Journal Article

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Png, Eileen, Hibberd, Martin L., Emonts, Marieke, Anderson, Suzanne, Salas, Antonio, Kuijpers, Taco W., Coin, Lachlan J., Borghini, Lisa, Zenz, Werner, Fink, Colin, Binder, Alexander, Pinnock, Ellie, Levin, Michael, Hazelzet, Jan, Schlapbach, Luregn J., Carrol, Enitan D., Pollard, Andrew J., Wright, Victoria J., de Groot, Ronald, Davila, Sonia, Van der Flier, Michiel, Secka, Fatou, Martinon-Torres, Federico

2019

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 38/39 / 45/15 / 45/23 / 631/208/200 / 631/208/205 / 631/250/255/1638 / Association analysis / Binding sites / Case-Control Studies / Cohort Studies / Disease / Epithelial cells / Genetic Association Studies / Genetic diversity / Genetic Predisposition to Disease / Genetic variance / Genomics / Genotyping / High-Throughput Nucleotide Sequencing / Humanities and Social Sciences / Humans / Hypopharyngeal Neoplasms - genetics / Hypopharyngeal Neoplasms - microbiology / Hypopharyngeal Neoplasms - pathology / Infectious diseases / Meningococcal disease / Meningococcal Infections - epidemiology / Meningococcal Infections - genetics / Meningococcal Infections - microbiology / multidisciplinary / Neisseria meningitidis - genetics / Neisseria meningitidis - isolation & purification / NF-κB protein / Phenotype / Phenotypes / Polymorphism, Single Nucleotide / Regulatory sequences / Regulatory Sequences, Nucleic Acid / RelA protein / Science / Science (multidisciplinary) / Single-nucleotide polymorphism / Tumor Cells, Cultured / Vaccines