Identification of regulatory variants associated with genetic susceptibility to meningococcal disease
Authors: Borghini Lisa , Png Eileen , Binder Alexander , Wright Victoria J. , Pinnock Ellie , de Groot Ronald , Hazelzet Jan , Emonts Marieke , Van der Flier Michiel , Schlapbach Luregn J. , Anderson Suzanne , Secka Fatou , Salas Antonio , Fink Colin , Carrol Enitan D. , Pollard Andrew J. , Coin Lachlan J. , Kuijpers Taco W. , Martinon-Torres Federico , Zenz Werner , Levin Michael , Hibberd Martin L. , Davila Sonia ,   EUCLIDS consortium, Gormley Stuart , Hamilton Shea , Herberg Jethro , Hourmat Bernardo , Hoggart Clive , Kaforou Myrsini , Sancho-Shimizu Vanessa , Abdulla Amina , Agapow Paul , Bartlett Maeve , Bellos Evangelos , Eleftherohorinou Hariklia , Galassini Rachel , Inwald David , Mashbat Meg , Menikou Stefanie , Mustafa Sobia , Nadel Simon , Rahman Rahmeen , Thakker Clare , Bokhandi S. , Power Sue , Barham Heather , Pathan N. , Ridout Jenna , White Deborah , Thurston Sarah , Faust S. , Patel S. , McCorkell Jenni , Davies P. , Cratev Lindsey , Navarra Helen , Carter Stephanie , Ramaiah R. , Patel Rekha , Tuffrey Catherine , Gribbin Andrew , McCready Sharon , Peters Mark , Hardy Katie , Standing Fran , O’Neill Lauren , Abelake Eugenia , Deep Akash , Nsirim Eniola , Willis Louise , Young Zoe , Royad C. , White Sonia , Fortune P. M. , Hudnott Phil , González Fernando Álvez , Barral-Arca Ruth , Cebey-López Miriam , Curras-Tuala María José , García Natalia , Vicente Luisa García , Gómez-Carballa Alberto , Rial Jose Gómez , Beiroa Andrea Grela , Grande Antonio Justicia , Iglesias Pilar Leboráns , Santos Alba Elena Martínez , Martinón-Torres Nazareth , Sánchez José María Martinón , Pérez Belén Mosquera , Pacheco Pablo Obando , Pardo-Seco Jacobo , Pischedda Sara , Calle Irene Rivero , Rodríguez-Tenreiro Carmen , Redondo-Collazo Lorenzo , Fernández Sonia Serén , Silva María del Sol Porto , Vega Ana , Reyes Susana Beatriz , León María Cruz León , Mingorance Álvaro Navarro , Barrios Xavier Gabaldó , Vergara Eider Oñate , Torre Andrés Concha , Vivanco Ana , Fernández Reyes , Sánchez Francisco Giménez , Forte Miguel Sánchez , Rojo Pablo , Contreras J. Ruiz , Palacios Alba , Navarro Marisa , Álvarez Cristina Álvarez , Lozano María José , Carreras Eduardo , Sanagustín Sonia Brió , Neth Olaf , Padilla Ma del Carmen Martínez , Tato Luis Manuel Prieto , Guillén Sara , Silveira Laura Fernández , Moreno David , van Furth A. M. Tutu , van der Flier M. , Boeddha N. P. , Driessen G. J. A. , Pajkrt D. , Sanders E. A. M. , van de Beek D. , van der Ende A. , Philipsen H. L. A. , Adeel A. O. A. , Breukels M. A. , Brinkman D. M. C. , de Korte C. C. M. M. , de Vries E. , de Waal W. J. , Dekkers R. , Dings-Lammertink A. , Doedens R. A. , Donker A. E. , Dousma M. , Faber T. E. , Gerrits G. P. J. M. , Gerver J. A. M. , Heidema J. , Homan-van der Veen J. , Jacobs M. A. M. , Jansen N. J. G. , Kawczynski P. , Klucovska K. , Kneyber M. C. J. , Koopman-Keemink Y. , Langenhorst V. J. , Leusink J. , Loza B. F. , Merth I. T. , Miedema C. J. , Neeleman C. , Noordzij J. G. , Obihara C. C. , van Overbeek-van Gils A. L. T. , Poortman G. H. , Potgieter S. T. , Potjewijd J. , Rosias P. P. R. , Sprong T. , ten Tussher G. W. , Thio B. J. , Tramper-Stranders G. A. , van Deuren M. , van der Meer H. , van Kuppevelt A. J. M. , van Wermeskerken A. M. , Verwijs W. A. , Wolfs T. F. W. , Agyeman Philipp , Aebi Christoph , Berger Christoph , Giannoni Eric , Stocker Martin , Posfay-Barbe Klara M , Heininger Ulrich , Bernhard-Stirnemann Sara , Niederer-Loher Anita , Kahlert Christian , Hasters Paul , Relly Christa , Baer Walter , Paulus Stéphane , Frederick Hannah , Jennings Rebecca , Johnston Joanne , Kenwright Rhian , Agbeko Rachel , Bojang Kalifa , Sarr Isatou , Kebbeh Ngane , Sey Gibbi , Saidykhan Momodou , Cole Fatoumatta , Thomas Gilleh , Antonio Martin , Walcher Wolfgang , Geishofer Gotho , Klobassa Daniela , Martin Müller , Pfurtscheller Klaus , Reiter Karl , Rödl Siegfried , Zobel Gerfried , Zöhrer Bettina , Töpke Bärbel , Fucik Peter , Gabriel Markwart , Penzien Johann M. , Diab Gedeon , Miething Robert , Deeg K. H. , Hammer Jürg , Heininger Ulrich , Varnholt Verena , Schmidt Andreas , Bindl Lutz , Sillaber Ursula , Huemer Christian , Meier Primrose , Simic-Schleicher G. , Markart Markus , Pfau Eberhard , Broede Hans , Ausserer Bernd , Kalhoff Hermann , Arpe Volker , Schweitzer-Krantz Susanne , Kasper Johannes-Martin , Loranth Kathrin , Bittrich Hans J. , Simma Burkhard , Klinge Jens , Fedlmaier Michael , Weigand Nicola , Herting Egbert , Grube Regina , Fusch Christoph , Gruber Alois , Schimmel Ulf , Knaufer-Schiefer Suzanne , Lässig Wolfgang , Hennenberger Axel , von der Wense Axel , Tillmann Roland , Schwarick Jürgen , Sitzmann Friedrich C. , Streif Werner , Müller Herbert , Kurnik Peter , Groneck Peter , Weiss Ute , Gröblacher-Roth Helene , Bensch Jürgen , Moser Reinhard , Schwarz Rudolf , Lenz Kurt , Hofmann Thomas , Göpel Wolfgang , Schulz Dietrich , Berger Thomas , Hauser Erwin , Förster Kai Martin , Peters Jochen , Nicolai T homas , Kumlien Björn , Beckmann Regina , Seitz Christiane , Hüseman D. , Schürmann Roland , Ta Van Hop , Weikmann Eckart , Evert W. , Hautz Jürgen , Seidenberg Jürgen , Wocko Lucia , Luigs Petra , Reiter Hans-Ludwig , Quietzach J. , König Michael , Herrmann Johanna , Mitter Horst , Seidler Ekkehard , Maak Bernhard , Sperl Wolfgang , Zwiauer Karl , Meissl Manfred , Koch Reinhard , Cremer Manfred , Breuer H. A. , Görke W. , Nossal Robert , Pernice Walter , Brangenberg Ralf , Salzer Hans R. , Koch Hartmut , Schaller Gerhard , Paky Franz , Straßer Friedrich , Eitelberger Franz , Sontheimer D. , Lischka Andreas , Kronberger Martina , Dilch Alfred , Scheibenpflug Christian , Bruckner Robert , Mahler Klaus , Runge Klaus , Kunze Wolfgang , Schermann Peter 
Published: May 2019

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.