Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Lisa Borghini*, Eileen Png, Alexander Binder, Victoria J. Wright, Ellie Pinnock, Ronald de Groot, Jan Hazelzet, Marieke Emonts, Michiel Van der Flier, Luregn J. Schlapbach, Suzanne Anderson, Fatou Secka, Antonio Salas, Colin Fink, Enitan D. Carrol, Andrew J. Pollard, Lachlan J. Coin, Taco W. Kuijpers, Federico Martinon-Torres, Werner ZenzMichael Levin, Martin L. Hibberd, Sonia Davila, Stuart Gormley, Shea Hamilton, Jethro Herberg, Bernardo Hourmat, Clive Hoggart, Myrsini Kaforou, Vanessa Sancho-Shimizu, Amina Abdulla, Paul Agapow, Maeve Bartlett, Evangelos Bellos, Hariklia Eleftherohorinou, Rachel Galassini, David Inwald, Meg Mashbat, Stefanie Menikou, Sobia Mustafa, Simon Nadel, Rahmeen Rahman, Clare Thakker, S. Bokhandi, Sue Power, Heather Barham, N. Pathan, Jenna Ridout, Deborah White, Sarah Thurston, S. Faust, S. Patel, Jenni McCorkell, P. Davies, Lindsey Cratev, Helen Navarra, Stephanie Carter, R. Ramaiah, Rekha Patel, Catherine Tuffrey, Andrew Gribbin, Sharon McCready, Mark Peters, Katie Hardy, Fran Standing, Lauren O’Neill, Eugenia Abelake, Akash Deep, Eniola Nsirim, Louise Willis, Zoe Young, C. Royad, Sonia White, P. M. Fortune, Phil Hudnott, Fernando Álvez González, Ruth Barral-Arca, Miriam Cebey-López, María José Curras-Tuala, Natalia García, Luisa García Vicente, Alberto Gómez-Carballa, Jose Gómez Rial, Andrea Grela Beiroa, Antonio Justicia Grande, Pilar Leboráns Iglesias, Alba Elena Martínez Santos, Nazareth Martinón-Torres, José María Martinón Sánchez, Belén Mosquera Pérez, Pablo Obando Pacheco, Jacobo Pardo-Seco, Sara Pischedda, Irene Rivero Calle, Carmen Rodríguez-Tenreiro, Lorenzo Redondo-Collazo, Sonia Serén Fernández, María del Sol Porto Silva, Ana Vega, Susana Beatriz Reyes, María Cruz León León, Álvaro Navarro Mingorance, Xavier Gabaldó Barrios, Eider Oñate Vergara, Andrés Concha Torre, Ana Vivanco, Reyes Fernández, Francisco Giménez Sánchez, Miguel Sánchez Forte, Pablo Rojo, J. Ruiz Contreras, Alba Palacios, Marisa Navarro, Cristina Álvarez Álvarez, María José Lozano, Eduardo Carreras, Sonia Brió Sanagustín, Olaf Neth, Ma del Carmen Martínez Padilla, Luis Manuel Prieto Tato, Sara Guillén, Laura Fernández Silveira, David Moreno, A. M.Tutu van Furth, M. van der Flier, N. P. Boeddha, G. J.A. Driessen, D. Pajkrt, E. A.M. Sanders, D. van de Beek, A. van der Ende, H. L.A. Philipsen, A. O.A. Adeel, M. A. Breukels, D. M.C. Brinkman, C. C.M.M. de Korte, E. de Vries, W. J. de Waal, R. Dekkers, A. Dings-Lammertink, R. A. Doedens, A. E. Donker, M. Dousma, T. E. Faber, G. P.J.M. Gerrits, J. A.M. Gerver, J. Heidema, J. Homan-van der Veen, M. A.M. Jacobs, N. J.G. Jansen, P. Kawczynski, K. Klucovska, M. C.J. Kneyber, Y. Koopman-Keemink, V. J. Langenhorst, J. Leusink, B. F. Loza, I. T. Merth, C. J. Miedema, C. Neeleman, J. G. Noordzij, C. C. Obihara, A. L.T. van Overbeek-van Gils, G. H. Poortman, S. T. Potgieter, J. Potjewijd, P. P.R. Rosias, T. Sprong, G. W. ten Tussher, B. J. Thio, G. A. Tramper-Stranders, M. van Deuren, H. van der Meer, A. J.M. van Kuppevelt, A. M. van Wermeskerken, W. A. Verwijs, T. F.W. Wolfs, Philipp Agyeman, Christoph Aebi, Christoph Berger, Eric Giannoni, Martin Stocker, Klara M. Posfay-Barbe, Ulrich Heininger, Sara Bernhard-Stirnemann, Anita Niederer-Loher, Christian Kahlert, Paul Hasters, Christa Relly, Walter Baer, Stéphane Paulus, Hannah Frederick, Rebecca Jennings, Joanne Johnston, Rhian Kenwright, Rachel Agbeko, Kalifa Bojang, Isatou Sarr, Ngane Kebbeh, Gibbi Sey, Momodou Saidykhan, Fatoumatta Cole, Gilleh Thomas, Martin Antonio, Wolfgang Walcher, Gotho Geishofer, Daniela Klobassa, Müller Martin, Klaus Pfurtscheller, Karl Reiter, Siegfried Rödl, Gerfried Zobel, Bettina Zöhrer, Bärbel Töpke, Peter Fucik, Markwart Gabriel, Johann M. Penzien, Gedeon Diab, Robert Miething, K. H. Deeg, Jürg Hammer, Ulrich Heininger, Verena Varnholt, Andreas Schmidt, Lutz Bindl, Ursula Sillaber, Christian Huemer, Primrose Meier, G. Simic-Schleicher, Markus Markart, Eberhard Pfau, Hans Broede, Bernd Ausserer, Hermann Kalhoff, Volker Arpe, Susanne Schweitzer-Krantz, Johannes Martin Kasper, Kathrin Loranth, Hans J. Bittrich, Burkhard Simma, Jens Klinge, Michael Fedlmaier, Nicola Weigand, Egbert Herting, Regina Grube, Christoph Fusch, Alois Gruber, Ulf Schimmel, Suzanne Knaufer-Schiefer, Wolfgang Lässig, Axel Hennenberger, Axel von der Wense, Roland Tillmann, Jürgen Schwarick, Friedrich C. Sitzmann, Werner Streif, Herbert Müller, Peter Kurnik, Peter Groneck, Ute Weiss, Helene Gröblacher-Roth, Jürgen Bensch, Reinhard Moser, Rudolf Schwarz, Kurt Lenz, Thomas Hofmann, Wolfgang Göpel, Dietrich Schulz, Thomas Berger, Erwin Hauser, Kai Martin Förster, Jochen Peters, T. homas Nicolai, Björn Kumlien, Regina Beckmann, Christiane Seitz, D. Hüseman, Roland Schürmann, Van Hop Ta, Eckart Weikmann, W. Evert, Jürgen Hautz, Jürgen Seidenberg, Lucia Wocko, Petra Luigs, Hans Ludwig Reiter, J. Quietzach, Michael König, Johanna Herrmann, Horst Mitter, Ekkehard Seidler, Bernhard Maak, Wolfgang Sperl, Karl Zwiauer, Manfred Meissl, Reinhard Koch, Manfred Cremer, H. A. Breuer, W. Görke, Robert Nossal, Walter Pernice, Ralf Brangenberg, Hans R. Salzer, Hartmut Koch, Gerhard Schaller, Franz Paky, Friedrich Straßer, Franz Eitelberger, D. Sontheimer, Andreas Lischka, Martina Kronberger, Alfred Dilch, Christian Scheibenpflug, Robert Bruckner, Klaus Mahler, Klaus Runge, Wolfgang Kunze, Peter Schermann, EUCLIDS consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA – a NF-kB subunit, master regulator of the response to infection – under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes.

Original languageEnglish
Article number6966
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

Cite this

Borghini, L., Png, E., Binder, A., Wright, V. J., Pinnock, E., de Groot, R., ... EUCLIDS consortium (2019). Identification of regulatory variants associated with genetic susceptibility to meningococcal disease. Scientific Reports, 9(1), [6966]. https://doi.org/10.1038/s41598-019-43292-6