, C. V., Siekierska, A., Schubert, J., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J. R., De Kovel, C. G. F., Thiele, H., Kecskes, A., Jacmin, M., Koeleman, B., Martin, B., de Witte, P. A. M., Biskup, S., De Jonghe, P., Helbig, I., Balling, R., Nuernberg, P., Crawford, A. D., Weber, Y. G., Lerche, H., and Esguerra, C. V.

Published
2015

31. A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides

Author

Genetica Groep Koeleman, Hersenen-Bedrijfsvoering, MMB, Child Health, 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, Gonzalez-Alvaro, Isidoro, Angel Gonzalez-Gay, Miguel, Gomez-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., Koeleman, B. P. C., LifeLines Cohort Study, Genetica Groep Koeleman, Hersenen-Bedrijfsvoering, MMB, Child Health, 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, Gonzalez-Alvaro, Isidoro, Angel Gonzalez-Gay, Miguel, Gomez-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., Koeleman, B. P. C., and LifeLines Cohort Study

Published
2015

34. X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face

Author

Harakalova, M., van den Boogaard, M.J., Sinke, R., van Lieshout, S., van Tuil, M.C., Duran, K., Renkens, I., Terhal, P.A., de Kovel, C., Nijman, I.J., van Haelst, M., Knoers, N.V., van Haaften, G., Kloosterman, W., Hennekam, R.C., Cuppen, E., Ploos van Amstel, H.K., Harakalova, M., van den Boogaard, M.J., Sinke, R., van Lieshout, S., van Tuil, M.C., Duran, K., Renkens, I., Terhal, P.A., de Kovel, C., Nijman, I.J., van Haelst, M., Knoers, N.V., van Haaften, G., Kloosterman, W., Hennekam, R.C., Cuppen, E., and Ploos van Amstel, H.K.

Abstract

BACKGROUND: We present a large Dutch family with seven males affected by a novel syndrome of X-linked intellectual disability, hypogonadism, gynaecomastia, truncal obesity, short stature and recognisable craniofacial manifestations resembling but not identical to Wilson-Turner syndrome. Seven female relatives show a much milder expression of the phenotype. METHODS AND RESULTS: We performed X chromosome exome (X-exome) sequencing in five individuals from this family and identified a novel intronic variant in the histone deacetylase 8 gene (HDAC8), c.164+5G>A, which disturbs the normal splicing of exon 2 resulting in exon skipping, and introduces a premature stop at the beginning of the histone deacetylase catalytic domain. The identified variant completely segregates in this family and was absent in 96 Dutch controls and available databases. Affected female carriers showed a notably skewed X-inactivation pattern in lymphocytes in which the mutated X-chromosome was completely inactivated. CONCLUSIONS: HDAC8 is a member of the protein family of histone deacetylases that play a major role in epigenetic gene silencing during development. HDAC8 specifically controls the patterning of the skull with the mouse HDAC8 knock-out showing craniofacial deformities of the skull. The present family provides the first evidence for involvement of HDAC8 in a syndromic form of intellectual disability., BACKGROUND: We present a large Dutch family with seven males affected by a novel syndrome of X-linked intellectual disability, hypogonadism, gynaecomastia, truncal obesity, short stature and recognisable craniofacial manifestations resembling but not identical to Wilson-Turner syndrome. Seven female relatives show a much milder expression of the phenotype. METHODS AND RESULTS: We performed X chromosome exome (X-exome) sequencing in five individuals from this family and identified a novel intronic variant in the histone deacetylase 8 gene (HDAC8), c.164+5G>A, which disturbs the normal splicing of exon 2 resulting in exon skipping, and introduces a premature stop at the beginning of the histone deacetylase catalytic domain. The identified variant completely segregates in this family and was absent in 96 Dutch controls and available databases. Affected female carriers showed a notably skewed X-inactivation pattern in lymphocytes in which the mutated X-chromosome was completely inactivated. CONCLUSIONS: HDAC8 is a member of the protein family of histone deacetylases that play a major role in epigenetic gene silencing during development. HDAC8 specifically controls the patterning of the skull with the mouse HDAC8 knock-out showing craniofacial deformities of the skull. The present family provides the first evidence for involvement of HDAC8 in a syndromic form of intellectual disability.

Published
2012

35. Evolutionary and Functional Analysis of Celiac Risk Loci Reveals SH2B3 as a Protective Factor against Bacterial Infection

Author

Zhernakova, A, Elbers, C, Ferwerda, B, Romanos, J, Trynka, G, Dubois, P, de Kovel, C, Franke, L, Oosting, M, Barisani, D, Bardella, M, Joosten, L, Saavalainen, P, van Heel, D, Catassi, C, Netea, M, Wijmenga, C, Elbers, CC, Dubois, PC, de Kovel, CGF, Bardella, MT, Joosten, LAB, van Heel, DA, Netea, MG, Wijmenga, C., BARISANI, DONATELLA, Zhernakova, A, Elbers, C, Ferwerda, B, Romanos, J, Trynka, G, Dubois, P, de Kovel, C, Franke, L, Oosting, M, Barisani, D, Bardella, M, Joosten, L, Saavalainen, P, van Heel, D, Catassi, C, Netea, M, Wijmenga, C, Elbers, CC, Dubois, PC, de Kovel, CGF, Bardella, MT, Joosten, LAB, van Heel, DA, Netea, MG, Wijmenga, C., and BARISANI, DONATELLA

Abstract

Celiac disease (CD) is an intolerance to dietary proteins of wheat, barley, and rye. CD may have substantial morbidity, yet it is quite common with a prevalence of 1%-2% in Western populations. It is not clear why the CD phenotype is so prevalent despite its negative effects on human health, especially because appropriate treatment in the form of a gluten-free diet has only been available since the 1950s, when dietary gluten was discovered to be the triggering factor. The high prevalence of CD might suggest that genes underlying this disease may have been favored by the process of natural selection. We assessed signatures of selection for ten confirmed CD-associated loci in several genome-wide data sets, comprising 8154 controls from four European populations and 195 individuals from a North African population, by studying haplotype lengths via the integrated haplotype score (iHS) method. Consistent signs of positive selection for CD-associated derived alleles were observed in three loci: IL12A, IL18RAP, and SH2B3. For the SH2B3 risk allele, we also show a difference in allele frequency distribution (Fst) between HapMap phase II populations. Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the SH2B3 rs3184504*A risk allele showed stronger activation of the NOD2 recognition pathway. This suggests that SH2B3 plays a role in protection against bacteria infection, and it provides a possible explanation for the selective sweep on SH2B3, which occurred sometime between 1200 and 1700 years ago.

Published
2010

36. OP0021 Genetic Factors for the Severity of ACPA-Negative Rheumatoid Arthritis in Two Cohorts of Early Disease: A Genome-Wide Study

Author

De Rooy, D., primary, Tsonaka, R., additional, Andersson, M., additional, Forslind, K., additional, Zhernakova, A., additional, de Kovel, C., additional, Koeleman, B., additional, van der Heijde, D., additional, Huizinga, T., additional, Toes, R., additional, Houwing-Duistermaat, J., additional, Svensson, B., additional, and van der Helm-van Mil, A., additional

Published
2013
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38. Effects of climate change on terrestrial ecosystems

Author

van de Geijn, S.C., Berendse, F., Bouten, W., Dijkstra, P., Gorrisen, A., Jetten, T.H., de Kovel, C., Kramer, K., Lankreijer, H., Mohren, G.M.J., Rozema, J., Schaap, M., Schapendonk, A.H.C.M., Takken, W., Veen, A.W.L., and Visser, A.

Subjects
Research Institute for Agrobiology and Soil Fertility, Life Science, Instituut voor Agrobiologisch en Bodemvruchtbaarheidsonderzoek
Published
1995

39. Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies

Author

de Kovel, C. G. F., primary, Trucks, H., additional, Helbig, I., additional, Mefford, H. C., additional, Baker, C., additional, Leu, C., additional, Kluck, C., additional, Muhle, H., additional, von Spiczak, S., additional, Ostertag, P., additional, Obermeier, T., additional, Kleefuss-Lie, A. A., additional, Hallmann, K., additional, Steffens, M., additional, Gaus, V., additional, Klein, K. M., additional, Hamer, H. M., additional, Rosenow, F., additional, Brilstra, E. H., additional, Kasteleijn-Nolst Trenite, D., additional, Swinkels, M. E. M., additional, Weber, Y. G., additional, Unterberger, I., additional, Zimprich, F., additional, Urak, L., additional, Feucht, M., additional, Fuchs, K., additional, Moller, R. S., additional, Hjalgrim, H., additional, De Jonghe, P., additional, Suls, A., additional, Ruckert, I.-M., additional, Wichmann, H.-E., additional, Franke, A., additional, Schreiber, S., additional, Nurnberg, P., additional, Elger, C. E., additional, Lerche, H., additional, Stephani, U., additional, Koeleman, B. P. C., additional, Lindhout, D., additional, Eichler, E. E., additional, and Sander, T., additional

Published
2009
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40. Association of the TGF-β receptor genes with abdominal aortic aneurysm

Author

Baas, A F, primary, Medic, J, additional, van 't Slot, R, additional, de Kovel, C G, additional, Zhernakova, A, additional, Geelkerken, R H, additional, Kranendonk, S E, additional, van Sterkenburg, S M, additional, Grobbee, D E, additional, Boll, A P, additional, Wijmenga, C, additional, Blankensteijn, J D, additional, and Ruigrok, Y M, additional

Published
2009
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41. Association of the TGF-β receptor genes with abdominal aortic aneurysm.

Author

Baas, A. F., Medic, J., van 't Slot, R., de Kovel, C. G., Zhernakova, A., Geelkerken, R. H., Kranendonk, S. E., van Sterkenburg, S. M., Grobbee, D. E., Boll, A. P., Wijmenga, C., Blankensteijn, J. D., and Ruigrok, Y. M.

Subjects
AORTIC aneurysms, ABDOMINAL aorta, THORACIC aneurysms, GENETIC polymorphisms, NUCLEOTIDES
Abstract

Abdominal aortic aneurysm (AAA) is a multifactorial condition. The transforming growth factor β (TGF-β) pathway regulates vascular remodeling and mutations in its receptor genes, TGFBR1 and TGFBR2, cause syndromes with thoracic aortic aneurysm (TAA). The TGF-β pathway may be involved in aneurysm development in general. We performed an association study by analyzing all the common genetic variants in TGFBR1 and TGFBR2 using tag single nucleotide polymorphisms (SNPs) in a Dutch AAA case–control population in a two-stage genotyping approach. In stage 1, analyzing 376 cases and 648 controls, three of the four TGFBR1 SNPs and nine of the 28 TGFBR2 SNPs had a P<0.07. Genotyping of these SNPs in an independent cohort of 360 cases and 376 controls in stage 2 confirmed association (P<0.05) for the same allele of one SNP in TGFBR1 and two SNPs in TGFBR2. Joint analysis of the 736 cases and 1024 controls showed statistically significant associations of these SNPs, which sustained after proper correction for multiple testing (TGFBR1 rs1626340 OR 1.32 95% CI 1.11–1.56 P=0.001 and TGFBR2 rs1036095 OR 1.32 95% CI 1.12–1.54 P=0.001 and rs4522809 OR 1.28 95% CI 1.12–1.46 P=0.0004). We conclude that genetic variations in TGFBR1 and TGFBR2 associate with AAA in the Dutch population. This suggests that AAA may develop partly by similar defects as TAA, which in the future may provide novel therapeutic options. [ABSTRACT FROM AUTHOR]

Published
2010
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42. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

Author

Patrick May, Simon Girard, Merle Harrer, Dheeraj R Bobbili, Julian Schubert, Stefan Wolking, Felicitas Becker, Pamela Lachance-Touchette, Caroline Meloche, Micheline Gravel, Cristina E Niturad, Julia Knaus, Carolien De Kovel, Mohamad Toliat, Anne Polvi, Michele Iacomino, Rosa Guerrero-López, Stéphanie Baulac, Carla Marini, Holger Thiele, Janine Altmüller, Kamel Jabbari, Ann-Kathrin Ruppert, Wiktor Jurkowski, Dennis Lal, Raffaella Rusconi, Sandrine Cestèle, Benedetta Terragni, Ian D Coombs, Christopher A Reid, Pasquale Striano, Hande Caglayan, Auli Siren, Kate Everett, Rikke S Møller, Helle Hjalgrim, Hiltrud Muhle, Ingo Helbig, Wolfram S Kunz, Yvonne G Weber, Sarah Weckhuysen, Peter De Jonghe, Sanjay M Sisodiya, Rima Nabbout, Silvana Franceschetti, Antonietta Coppola, Maria S Vari, Dorothée Kasteleijn-Nolst Trenité, Betul Baykan, Ugur Ozbek, Nerses Bebek, Karl M Klein, Felix Rosenow, Dang K Nguyen, François Dubeau, Lionel Carmant, Anne Lortie, Richard Desbiens, Jean-François Clément, Cécile Cieuta-Walti, Graeme J Sills, Pauls Auce, Ben Francis, Michael R Johnson, Anthony G Marson, Bianca Berghuis, Josemir W Sander, Andreja Avbersek, Mark McCormack, Gianpiero L Cavalleri, Norman Delanty, Chantal Depondt, Martin Krenn, Fritz Zimprich, Sarah Peter, Marina Nikanorova, Robert Kraaij, Jeroen van Rooij, Rudi Balling, M Arfan Ikram, André G Uitterlinden, Giuliano Avanzini, Stephanie Schorge, Steven Petrou, Massimo Mantegazza, Thomas Sander, Eric LeGuern, Jose M Serratosa, Bobby P C Koeleman, Aarno Palotie, Anna-Elina Lehesjoki, Michael Nothnagel, Peter Nürnberg, Snezana Maljevic, Federico Zara, Patrick Cossette, Roland Krause, Holger Lerche, Edoardo Ferlazzo, Carlo di Bonaventura, Angela La Neve, Paolo Tinuper, Francesca Bisulli, Aglaia Vignoli, Giuseppe Capovilla, Giovanni Crichiutti, Antonio Gambardella, Vincenzo Belcastro, Amedeo Bianchi, Destina Yalçın, Gulsen Dizdarer, Kezban Arslan, Zuhal Yapıcı, Demet Kuşcu, Costin Leu, Kristin Heggeli, Joseph Willis, Sarah R Langley, Andrea Jorgensen, Prashant Srivastava, Sarah Rau, Christian Hengsbach, Anja C.M. Sonsma, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratory of Molecular Genetics of Stem Cells [University of Montreal], University of Montreal-Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), University of Tübingen, University Medical Center [Utrecht], Universita degli studi di Genova, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), A.Meyer Children's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), University of Cologne, The Genome Analysis Centre (TGAC), Cologne Center for Genomics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Department of Neurophysiopathology, Besta Neurological Institute, University of Southern Denmark (SDU), Medical Genetics Laboratory, Children’s Hospital of Philadelphia (CHOP ), Universitätsklinikum Bonn (UKB), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituco Neurologico C. Besta, Instituto Neurologico C. Besta, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), University of Liverpool, Institute of Neurology [London], Royal College of Surgeons in Ireland (RCSI), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Medizinische Universität Wien = Medical University of Vienna, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Medical Informatics and Statistics, Pediatric Neurology and Neuromuscular Diseases Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Hertie Institute for Clinical Brain Research [Tubingen], Regional Epilepsy Center, Reggio Calabria, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Wellcome Trust, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, Internal Medicine, Epidemiology, Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Università degli studi di Genova = University of Genoa (UniGe), Heart Center Leipzig, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Acibadem University Dspace, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Nice Sophia Antipolis (... - 2019) (UNS), University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Medicum, Research Programme for Molecular Neurology, Research Programs Unit, Neuroscience Center, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, Epicure Consortium, EuroEPINOMICS COGIE Consortium, EpiPGX Consortium, May, Gabriella, Girard, S., Harrer, M., Bobbili, D. R., Schubert, J., Wolking, S., Becker, F., Lachance-Touchette, P., Meloche, C., Gravel, M., Niturad, C. E., Knaus, J., De Kovel, C., Toliat, M., Polvi, A., Iacomino, M., Guerrero-López, R., Baulac, S., Marini, C., Thiele, H., Altmüller, J., Jabbari, K., Ruppert, A. -K., Jurkowski, W., Lal, D., Rusconi, R., Cestèle, S., Terragni, B., Coombs, I. D., Reid, C. A., Striano, P., Caglayan, H., Siren, A., Everett, K., Møller, R. S., Hjalgrim, H., Muhle, H., Helbig, I., Kunz, W. S., Weber, Y. G., Weckhuysen, S., Jonghe, P. D., Sisodiya, S. M., Nabbout, R., Franceschetti, S., Coppola, A., Vari, M. S., Kasteleijn-Nolst Trenité, D., Baykan, B., Ozbek, U., Bebek, N., Klein, K. M., Rosenow, F., Nguyen, D. K., Dubeau, F., Carmant, L., Lortie, A., Desbiens, R., Clément, J. -F., Cieuta-Walti, C., Sills, G. J., Auce, P., Francis, B., Johnson, M. R., Marson, A. G., Berghuis, B., Sander, J. W., Avbersek, A., Mccormack, M., Cavalleri, G. L., Delanty, N., Depondt, C., Krenn, M., Zimprich, F., Peter, S., Nikanorova, M., Kraaij, R., van Rooij, J., Balling, R., Ikram, M. A., Uitterlinden, A. G., Avanzini, Giulio, Schorge, S., Petrou, S., Mantegazza, M., Sander, T., Leguern, E., Serratosa, J. M., Koeleman, B. P. C., Palotie, A., Lehesjoki, A. -E., Nothnagel, M., Nürnberg, P., Maljevic, S., Zara, F., Cossette, P., Krause, R., Lerche, H., De Jonghe, P., Arfan Ikram, M., Ferlazzo, E., di Bonaventura, C., La Neve, A., Tinuper, P., Bisulli, F., Vignoli, Massimo, Capovilla, G., Crichiutti, G., Gambardella, A., Belcastro, V., Bianchi, A., Yalçın, D., Dizdarer, G., Arslan, K., Yapıcı, Z., Kuşcu, D., Leu, C., Heggeli, K., Willis, J., Langley, S. R., Jorgensen, A., Srivastava, P., Rau, S., Hengsbach, C., Sonsma, A. C. M., University of Montreal-Institute for Research in Immunology and Cancer (IRIC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], Hôpital Erasme (Bruxelles), May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicita, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Denni, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, Jonghe, Peter De, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerse, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, Françoi, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-Françoi, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Paul, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M Arfan, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thoma, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, De Jonghe, Peter, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, and Sonsma, Anja C.M.

Subjects
0301 basic medicine, GAMMA-2-SUBUNIT, [SDV]Life Sciences [q-bio], GABRA5, Clinical Neurology, 15Q13.3 MICRODELETIONS, ABSENCE EPILEPSY, SEQUENCE DATA, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 3124 Neurology and psychiatry, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic variation, medicine, EPILEPTIC ENCEPHALOPATHIES, Exome, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetic association, Genetics, RISK, Science & Technology, FEBRILE SEIZURES, Neurology & Neurosurgery, biology, 3112 Neurosciences, 1103 Clinical Sciences, MOUSE MODEL, medicine.disease, ASSOCIATION ANALYSIS, 030104 developmental biology, DE-NOVO MUTATIONS, Cohort, biology.protein, Neurology (clinical), Human medicine, Neurosciences & Neurology, 1109 Neurosciences, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Cohort study
Abstract

BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).

Published
2018
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43. CHD2 variants are a risk factor for photosensitivity in epilepsy

Author

Galizia, Elizabeth C, Myers, Candace T, Leu, Costin, de Kovel, Carolien G F, Afrikanova, Tatiana, Cordero-Maldonado, Maria Lorena, Martins, Teresa G, Jacmin, Maxime, Drury, Suzanne, Krishna Chinthapalli, V, Muhle, Hiltrud, Pendziwiat, Manuela, Sander, Thomas, Ruppert, Ann-Kathrin, Møller, Rikke S, Thiele, Holger, Krause, Roland, Schubert, Julian, Lehesjoki, Anna-Elina, Nürnberg, Peter, Lerche, Holger, Palotie, Aarno, Coppola, Antonietta, Striano, Salvatore, Gaudio, Luigi Del, Boustred, Christopher, Schneider, Amy L, Lench, Nicholas, Jocic-Jakubi, Bosanka, Covanis, Athanasios, Capovilla, Giuseppe, Veggiotti, Pierangelo, Piccioli, Marta, Parisi, Pasquale, Cantonetti, Laura, Sadleir, Lynette G, Mullen, Saul A, Berkovic, Samuel F, Stephani, Ulrich, Helbig, Ingo, Crawford, Alexander D, Esguerra, Zara, Federico, Striano, Pasquale, Camila, V, Kasteleijn-Nolst Trenité, Dorothee G A, Koeleman, Bobby P C, Mefford, Heather C, Scheffer, Ingrid E, Sisodiya, Sanjay M, Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Galizia, E. C., Myers, C. T., Leu, C., De Kovel, C. G. F., Afrikanova, T., Cordero-Maldonado, M. L., Martins, T. G., Jacmin, M., Drury, S., Chinthapalli, V. K., Muhle, H., Pendziwiat, M., Sander, T., Ruppert, A. -K., Moller, R. S., Thiele, H., Krause, R., Schubert, J., Lehesjoki, A. -E., Nürnberg, P., Lerche, H., Palotie, A., Coppola, A., Striano, S., Del Gaudio, L., Boustred, C., Schneider, A. L., Lench, N., Jocic-Jakubi, B., Covanis, A., Capovilla, G., Veggiotti, P., Piccioli, M., Parisi, P., Cantonetti, L., Sadleir, L. G., Mullen, S. A., Berkovic, S. F., Stephani, U., Helbig, I., Crawford, A. D., Esguerra, C. V., Trenité, D. G. A. K. -N., Koeleman, B. P. C., Mefford, H. C., Scheffer, I. E., and Sisodiya, S. M.

Subjects
INTELLECTUAL DISABILITY, Neurology [D14] [Human health sciences], seizure, Epilepsy, Reflex, Research Support, N.I.H., Extramural, eyelid myoclonia with absences, photosensitive, animals, DNA-binding proteins, electroencephalography, epilepsy, reflex, gene knockdown techniques, humans, mutation, photic stimulation, risk factors, zebrafish, genetic predisposition to disease, Risk Factors, Reflex, Journal Article, Animals, Humans, MICRODELETION, Genetic Predisposition to Disease, JUVENILE MYOCLONIC EPILEPSY, Zebrafish, COPY NUMBER VARIANTS, Epilepsy, Neurologie [D14] [Sciences de la santé humaine], Research Support, Non-U.S. Gov't, Electroencephalography, Original Articles, GENETIC DISSECTION, FAMILY, DNA-Binding Proteins, DE-NOVO MUTATIONS, Gene Knockdown Techniques, Mutation, Photic Stimulation, LENNOX-GASTAUT SYNDROME, IDIOPATHIC GENERALIZED EPILEPSY, ENCEPHALOPATHIES
Abstract

Photosensitivity in epilepsy is common and has high heritability, but its genetic basis remains uncertain. Galizia et al. reveal an overrepresentation of unique variants of CHD2 — which encodes the transcriptional regulator ‘chromodomain helicase DNA-binding protein 2’ — in photosensitive epilepsies, and show that chd2 knockdown in zebrafish causes photosensitivity., Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2·17 × 10−5). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3·50 × 10−4). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.

Published
2015
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44. Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappa B signalling

Author

Donatella Barisani, Chris J. J. Mulder, Graham A. Heap, M.L. Mearin, Jihane Romanos, Cisca Wijmenga, Fiona M. Stevens, Gosia Trynka, Marcel Bruinenberg, David S Sanders, Graham Turner, Peter D. Howdle, Valerie Trimble, D A van Heel, Lude Franke, Wieke H. M. Verbeek, Dermot Kelleher, Alexandra Zhernakova, C. G. F. de Kovel, Karen A. Hunt, Geoffrey Holmes, Ross McManus, Julian R.F. Walters, Anthony W. Ryan, Maria Teresa Bardella, Mathieu Platteel, University of Groningen, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Gastroenterology and hepatology, Other Research, Trynka, G, Zhernakova, A, Romanos, J, Franke, L, Hunt, K, Turner, G, Bruinenberg, M, Heap, G, Platteel, M, Ryan, A, de Kovel, C, Holmes, G, Howdle, P, Walters, J, Sanders, D, Mulder, C, Mearin, M, Verbeek, W, Trimble, V, Stevens, F, Kelleher, D, Barisani, D, Bardella, M, Mcmanus, R, van Heel, D, and Wijmenga, C

Subjects
Male, Linkage disequilibrium, Genotype, Genome-wide association study, Single-nucleotide polymorphism, Human leukocyte antigen, Biology, Polymorphism, Single Nucleotide, TNFAIP3, Linkage Disequilibrium, Coeliac disease, 6Q23, REGION, INFLAMMATION, medicine, Humans, IMMUNE-RESPONSE, Genetic Predisposition to Disease, Risk factor, GENOME-WIDE ASSOCIATION, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Tumor Necrosis Factor alpha-Induced Protein 3, GENE-EXPRESSION, BIO/13 - BIOLOGIA APPLICATA, Intracellular Signaling Peptides and Proteins, NF-kappa B, Gastroenterology, Case-control study, Nuclear Proteins, celiac disease, NFkB, medicine.disease, RHEUMATOID-ARTHRITIS, DNA-Binding Proteins, Celiac Disease, A20, Case-Control Studies, Immunology, Female, Genes, rel, Signal Transduction
Abstract

Objective: Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. Design: 458 SNPs were assayed in 1682 cases and 3258 controls from three populations (UK, Irish and Dutch). We combined the results with the original GWAS cohort (767 UK cases and 1422 controls); six SNPs showed association with p

Published
2009
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45. Using ancestry-informative markers to identify fine structure across 15 populations of European origin

Author

Huckins, Laura M, Boraska, Vesna, Southam, L, Karhunen, L, Meulenbelt, I, Slagboom, P E, Tortorella, A, Maj, M, Dedoussis, G, Dikeos, D, Gonidakis, F, Tziouvas, K, Tsitsika, A, Rayner, N William, Papezova, H, Slachtova, L, Martaskova, D, Kennedy, J L, Levitan, R D, Yilmaz, Z, Huemer, J, Koubek, D, Merl, E, Wagner, G, Tachmazidou, I, Lichtenstein, P, Breen, G, Cohen-Woods, S, Farmer, A, McGuffin, P, Cichon, Sven, Giegling, I, Herms, S, Rujescu, D, Schreiber, S, Klump, K L, Wichmann, H-E, Dina, C, Sladek, R, Gambaro, G, Soranzo, N, Julia, A, Marsal, S, Rabionet, R a, Gaborieau, V, Dick, D M, Treasure, J, Palotie, A, Ripatti, S, Widén, E, Andreassen, O A, Espeseth, T, Lundervold, A, Reinvang, I, Steen, V M, Hellard, S Le, Mattingsda, M, Lewis, C M, Ntalla, I, Bencko, V, Foretova, L, Janout, V, Navratilova, M, Gallinger, S, Pinto, D, Scherer, S W, Aschauer, H, Carlberg, L, Schmidt, U, Schosser, A, Alfredsson, L, Ding, B, Klareskog, L, Padyukov, L, Finan, C, Kalsi, G, Roberts, M, Logan, D W, Peltonen, L, Tozzi, F, Ritchie, G R S, Courtet, P, Guillame, S, Jaussent, I, Barrett, J C, Estivill, X, Hinney, A, Sullivan, P F, Collier, D A, Zeggini, E, Kiezebrink, K, Bulik, C M, Anderson, Carl A, Barrett, Jeffrey C, Floyd, James AB, Franklin, Christopher S, McGinnis, Ralph, Soranzo, Nicole, Zeggini, Eleftheria, Sambrook, Jennifer, Stephens, Jonathan, Hebebrand, J, Ouwehand, Willem H, McArdle, Wendy L, Ring, Susan M, Strachan, David P, Alexander, Graeme, Bulik, Cynthia M, Collier, David A, Conlon, Peter J, Dominiczak, Anna, Duncanson, Audrey, Gorwood, P, Hill, Adrian, Langford, Cordelia, Lord, Graham, Maxwell, Alexander P, Morgan, Linda, Peltonen, Leena, Sandford, Richard N, Sheerin, Neil, Vannberg, Fredrik O, Adan, R A H, Genotyping, D N A, Blackburn, Hannah, Chen, Wei-Min, Edkins, Sarah, Gillman, Mathew, Gray, Emma, Hunt, Sarah E, nengut-Gumuscu, Suna, Kas, M J H, Potter, Simon, Rich, Stephen S, Simpkin, Douglas, Whittaker, Pamela, Sullivan, Patrick F, Tyler-Smith, Chris, Tachmazidou, Ioanna, avaro, A F, Santonastaso, P, Fernández-Aranda, F, Gratacos, M, Rybakowski, F, Dmitrzak-Weglarz, M, Kaprio, J, Floyd, James A B, 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, Southam, Lorraine, Hakonarson, H, Berrettini, W H, Guo, Y, Li, D, Schork, N J, Komaki, G, Ando, T, Inoko, H, Esko, T, Fischer, K, Boraska, V, 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, Franklin, C S, Taico, C, Zerwas, S, Trace, S E, Davis, O S P, Helder, S, Bühren, K, Burghardt, R, de Zwaan, M, Egberts, K, Ehrlich, S, Floyd, J A B, Herpertz-Dahlmann, B, Herzog, W, Imgart, H, Scherag, A, Scherag, S, Zipfel, S, Boni, C, Ramoz, N, Versini, A, Brandys, M K, Thornton, L M, Danner, U N, de Kove, C, Hendriks, J, Koeleman, B P C, Ophoff, R A, Strengman, E, van Elburg, A A, Bruson, A, Clementi, M, Degortes, D, Huckins, L M, Forzan, M, Tenconi, E, Docampo, E, Escaramís, G, Jiménez-Murcia, S, Lissowska, J, Rajewski, A, Szeszenia-Dabrowska, N, Slopien, A, Hauser, J, Huckins, Laura M., Boraska, Vesna, Franklin, Christopher S., Floyd, J. A. B., Southam, Lorraine, Sullivan, P. F., Bulik, Cynthia M, Collier, David A, Tyler-Smith, Chri, Zeggini, Eleftheria, Tachmazidou, Ioanna, Thornton, L. M., William Rayner, N., Klump, K. L., 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., 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., Davis, O. S. P., Dackor, J., Desocio, J. E., Hilliard, C. E., O'Toole, J. K., Pantel, J., Szatkiewicz, J. P., Taico, C., Zerwas, S., Trace, S. E., Helder, S., Bühren, K., Burghardt, R., de Zwaan, M., Egberts, K., Ehrlich, S., Herpertz-Dahlmann, B., Herzog, W., Imgart, H., Scherag, A., 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., 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, Ra, 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., Finan, C., Kalsi, G., Roberts, M., Logan, D. W., Peltonen, Leena, Ritchie, G. R. S., Courtet, P., Guillame, S., Jaussent, I., Barrett, J. C., Estivill, X., Hinney, A., Bulik, C. M., Mcginnis, Ralph, Sambrook, Jennifer, Stephens, Jonathan, Ouwehand, Willem H, Mcardle, Wendy L, Ring, Susan M, Strachan, David P, Alexander, Graeme, Conlon, Peter J, Dominiczak, Anna, Duncanson, Audrey, Hill, Adrian, Langford, Cordelia, Lord, Graham, Maxwell, Alexander P, Morgan, Linda, Sandford, Richard N, Sheerin, Neil, Vannberg, Fredrik O, Blackburn, Hannah, Chen, Wei-Min, Edkins, Sarah, Gillman, Mathew, Gray, Emma, Hunt, Sarah E, Onengut-Gumuscu, Suna, Potter, Simon, Rich, Stephen S, Simpkin, Dougla, Whittaker, Pamela, Hebebrand, Johannes (Beitragende*r), Scherag, S (Beitragende*r), Hinney, Anke (Beitragende*r), Hjelt Institute (-2014), Department of Public Health, Institute for Molecular Medicine Finland, Research Programs Unit, Research Programme of Molecular Medicine, Biostatistics Helsinki, Complex Disease Genetics, Genomics of Neurological and Neuropsychiatric Disorders, Genetic Epidemiology, Sullivan, Patrick F [0000-0002-6619-873X], and Apollo - University of Cambridge Repository

Subjects
Anorexia Nervosa, Genotyping Techniques, DIVERSITY, Medizin, SNPne, Genome-wide association study, 0302 clinical medicine, Gene Frequency, Genetic Marker, Settore MED/14 - NEFROLOGIA, AIM, WTCCC3, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Genetics, Genetics & Heredity, 0303 health sciences, education.field_of_study, Principal Component Analysis, ASSOCIATION, Single Nucleotide, 3142 Public health care science, environmental and occupational health, 3. Good health, Phylogeography, population stratification, AIMs, principal component analysis, SET, Human, Genetic Markers, population stratification, Population, Clinical Sciences, European Continental Ancestry Group, AIMs, Reproducibility of Result, Single-nucleotide polymorphism, Ancestry-informative marker, Biology, principal component analysi, Population stratification, population stratification, principal component analysis, Polymorphism, Single Nucleotide, Article, White People, 03 medical and health sciences, Genetic, Clinical Research, ddc:570, Humans, Polymorphism, education, Allele frequency, 030304 developmental biology, GCAN, Oligonucleotide Array Sequence Analysi, Human Genome, Reproducibility of Results, Minor allele frequency, Genetics, Population, Evolutionary biology, Sample Size, 3111 Biomedicine, Genotyping Technique, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify population structure in such studies using only common variants with minor allele frequency (MAF) >5%; we find that this may result in highly informative SNPs being discarded, and suggest that instead all SNPs with MAF >1% may be used. We established informative axes of variation identified via principal component analysis and highlight important features of the genetic structure of diverse European-descent populations, some studied for the first time at this scale. Finally, we investigated the substructure within each of these 15 populations and identified SNPs that help capture hidden stratification. This work can provide information regarding the designing and interpretation of association results in the International Consortia.European Journal of Human Genetics advance online publication, 19 February 2014; doi:10.1038/ejhg.2014.1.

Published
2014
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46. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Author

Eva M. Reinthaler, Dennis Lal, Sebastien Lebon, Michael S. Hildebrand, Hans-Henrik M. Dahl, Brigid M. Regan, Martha Feucht, Hannelore Steinböck, Birgit Neophytou, Gabriel M. Ronen, Laurian Roche, Ursula Gruber-Sedlmayr, Julia Geldner, Edda Haberlandt, Per Hoffmann, Stefan Herms, Christian Gieger, Melanie Waldenberger, Andre Franke, Michael Wittig, Susanne Schoch, Albert J. Becker, Andreas Hahn, Katrin Männik, Mohammad R. Toliat, Georg Winterer, Holger Lerche, Peter Nürnberg, Heather Mefford, Ingrid E. Scheffer, Samuel F. Berkovic, Jacques S. Beckmann, Thomas Sander, Sebastien Jacquemont, Alexandre Reymond, Fritz Zimprich, Bernd A. Neubauer, Bernd Neubauer, Martina Mörzinger, Arvid Suls, Sarah Weckhuysen, Lieve Claes, Liesbet Deprez, Katrien Smets, Tine Van Dyck, Tine Deconinck, Peter De Jonghe, Rikke S Møller, Laura L. Klitten, Helle Hjalgrim, Kiel Campus, Ingo Helbig, Hiltrud Muhle, Philipp Ostertag, Sarah von Spiczak, Ulrich Stephani, Holger Trucks, Christian E. Elger, Ailing A. Kleefuß-Lie, Wolfram S. Kunz, Rainer Surges, Verena Gaus, Dieter Janz, Bettina Schmitz, Felix Rosenow, Karl Martin Klein, Philipp S. Reif, Wolfgang H. Oertel, Hajo M. Hamer, Felicitas Becker, Yvonne Weber, Bobby P.C. Koeleman, Carolien de Kovel, Dick Lindhout, Agnès Ameil, Joris Andrieux, Sonia Bouquillon, Odile Boute, Jeanne de Flandre, Jean Marie Cuisset, Jean-Christophe Cuvellier, Roger Salengro, Albert David, Bert de Vries, Marie-Ange Delrue, Martine Doco-Fenzy, Bridget A. Fernandez, Delphine Heron, Boris Keren, Robert Lebel, Bruno Leheup, Suzanne Lewis, Maria Antonietta Mencarelli, Cyril Mignot, Jean-Claude Minet, Alexandre Moerman, Fanny Morice-Picard, Mafalda Mucciolo, Katrin Ounap, Laurent Pasquier, Florence Petit, Francesca Ragona, Evica Rajcan-Separovic, Alessandra Renieri, Claudine Rieubland, Damien Sanlaville, Elisabeth Sarrazin, Yiping Shen, Mieke van Haelst, Anneke Vulto-van Silfhout, 16p11.2 European Consortium, EPICURE Consortium, EuroEPINOMICS Consortium, Reinthaler, EM., Zimprich, F., Feucht, M., Steinböck, H., Neophytou, B., Geldner, J., Gruber-Sedlmayr, U., Haberlandt, E., Ronen, GM., Roche, L., Lal, D., Nürnberg, P., Sander, T., Lerche, H., Neubauer, B., Mörzinger, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Møller, RS., Klitten, LL., Hjalgrim, H., Campus, K., Helbig, I., Muhle, H., Ostertag, P., von Spiczak, S., Stephani, U., Trucks, H., Elger, CE., Kleefuß-Lie, AA., Kunz, WS., Surges, R., Gaus, V., Janz, D., Schmitz, B., Rosenow, F., Klein, KM., Reif, PS., Oertel, WH., Hamer, HM., Becker, F., Weber, Y., Koeleman, BP., de Kovel, C., Lindhout, D., Ameil, A., Andrieux, J., Bouquillon, S., Boute, O., Cordier, MP., Cuisset, JM., Cuvellier, JC., David, A., de Vries, B., Delrue, MA., Doco-Fenzy, M., Fernandez, BA., Heron, D., Keren, B., Lebel, R., Leheup, B., Lewis, S., Mencarelli, MA., Mignot, C., Minet, JC., Moerman, A., Morice-Picard, F., Mucciolo, M., Ounap, K., Pasquier, L., Petit, F., Ragona, F., Rajcan-Separovic, E., Renieri, A., Rieubland, C., Sanlaville, D., Sarrazin, E., Shen, Y., van Haelst, M., Vulto-van Silfhout, A., and Other departments

Subjects
Male, DNA Copy Number Variations, Chromosomes, Human, Pair 22, 610 Medicine & health, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Temporal lobe, Epilepsy, Gene duplication, Chromosome Duplication, Genetics, medicine, Humans, Copy-number variation, Child, Molecular Biology, Genetics (clinical), Chromosomes, Human, Pair 15, Infant, General Medicine, Odds ratio, medicine.disease, Epilepsy, Rolandic, Rolandic epilepsy, Exact test, Chromosomes, Human, Pair 1, Child, Preschool, Female, Chromosomes, Human, Pair 16
Abstract

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

Published
2014
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47. Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection

Author

Mihai G. Netea, Jihane Romanos, Carlo Catassi, Bart Ferwerda, Leo A. B. Joosten, Gosia Trynka, Clara C. Elbers, Alexandra Zhernakova, Carolien G.F. de Kovel, Maria Teresa Bardella, Donatella Barisani, Patrick Dubois, Cisca Wijmenga, David A. van Heel, Lude Franke, Päivi Saavalainen, Marije Oosting, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Translational Immunology Groningen (TRIGR), Stem Cell Aging Leukemia and Lymphoma (SALL), Zhernakova, A, Elbers, C, Ferwerda, B, Romanos, J, Trynka, G, Dubois, P, de Kovel, C, Franke, L, Oosting, M, Barisani, D, Bardella, M, Joosten, L, Saavalainen, P, van Heel, D, Catassi, C, Netea, M, Wijmenga, C, Epidemiology and Data Science, and ANS - Neuroinfection & -inflammation

Subjects
POSITIVE SELECTION, Nod2 Signaling Adaptor Protein, Genome-wide association study, BLOOD-PRESSURE, VARIANTS, SUSCEPTIBILITY, DISEASE, 0302 clinical medicine, Africa, Northern, Genotype, Genetics(clinical), Genetics (clinical), POPULATION, Genetics, 0303 health sciences, education.field_of_study, Intracellular Signaling Peptides and Proteins, Bacterial Infections, 3. Good health, Pathogenesis and modulation of inflammation [N4i 1], Europe, 030220 oncology & carcinogenesis, Disease Susceptibility, Infection and autoimmunity [NCMLS 1], Population, Locus (genetics), Biology, Bacterial Infection, Polymorphism, Single Nucleotide, Evolution, Molecular, 03 medical and health sciences, Report, Humans, COHORT, Allele, Selection, Genetic, GENOME-WIDE ASSOCIATION, education, Allele frequency, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Protein, MORTALITY, Haplotype, Proteins, Celiac Disease, Genetics, Population, Immunology, Selective sweep
Abstract

Contains fulltext : 88653.pdf (Publisher’s version ) (Closed access) Celiac disease (CD) is an intolerance to dietary proteins of wheat, barley, and rye. CD may have substantial morbidity, yet it is quite common with a prevalence of 1%-2% in Western populations. It is not clear why the CD phenotype is so prevalent despite its negative effects on human health, especially because appropriate treatment in the form of a gluten-free diet has only been available since the 1950s, when dietary gluten was discovered to be the triggering factor. The high prevalence of CD might suggest that genes underlying this disease may have been favored by the process of natural selection. We assessed signatures of selection for ten confirmed CD-associated loci in several genome-wide data sets, comprising 8154 controls from four European populations and 195 individuals from a North African population, by studying haplotype lengths via the integrated haplotype score (iHS) method. Consistent signs of positive selection for CD-associated derived alleles were observed in three loci: IL12A, IL18RAP, and SH2B3. For the SH2B3 risk allele, we also show a difference in allele frequency distribution (Fst) between HapMap phase II populations. Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the SH2B3 rs3184504*A risk allele showed stronger activation of the NOD2 recognition pathway. This suggests that SH2B3 plays a role in protection against bacteria infection, and it provides a possible explanation for the selective sweep on SH2B3, which occurred sometime between 1200 and 1700 years ago.

Published
2010

48. Mapping brain asymmetry in health and disease through the ENIGMA consortium.

Author

Kong XZ, Postema MC, Guadalupe T, de Kovel C, Boedhoe PSW, Hoogman M, Mathias SR, van Rooij D, Schijven D, Glahn DC, Medland SE, Jahanshad N, Thomopoulos SI, Turner JA, Buitelaar J, van Erp TGM, Franke B, Fisher SE, van den Heuvel OA, Schmaal L, Thompson PM, and Francks C

Subjects
Autism Spectrum Disorder diagnostic imaging, Cerebral Cortex diagnostic imaging, Depressive Disorder, Major diagnostic imaging, Gray Matter diagnostic imaging, Humans, Multicenter Studies as Topic, Obsessive-Compulsive Disorder diagnostic imaging, Autism Spectrum Disorder pathology, Cerebral Cortex anatomy & histology, Depressive Disorder, Major pathology, Gray Matter anatomy & histology, Magnetic Resonance Imaging, Neuroimaging, Obsessive-Compulsive Disorder pathology
Abstract

Left-right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last 4 years, the ENIGMA-Laterality Working Group has published six studies of gray matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population-level mapping of average asymmetry was achieved, including an intriguing fronto-occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA's multi-dataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for gray matter asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders: autism spectrum disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; pediatric obsessive-compulsive disorder was associated with altered subcortical asymmetry; major depressive disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Published
2022
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49. Influence of common SCN1A promoter variants on the severity of SCN1A-related phenotypes.

Author

de Lange IM, Weuring W, van 't Slot R, Gunning B, Sonsma ACM, McCormack M, de Kovel C, van Gemert LJJM, Mulder F, van Kempen MJA, Knoers NVAM, Brilstra EH, and Koeleman BPC

Subjects
5' Untranslated Regions, Adolescent, Adult, Alleles, Cell Line, Tumor, Child, Child, Preschool, Epilepsy genetics, Genes, Reporter, Genome-Wide Association Study, Haplotypes, Humans, Male, Phenotype, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Severity of Illness Index, Young Adult, Epilepsy pathology, NAV1.1 Voltage-Gated Sodium Channel genetics
Abstract

Background: Pathogenic variants in SCN1A cause variable epilepsy disorders with different disease severities. We here investigate whether common variation in the promoter region of the unaffected SCN1A allele could reduce normal expression, leading to a decreased residual function of Nav1.1, and therefore to more severe clinical outcomes in patients affected by pathogenic SCN1A variants., Methods: Five different SCN1A promoter-haplotypes were functionally assessed in SH-SY5Y cells using Firefly and Renilla luciferase assays. The SCN1A promoter region was analyzed in a cohort of 143 participants with SCN1A pathogenic variants. Differences in clinical features and outcomes between participants with and without common variants in the SCN1A promoter-region of their unaffected allele were investigated., Results: All non-wildtype haplotypes showed a significant reduction in luciferase expression, compared to the wildtype promoter-region (65%-80%, p = 0.039-0.0023). No statistically significant differences in clinical outcomes were observed between patients with and without common promoter variants. However, patients with a wildtype promoter-haplotype on their unaffected SCN1A allele showed a nonsignificant trend for milder phenotypes., Conclusion: The nonsignificant observed trends in our study warrant replication studies in larger cohorts to explore the potential modifying role of these common SCN1A promoter-haplotypes., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Published
2019
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50. Rare coding variants in genes encoding GABA A receptors in genetic generalised epilepsies: an exome-based case-control study.

Author

May P, Girard S, Harrer M, Bobbili DR, Schubert J, Wolking S, Becker F, Lachance-Touchette P, Meloche C, Gravel M, Niturad CE, Knaus J, De Kovel C, Toliat M, Polvi A, Iacomino M, Guerrero-López R, Baulac S, Marini C, Thiele H, Altmüller J, Jabbari K, Ruppert AK, Jurkowski W, Lal D, Rusconi R, Cestèle S, Terragni B, Coombs ID, Reid CA, Striano P, Caglayan H, Siren A, Everett K, Møller RS, Hjalgrim H, Muhle H, Helbig I, Kunz WS, Weber YG, Weckhuysen S, Jonghe P, Sisodiya SM, Nabbout R, Franceschetti S, Coppola A, Vari MS, Kasteleijn-Nolst Trenité D, Baykan B, Ozbek U, Bebek N, Klein KM, Rosenow F, Nguyen DK, Dubeau F, Carmant L, Lortie A, Desbiens R, Clément JF, Cieuta-Walti C, Sills GJ, Auce P, Francis B, Johnson MR, Marson AG, Berghuis B, Sander JW, Avbersek A, McCormack M, Cavalleri GL, Delanty N, Depondt C, Krenn M, Zimprich F, Peter S, Nikanorova M, Kraaij R, van Rooij J, Balling R, Ikram MA, Uitterlinden AG, Avanzini G, Schorge S, Petrou S, Mantegazza M, Sander T, LeGuern E, Serratosa JM, Koeleman BPC, Palotie A, Lehesjoki AE, Nothnagel M, Nürnberg P, Maljevic S, Zara F, Cossette P, Krause R, and Lerche H

Subjects
Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Child, Child, Preschool, Cohort Studies, Epilepsy, Generalized ethnology, Europe, Family Health, Female, Humans, Infant, Infant, Newborn, International Cooperation, Male, Middle Aged, Models, Molecular, Young Adult, Epilepsy, Generalized genetics, Genetic Predisposition to Disease genetics, Genetic Variation genetics, Receptors, GABA-A genetics, Exome Sequencing methods
Abstract

Background: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy., Methods: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABA A receptors and was compared to the respective GABA A receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes., Findings: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABA A receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; p Nonsyn =0·0014, adjusted p Nonsyn =0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; p Nonsyn =0·0081, adjusted p Nonsyn =0·016). Comparison of genes encoding GABA A receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABA A receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; p Nonsyn =0·013, adjusted p Nonsyn =0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors., Interpretation: Functionally relevant variants in genes encoding GABA A receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy., Funding: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Published
2018
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