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7 results on '"Nürnberg, P. (Peter)"'

1. Rare gene deletions in genetic generalized and Rolandic epilepsies

Author

Jabbari, K. (Kamel), Bobbili, D.R. (Dheeraj R.), Lal, D. (Dennis), Reinthaler, E.M. (Eva M.), Schubert, J. (Julian), Wolking, S. (Stefan), Sinha, V. (Vishal), Motameny, S. (Susanne), Thiele, H. (Holger), Kawalia, A. (Amit), Altmüller, J. (Janine), Toliat, M.R. (Mohammad Reza), Kraaij, R. (Robert), van Rooij, J. (Jeroen), Uitterlinden, A.G. (André G.), Ikram, M.A. (Arfan), Zara, F. (Federico), Lehesjoki, A.E., Krause, R. (Roland), Zimprich, F. (Fritz), Sander, T. (Thomas), Neubauer, B.A. (Bernd A.), May, P. (Patrick), Lerche, H. (Holger), Nürnberg, P. (Peter), Jabbari, K. (Kamel), Bobbili, D.R. (Dheeraj R.), Lal, D. (Dennis), Reinthaler, E.M. (Eva M.), Schubert, J. (Julian), Wolking, S. (Stefan), Sinha, V. (Vishal), Motameny, S. (Susanne), Thiele, H. (Holger), Kawalia, A. (Amit), Altmüller, J. (Janine), Toliat, M.R. (Mohammad Reza), Kraaij, R. (Robert), van Rooij, J. (Jeroen), Uitterlinden, A.G. (André G.), Ikram, M.A. (Arfan), Zara, F. (Federico), Lehesjoki, A.E., Krause, R. (Roland), Zimprich, F. (Fritz), Sander, T. (Thomas), Neubauer, B.A. (Bernd A.), May, P. (Patrick), Lerche, H. (Holger), and Nürnberg, P. (Peter)

Abstract

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as important risk factors in brain disorders. We performed a systematic survey of rare deletions affecting protein-coding genes derived from exome data of patients with common forms of genetic epilepsies. We analysed exomes from 390 European patients (196 GGE and 194 RE) and 572 population controls to identify low-frequency genic deletions. We found that 75 (32 GGE and 43 RE) patients out of 390, i.e. ~19%, carried rare genic deletions. In particular, large deletions (<400 kb) represent a higher burden in both GGE and RE syndromes as compared to controls. The detected low-frequency deletions (1) share genes with brain-expressed exons that are under negative select

Published
2018
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2. Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma

Author

Nieuwenhuis, M.A., Siedlinski, M., van den Berge, M., Granell, R. (Raquel), Li, X., Niens, M., Vlies, P. (P.) van der, Altmüller, J. (Janine), Nürnberg, P. (Peter), Kerkhof, M. (Marjan), Schayck, O.C.P. (Onno), Riemersma, R.A. (Roland), Molen, T. (Thys) van der, Monchy, J.G. de, Bossé, Y., Sandford, A. (Andrew), Bruijnzeel-Koomen, C.A., Gerth van Wijk, R., ten Hacken, N.H., Timens, W. (Wim), Boezen, H.M. (Marike), Henderson, J., Kabesch, M. (Michael), Vonk, J.M. (Judith), Postma, D.S. (Dirkje), Koppelman, G.H. (Gerard), Nieuwenhuis, M.A., Siedlinski, M., van den Berge, M., Granell, R. (Raquel), Li, X., Niens, M., Vlies, P. (P.) van der, Altmüller, J. (Janine), Nürnberg, P. (Peter), Kerkhof, M. (Marjan), Schayck, O.C.P. (Onno), Riemersma, R.A. (Roland), Molen, T. (Thys) van der, Monchy, J.G. de, Bossé, Y., Sandford, A. (Andrew), Bruijnzeel-Koomen, C.A., Gerth van Wijk, R., ten Hacken, N.H., Timens, W. (Wim), Boezen, H.M. (Marike), Henderson, J., Kabesch, M. (Michael), Vonk, J.M. (Judith), Postma, D.S. (Dirkje), and Koppelman, G.H. (Gerard)

Abstract

Background: Genomewide association studies (GWASs) of asthma have identified single-nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis-eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor's diagnosed) asthma to our GWAS of asthma with BHR. Methods: A GWAS was performed in 920 asthmatics with BHR and 980 controls. Top SNPs of our GWAS were analysed in four replication cohorts, and lung cis-eQTL analysis was performed on replicated SNPs. We investigated association of SNPs previously associated with asthma in our data. Results: A total of 368 SNPs were followed up for replication. Six SNPs in genes encoding ABI3BP, NAF1, MICA and the 17q21 locus replicated in one or more cohorts, with one locus (17q21) achieving genomewide significance after meta-analysis. Five of 6 replicated SNPs regulated 35 gene transcripts in whole lung. Eight of 20 asthma-associated SNPs from previous GWAS were significantly associated with asthma and BHR. Three SNPs, in IL-33 and GSDMB, showed larger effect sizes in our data compared to p

Published
2016
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3. Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes

Author

Lal, D. (Dennis), Reinthaler, E.M. (Eva M.), Dejanovic, B. (Borislav), May, P. (Patrick), Thiele, H. (Holger), Lehesjoki, A.E., Schwarz, G. (Günter), Riesch, E. (Erik), Ikram, M.A. (Arfan), Duijn, C.M. (Cornelia) van, Uitterlinden, A.G. (André), Hofman, A. (Albert), Steinböck, H. (Hannelore), Gruber-Sedlmayr, U. (Ursula), Neophytou, B. (Birgit), Zara, F. (Federico), Hahn, A. (Andreas), Gormley, A.M., Becker, F. (Felicitas), Weber, Y.G. (Yvonne G.), Cilio, M.R. (Maria Roberta), Kunz, W.S. (Wolfram S.), Krause, R. (Roland), Zimprich, F. (Fritz), Lemke, J.R. (Johannes R.), Nürnberg, P. (Peter), Sander, T. (Thomas), Lerche, H. (Holger), Neubauer, B.A. (Bernd A.), Palotie, A. (Aarno), Ruppert, A.-K. (Ann-Kathrin), Suls, A. (A.), Siren, A. (Auli), Koeleman, B.P.C. (Bobby), Haberlandt, E. (Edda), Ronen, G.M. (Gabriel M.), Caglayan, H. (Hande), Hjalgrim, H. (Helle), Muhle, H. (Hiltrud), Schulz, H. (Herbert), Helbig, I. (Ingo), Altmüller, J. (Janine), Geldner, J. (Julia), Schubert, J. (Julian), Jabbari, K. (Kamel), Everett, K. (Kate), Feucht, M. (Martha), Balestri, M. (Martina), Nothnagel, M. (Michael), Striano, P. (Pasquale), Møller, R.S. (Rikke), Nabbout, R. (Rima), Balling, R. (Rudi), Baulac, S. (Stephanie), Kunz, W. (Wolfram), Bianchi, A. (Amedeo), La Neve, A. (Angela), Minetti, C., Giuseppe, C. (Capovilla), Lal, D. (Dennis), Reinthaler, E.M. (Eva M.), Dejanovic, B. (Borislav), May, P. (Patrick), Thiele, H. (Holger), Lehesjoki, A.E., Schwarz, G. (Günter), Riesch, E. (Erik), Ikram, M.A. (Arfan), Duijn, C.M. (Cornelia) van, Uitterlinden, A.G. (André), Hofman, A. (Albert), Steinböck, H. (Hannelore), Gruber-Sedlmayr, U. (Ursula), Neophytou, B. (Birgit), Zara, F. (Federico), Hahn, A. (Andreas), Gormley, A.M., Becker, F. (Felicitas), Weber, Y.G. (Yvonne G.), Cilio, M.R. (Maria Roberta), Kunz, W.S. (Wolfram S.), Krause, R. (Roland), Zimprich, F. (Fritz), Lemke, J.R. (Johannes R.), Nürnberg, P. (Peter), Sander, T. (Thomas), Lerche, H. (Holger), Neubauer, B.A. (Bernd A.), Palotie, A. (Aarno), Ruppert, A.-K. (Ann-Kathrin), Suls, A. (A.), Siren, A. (Auli), Koeleman, B.P.C. (Bobby), Haberlandt, E. (Edda), Ronen, G.M. (Gabriel M.), Caglayan, H. (Hande), Hjalgrim, H. (Helle), Muhle, H. (Hiltrud), Schulz, H. (Herbert), Helbig, I. (Ingo), Altmüller, J. (Janine), Geldner, J. (Julia), Schubert, J. (Julian), Jabbari, K. (Kamel), Everett, K. (Kate), Feucht, M. (Martha), Balestri, M. (Martina), Nothnagel, M. (Michael), Striano, P. (Pasquale), Møller, R.S. (Rikke), Nabbout, R. (Rima), Balling, R. (Rudi), Baulac, S. (Stephanie), Kunz, W. (Wolfram), Bianchi, A. (Amedeo), La Neve, A. (Angela), Minetti, C., and Giuseppe, C. (Capovilla)

Abstract

Objective: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods: We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation: We identified 8 known missense mutations, previously reported as patho

Published
2016
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4. Mutational dynamics between primary and relapse neuroblastomas

Author

Schramm, A. (Alexander), Köster, J. (Johannes), Assenov, Y. (Yassen), Althoff, K. (Kristina), Peifer, M. (Martin), Mahlow, E. (Ellen), Odersky, A. (Andrea), Beisser, D. (Daniela), Ernst, C. (Corinna), Henssen, A.G. (Anton), Stephan, H. (Harald), Schröder, C. (Christopher), Heukamp, L. (Lukas), Engesser, A. (Anne), Kahlert, Y. (Yvonne), Theissen, J. (Jessica), Hero, B. (Barbara), Roels, F. (Frederik), Altmüller, J. (Janine), Nürnberg, P. (Peter), Astrahantseff, K. (Kathy), Gloeckner, C. (Christian), De Preter, K. (Katleen), Plass, C. (Christoph), Lee, S. (Sangkyun), Lode, H.N. (Holger), Henrich, K.-O. (Kai-Oliver), Gartlgruber, M. (Moritz), Speleman, F. (Frank), Schmezer, P. (Peter), Westermann, F. (Frank), Rahmann, S. (Sven), Fischer, M. (Matthias), Eggert, A. (Angelika), Schulte, J.H. (Johannes), Schramm, A. (Alexander), Köster, J. (Johannes), Assenov, Y. (Yassen), Althoff, K. (Kristina), Peifer, M. (Martin), Mahlow, E. (Ellen), Odersky, A. (Andrea), Beisser, D. (Daniela), Ernst, C. (Corinna), Henssen, A.G. (Anton), Stephan, H. (Harald), Schröder, C. (Christopher), Heukamp, L. (Lukas), Engesser, A. (Anne), Kahlert, Y. (Yvonne), Theissen, J. (Jessica), Hero, B. (Barbara), Roels, F. (Frederik), Altmüller, J. (Janine), Nürnberg, P. (Peter), Astrahantseff, K. (Kathy), Gloeckner, C. (Christian), De Preter, K. (Katleen), Plass, C. (Christoph), Lee, S. (Sangkyun), Lode, H.N. (Holger), Henrich, K.-O. (Kai-Oliver), Gartlgruber, M. (Moritz), Speleman, F. (Frank), Schmezer, P. (Peter), Westermann, F. (Frank), Rahmann, S. (Sven), Fischer, M. (Matthias), Eggert, A. (Angelika), and Schulte, J.H. (Johannes)

Abstract

Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection durin

Published
2015
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5. Mutational dynamics between primary and relapse neuroblastomas

Author

Schramm, A. (Alexander), Köster, J. (Johannes), Assenov, Y. (Yassen), Althoff, K. (Kristina), Peifer, M. (Martin), Mahlow, E. (Ellen), Odersky, A. (Andrea), Beisser, D. (Daniela), Ernst, C. (Corinna), Henssen, A.G. (Anton), Stephan, H. (Harald), Schröder, C. (Christopher), Heukamp, L. (Lukas), Engesser, A. (Anne), Kahlert, Y. (Yvonne), Theissen, J. (Jessica), Hero, B. (Barbara), Roels, F. (Frederik), Altmüller, J. (Janine), Nürnberg, P. (Peter), Astrahantseff, K. (Kathy), Gloeckner, C. (Christian), De Preter, K. (Katleen), Plass, C. (Christoph), Lee, S. (Sangkyun), Lode, H.N. (Holger), Henrich, K.-O. (Kai-Oliver), Gartlgruber, M. (Moritz), Speleman, F. (Frank), Schmezer, P. (Peter), Westermann, F. (Frank), Rahmann, S. (Sven), Fischer, M. (Matthias), Eggert, A. (Angelika), Schulte, J.H. (Johannes), Schramm, A. (Alexander), Köster, J. (Johannes), Assenov, Y. (Yassen), Althoff, K. (Kristina), Peifer, M. (Martin), Mahlow, E. (Ellen), Odersky, A. (Andrea), Beisser, D. (Daniela), Ernst, C. (Corinna), Henssen, A.G. (Anton), Stephan, H. (Harald), Schröder, C. (Christopher), Heukamp, L. (Lukas), Engesser, A. (Anne), Kahlert, Y. (Yvonne), Theissen, J. (Jessica), Hero, B. (Barbara), Roels, F. (Frederik), Altmüller, J. (Janine), Nürnberg, P. (Peter), Astrahantseff, K. (Kathy), Gloeckner, C. (Christian), De Preter, K. (Katleen), Plass, C. (Christoph), Lee, S. (Sangkyun), Lode, H.N. (Holger), Henrich, K.-O. (Kai-Oliver), Gartlgruber, M. (Moritz), Speleman, F. (Frank), Schmezer, P. (Peter), Westermann, F. (Frank), Rahmann, S. (Sven), Fischer, M. (Matthias), Eggert, A. (Angelika), and Schulte, J.H. (Johannes)

Abstract

Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative CHD5 neuroblastoma tumor suppressor, chromosome 9p losses, DOCK8 mutations, inactivating mutations in PTPN14 and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in HRAS, KRAS and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.

Published
2015
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6. Clinal distribution of human genomic diversity across the Netherlands despite archaeological evidence for genetic discontinuities in Dutch population history

Author

Lao Grueso, O. (Oscar), Altena, E. (Eveline), Becker, C.R. (Christian), Brauer, S. (Silke), Kraaijenbrink, T. (Thirsa), Oven, M. (Mannis) van, Nürnberg, P. (Peter), Knijff, P. (Peter) de, Kayser, M.H. (Manfred), Lao Grueso, O. (Oscar), Altena, E. (Eveline), Becker, C.R. (Christian), Brauer, S. (Silke), Kraaijenbrink, T. (Thirsa), Oven, M. (Mannis) van, Nürnberg, P. (Peter), Knijff, P. (Peter) de, and Kayser, M.H. (Manfred)

Abstract

Background: The presence of a southeast to northwest gradient across Europe in human genetic diversity is a well-established observation and has recently been confirmed by genome-wide single nucleotide polymorphism (SNP) data. This pattern is traditionally explained by major prehistoric human migration events in Palaeolithic and Neolithic times. Here, we investigate whether (similar) spatial patterns in human genomic diversity also occur on a micro-geographic scale within Europe, such as in the Netherlands, and if so, whether these patterns could also be explained by more recent demographic events, such as those that occurred in Dutch population history.Methods: We newly collected data on a total of 999 Dutch individuals sampled at 54 sites across the country at 443,816 autosomal SNPs using the Genome-Wide Human SNP Array 5.0 (Affymetrix). We studied the individual genetic relationships by means of classical multidimensional scaling (MDS) using different genetic distance matrices, spatial ancestry analysis (SPA), and ADMIXTURE software. We further performed dedicated analyses to search for spatial patterns in the genomic variation and conducted simulations (SPLATCHE2) to provide a historical interpretation of the observed spatial patterns.Results: We detected a subtle but clearly noticeable genomic population substructure in the Dutch population, allowing differentiation of a north-eastern, central-western, central-northern and a southern group. Furthermore, we observed a statistically significant southeast to northwest cline in the distribution of genomic diversity across the Netherlands, similar to earlier findings from across Europe. Simulation analyses indicate that this genomic gradient could similarly be caused by ancient as well as by the more recent events in Dutch history.Conclusions: Considering the strong archaeological evidence for genetic discontinuity in the Netherlands, we interpret the observed clinal pattern of genomic diversity as being caused by r

Published
2013
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7. Genome-wide Analysis Indicates More Asian than Melanesian Ancestry of Polynesians

Author

Kayser, M.H. (Manfred), Lao Grueso, O. (Oscar), Saar, K. (Kathrin), Brauer, S. (Silke), Wang, X. (Xinyu), Nürnberg, P. (Peter), Trent, R.J. (Ronald), Stoneking, M. (Mark), Kayser, M.H. (Manfred), Lao Grueso, O. (Oscar), Saar, K. (Kathrin), Brauer, S. (Silke), Wang, X. (Xinyu), Nürnberg, P. (Peter), Trent, R.J. (Ronald), and Stoneking, M. (Mark)

Abstract

Analyses of mitochondrial DNA (mtDNA) and nonrecombining Y chromosome (NRY) variation in the same populations are sometimes concordant but sometimes discordant. Perhaps the most dramatic example known of the latter concerns Polynesians, in which about 94% of Polynesian mtDNAs are of East Asian origin, while about 66% of Polynesian Y chromosomes are of Melanesian origin. Here we analyze on a genome-wide scale, to our knowledge for the first time, the origins of the autosomal gene pool of Polynesians by screening 377 autosomal short tandem repeat (STR) loci in 47 Pacific Islanders and compare the results with those obtained from 44 Chinese and 24 individuals from Papua New Guinea. Our data indicate that on average about 79% of the Polynesian autosomal gene pool is of East Asian origin and 21% is of Melanesian origin. The genetic data thus suggest a dual origin of Polynesians with a high East Asian but also considerable Melanesian component, reflecting sex-biased admixture in Polynesian history in agreement with the Slow Boat model. More generally, these results also demonstrate that conclusions based solely on uniparental markers, which are frequently used in population history studies, may not accurately reflect the history of the autosomal gene pool of a population.

Published
2008
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