Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

EUCLIDS consortium

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
Externally publishedYes

Cite this

@article{8c6c365a77914896b772cd492cac459d,
title = "Identification of regulatory variants associated with genetic susceptibility to meningococcal disease",
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.",
author = "Lisa Borghini and Eileen Png and Alexander Binder and Wright, {Victoria J.} and Ellie Pinnock and {de Groot}, Ronald and Jan Hazelzet and Marieke Emonts and {Van der Flier}, Michiel and Schlapbach, {Luregn J.} and Suzanne Anderson and Fatou Secka and Antonio Salas and Colin Fink and Carrol, {Enitan D.} and Pollard, {Andrew J.} and Coin, {Lachlan J.} and Kuijpers, {Taco W.} and Federico Martinon-Torres and Werner Zenz and Michael Levin and Hibberd, {Martin L.} and Sonia Davila and Stuart Gormley and Shea Hamilton and Jethro Herberg and Bernardo Hourmat and Clive Hoggart and Myrsini Kaforou and Vanessa Sancho-Shimizu and Amina Abdulla and Paul Agapow and Maeve Bartlett and Evangelos Bellos and Hariklia Eleftherohorinou and Rachel Galassini and David Inwald and Meg Mashbat and Stefanie Menikou and Sobia Mustafa and Simon Nadel and Rahmeen Rahman and Clare Thakker and S. Bokhandi and Sue Power and Heather Barham and N. Pathan and Jenna Ridout and Deborah White and Sarah Thurston and {EUCLIDS consortium}",
year = "2019",
month = "12",
day = "1",
doi = "10.1038/s41598-019-43292-6",
language = "English",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

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

In: Scientific Reports, Vol. 9, No. 1, 6966, 01.12.2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

AU - Borghini, Lisa

AU - Png, Eileen

AU - Binder, Alexander

AU - Wright, Victoria J.

AU - Pinnock, Ellie

AU - de Groot, Ronald

AU - Hazelzet, Jan

AU - Emonts, Marieke

AU - Van der Flier, Michiel

AU - Schlapbach, Luregn J.

AU - Anderson, Suzanne

AU - Secka, Fatou

AU - Salas, Antonio

AU - Fink, Colin

AU - Carrol, Enitan D.

AU - Pollard, Andrew J.

AU - Coin, Lachlan J.

AU - Kuijpers, Taco W.

AU - Martinon-Torres, Federico

AU - Zenz, Werner

AU - Levin, Michael

AU - Hibberd, Martin L.

AU - Davila, Sonia

AU - Gormley, Stuart

AU - Hamilton, Shea

AU - Herberg, Jethro

AU - Hourmat, Bernardo

AU - Hoggart, Clive

AU - Kaforou, Myrsini

AU - Sancho-Shimizu, Vanessa

AU - Abdulla, Amina

AU - Agapow, Paul

AU - Bartlett, Maeve

AU - Bellos, Evangelos

AU - Eleftherohorinou, Hariklia

AU - Galassini, Rachel

AU - Inwald, David

AU - Mashbat, Meg

AU - Menikou, Stefanie

AU - Mustafa, Sobia

AU - Nadel, Simon

AU - Rahman, Rahmeen

AU - Thakker, Clare

AU - Bokhandi, S.

AU - Power, Sue

AU - Barham, Heather

AU - Pathan, N.

AU - Ridout, Jenna

AU - White, Deborah

AU - Thurston, Sarah

AU - EUCLIDS consortium

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85065322281&partnerID=8YFLogxK

U2 - 10.1038/s41598-019-43292-6

DO - 10.1038/s41598-019-43292-6

M3 - Article

VL - 9

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 6966

ER -