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Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes

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Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes. / Prescott, Natalie J; Lehne, Benjamin; Stone, Kristina; Lee, James C; Taylor, Kirstin; Knight, Jo; Papouli, Efterpi; Mirza, Muddassar M; Simpson, Michael A; Spain, Sarah L; Lu, Grace; Fraternali, Franca; Bumpstead, Suzannah J; Gray, Emma; Amar, Ariella; Bye, Hannah; Green, Peter; Chung-Faye, Guy; Hayee, Bu'Hussain; Pollok, Richard; Satsangi, Jack; Parkes, Miles; Barrett, Jeffrey C; Mansfield, John C; Sanderson, Jeremy; Lewis, Cathryn M; Weale, Michael E; Schlitt, Thomas; Mathew, Christopher G; UK IBD Genetics Consortium.

In: PL o S Genetics, Vol. 11, No. 2, e1004955, 11.02.2015.

Research output: Contribution to journalArticle

Harvard

Prescott, NJ, Lehne, B, Stone, K, Lee, JC, Taylor, K, Knight, J, Papouli, E, Mirza, MM, Simpson, MA, Spain, SL, Lu, G, Fraternali, F, Bumpstead, SJ, Gray, E, Amar, A, Bye, H, Green, P, Chung-Faye, G, Hayee, BH, Pollok, R, Satsangi, J, Parkes, M, Barrett, JC, Mansfield, JC, Sanderson, J, Lewis, CM, Weale, ME, Schlitt, T, Mathew, CG & UK IBD Genetics Consortium 2015, 'Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes', PL o S Genetics, vol. 11, no. 2, e1004955. https://doi.org/10.1371/journal.pgen.1004955

APA

Prescott, N. J., Lehne, B., Stone, K., Lee, J. C., Taylor, K., Knight, J., Papouli, E., Mirza, M. M., Simpson, M. A., Spain, S. L., Lu, G., Fraternali, F., Bumpstead, S. J., Gray, E., Amar, A., Bye, H., Green, P., Chung-Faye, G., Hayee, BH., ... UK IBD Genetics Consortium (2015). Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes. PL o S Genetics, 11(2), [e1004955]. https://doi.org/10.1371/journal.pgen.1004955

Vancouver

Prescott NJ, Lehne B, Stone K, Lee JC, Taylor K, Knight J et al. Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes. PL o S Genetics. 2015 Feb 11;11(2). e1004955. https://doi.org/10.1371/journal.pgen.1004955

Author

Prescott, Natalie J ; Lehne, Benjamin ; Stone, Kristina ; Lee, James C ; Taylor, Kirstin ; Knight, Jo ; Papouli, Efterpi ; Mirza, Muddassar M ; Simpson, Michael A ; Spain, Sarah L ; Lu, Grace ; Fraternali, Franca ; Bumpstead, Suzannah J ; Gray, Emma ; Amar, Ariella ; Bye, Hannah ; Green, Peter ; Chung-Faye, Guy ; Hayee, Bu'Hussain ; Pollok, Richard ; Satsangi, Jack ; Parkes, Miles ; Barrett, Jeffrey C ; Mansfield, John C ; Sanderson, Jeremy ; Lewis, Cathryn M ; Weale, Michael E ; Schlitt, Thomas ; Mathew, Christopher G ; UK IBD Genetics Consortium. / Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes. In: PL o S Genetics. 2015 ; Vol. 11, No. 2.

Bibtex Download

@article{8f8fdbae8bfd47c987f9f16877e7c529,
title = "Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes",
abstract = "The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1-5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.",
author = "Prescott, {Natalie J} and Benjamin Lehne and Kristina Stone and Lee, {James C} and Kirstin Taylor and Jo Knight and Efterpi Papouli and Mirza, {Muddassar M} and Simpson, {Michael A} and Spain, {Sarah L} and Grace Lu and Franca Fraternali and Bumpstead, {Suzannah J} and Emma Gray and Ariella Amar and Hannah Bye and Peter Green and Guy Chung-Faye and Bu'Hussain Hayee and Richard Pollok and Jack Satsangi and Miles Parkes and Barrett, {Jeffrey C} and Mansfield, {John C} and Jeremy Sanderson and Lewis, {Cathryn M} and Weale, {Michael E} and Thomas Schlitt and Mathew, {Christopher G} and {UK IBD Genetics Consortium}",
year = "2015",
month = feb,
day = "11",
doi = "10.1371/journal.pgen.1004955",
language = "English",
volume = "11",
journal = "PL o S Genetics",
issn = "1553-7390",
number = "2",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes

AU - Prescott, Natalie J

AU - Lehne, Benjamin

AU - Stone, Kristina

AU - Lee, James C

AU - Taylor, Kirstin

AU - Knight, Jo

AU - Papouli, Efterpi

AU - Mirza, Muddassar M

AU - Simpson, Michael A

AU - Spain, Sarah L

AU - Lu, Grace

AU - Fraternali, Franca

AU - Bumpstead, Suzannah J

AU - Gray, Emma

AU - Amar, Ariella

AU - Bye, Hannah

AU - Green, Peter

AU - Chung-Faye, Guy

AU - Hayee, Bu'Hussain

AU - Pollok, Richard

AU - Satsangi, Jack

AU - Parkes, Miles

AU - Barrett, Jeffrey C

AU - Mansfield, John C

AU - Sanderson, Jeremy

AU - Lewis, Cathryn M

AU - Weale, Michael E

AU - Schlitt, Thomas

AU - Mathew, Christopher G

AU - UK IBD Genetics Consortium

PY - 2015/2/11

Y1 - 2015/2/11

N2 - The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1-5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.

AB - The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1-5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.

U2 - 10.1371/journal.pgen.1004955

DO - 10.1371/journal.pgen.1004955

M3 - Article

C2 - 25671699

VL - 11

JO - PL o S Genetics

JF - PL o S Genetics

SN - 1553-7390

IS - 2

M1 - e1004955

ER -

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