TY - JOUR
T1 - Identification of regulatory variants associated with genetic susceptibility to meningococcal disease
AU - EUCLIDS consortium
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 - Peters, Jochen
N1 - Publisher Copyright:
© 2019, The Author(s).
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 - https://www.scopus.com/pages/publications/85065322281
U2 - 10.1038/s41598-019-43292-6
DO - 10.1038/s41598-019-43292-6
M3 - Article
C2 - 31061469
AN - SCOPUS:85065322281
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 6966
ER -
SDG 3 Good Health and Well-being