Journal article

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 Zenz Show all

Scientific Reports | NATURE PUBLISHING GROUP | Published : 2019

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..

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University of Melbourne Researchers

Grants

Awarded by Agency for Science Technology and Research of Singapore (A*STAR) - European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS


Awarded by Instituto de Salud Carlos III (Proyecto de Investigacion en Salud, Accion Estrategica en Salud)


Awarded by Conselleria de Sanidade, Xunta de Galicia


Awarded by Fondo de Investigacion Sanitaria (FIS)


Awarded by Swiss National Science Foundation


Awarded by Foundation for the Health of Children and Adolescents


Funding Acknowledgements

We thank Kumar Vikrant for his advices on the association analysis as well as Phua Zai Yang for his help on the library preparation and hybridization. The Next Generation Sequencing Platform and the Research Pipeline Development team at the Genome Institute of Singapore made the sequencing possible as well as data processing and mapping of the reads. In addition, we acknowledge A*STAR for the SINGA scholarship awarded to LB. Finally, we would like to thank all children and parents who participated in this study. S.D., E.P., M.H. and L.B. were supported by the Agency for Science Technology and Research of Singapore (A*STAR). This work has been partially funded by the European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS Grant Agreement No. 279185. The UK meningococcal cohort was established with support from Meningitis Research Foundation through grants to Imperial College London. The Research from Newcastle partners was supported by the National Institute for Health Research Newcastle Biomedical Research Centre based at Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The ESIGEM Research group activities were supported by grants from Instituto de Salud Carlos III (Proyecto de Investigacion en Salud, Accion Estrategica en Salud: proyecto GePEM PI16/01478) (A.S.); Conselleria de Sanidade, Xunta de Galicia (RHI07/2-intensificacion actividad investigadora, PS09749 and 10PXIB918184PR), Instituto de Salud Carlos III (Intensificacion de la actividad investigadora 2007-2016), Convenio de colaboracion de investigacion (Wyeth Espana-Fundacion IDICHUS 2007-2011), Convenio de colaboracion de investigacion (Novartis Espana-Fundacion IDICHUS 2010-2011), Fondo de Investigacion Sanitaria (FIS; PI070069/PI1000540) del plan nacional de I + D + I and 'fondos FEDER' (F.M.T.). The Swiss Pediatric Sepsis study was funded by grants from the Swiss National Science Foundation (342730_153158/1), the Swiss Society of Intensive Care, the Bangerter Foundation, the Vinetum and Borer Foundation, and the Foundation for the Health of Children and Adolescents. The Western Europe Meningococcal Study was supported by grants no 8842, 10112 and 12710 of the Oesterreichische Nationalbank (Austria), grants A3-16.K-8/2008-11 and A3-16.K-8/2006-9 of the Department for Science and Research of the Styrian federal government (Austria) and the non for profit association 'In Vita', Graz (Austria).