Identification of regulatory variants associated with genetic susceptibility to meningococcal disease.

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; ... (2019). Identification of regulatory variants associated with genetic susceptibility to meningococcal disease. Scientific reports, 9(1), p. 6966. Springer Nature 10.1038/s41598-019-43292-6

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine

UniBE Contributor:

Schlapbach, Luregn Jan

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2045-2322

Publisher:

Springer Nature

Funders:

[42] Schweizerischer Nationalfonds
[72] Vinetum Foundation
[28] Gottfried und Julia Bangerter Rhyner Stiftung
[UNSPECIFIED] Foundation for Health of Children and Adolescents

Language:

English

Submitter:

Andrea Stettler

Date Deposited:

30 Dec 2019 11:32

Last Modified:

05 Jan 2020 02:44

Publisher DOI:

10.1038/s41598-019-43292-6

PubMed ID:

31061469

BORIS DOI:

10.7892/boris.137755

URI:

https://boris.unibe.ch/id/eprint/137755

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