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Exome analysis of rare and common variants within the NOD signaling pathway

Exome analysis of rare and common variants within the NOD signaling pathway
Exome analysis of rare and common variants within the NOD signaling pathway
Pediatric inflammatory bowel disease (pIBD) is a chronic heterogeneous disorder. This study looks at the burden of common and rare coding mutations within 41 genes comprising the NOD signaling pathway in pIBD patients. 136 pIBD and 106 control samples underwent whole-exome sequencing. We compared the burden of common, rare and private mutation between these two groups using the SKAT-O test. An independent replication cohort of 33 cases and 111 controls was used to validate significant findings. We observed variation in 40 of 41 genes comprising the NOD signaling pathway. Four genes were significantly associated with disease in the discovery cohort (BIRC2 p = 0.004, NFKB1 p =  0.005, NOD2 p = 0.029 and SUGT1 p = 0.047). Statistical significance was replicated for BIRC2 (p = 0.041) and NOD2 (p = 0.045) in an independent validation cohort. A gene based test on the combined discovery and replication cohort confirmed association for BIRC2 (p = 0.030). We successfully applied burden of mutation testing that jointly assesses common and rare variants, identifying two previously implicated genes (NFKB1 and NOD2) and confirmed a possible role in disease risk in a previously unreported gene (BIRC2). The identification of this novel gene provides a wider role for the inhibitor of apoptosis gene family in IBD pathogenesis.
1-11
Andreoletti, Gaia
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Shakhnovich, Valentina
d7e952a5-f9b4-4f3a-827a-d6c1c8cdfc18
Cristenson, Kathy
ae651345-3293-4137-ab45-9f6719a9c481
Coelho, Tracy
a78b627c-ea78-41e1-9553-0390921e3c93
Haggarty, Rachel
d79fd59d-2cdc-465a-93e4-b0aeb78583c6
Afzal, Nadeem A.
62505946-2503-42ba-9b02-85513bb3ec87
Batra, Akshay
822f891e-87ca-41d9-b68d-27c395e88809
Petersen, Britt-Sabina
f03a2bba-2302-48a1-9b11-e9e1853cf333
Mort, Matthew
fcdab88f-f80c-41c9-ad81-1aec03536b77
Beattie, R.M.
977a2f68-2bcf-4436-87e7-28a39952adda
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Andreoletti, Gaia
75cfc74e-f938-48c8-b3d5-5b377297d008
Shakhnovich, Valentina
d7e952a5-f9b4-4f3a-827a-d6c1c8cdfc18
Cristenson, Kathy
ae651345-3293-4137-ab45-9f6719a9c481
Coelho, Tracy
a78b627c-ea78-41e1-9553-0390921e3c93
Haggarty, Rachel
d79fd59d-2cdc-465a-93e4-b0aeb78583c6
Afzal, Nadeem A.
62505946-2503-42ba-9b02-85513bb3ec87
Batra, Akshay
822f891e-87ca-41d9-b68d-27c395e88809
Petersen, Britt-Sabina
f03a2bba-2302-48a1-9b11-e9e1853cf333
Mort, Matthew
fcdab88f-f80c-41c9-ad81-1aec03536b77
Beattie, R.M.
977a2f68-2bcf-4436-87e7-28a39952adda
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9

Andreoletti, Gaia, Shakhnovich, Valentina, Cristenson, Kathy, Coelho, Tracy, Haggarty, Rachel, Afzal, Nadeem A., Batra, Akshay, Petersen, Britt-Sabina, Mort, Matthew, Beattie, R.M. and Ennis, Sarah (2017) Exome analysis of rare and common variants within the NOD signaling pathway. Scientific Reports, 7, 1-11. (doi:10.1038/srep46454).

Record type: Article

Abstract

Pediatric inflammatory bowel disease (pIBD) is a chronic heterogeneous disorder. This study looks at the burden of common and rare coding mutations within 41 genes comprising the NOD signaling pathway in pIBD patients. 136 pIBD and 106 control samples underwent whole-exome sequencing. We compared the burden of common, rare and private mutation between these two groups using the SKAT-O test. An independent replication cohort of 33 cases and 111 controls was used to validate significant findings. We observed variation in 40 of 41 genes comprising the NOD signaling pathway. Four genes were significantly associated with disease in the discovery cohort (BIRC2 p = 0.004, NFKB1 p =  0.005, NOD2 p = 0.029 and SUGT1 p = 0.047). Statistical significance was replicated for BIRC2 (p = 0.041) and NOD2 (p = 0.045) in an independent validation cohort. A gene based test on the combined discovery and replication cohort confirmed association for BIRC2 (p = 0.030). We successfully applied burden of mutation testing that jointly assesses common and rare variants, identifying two previously implicated genes (NFKB1 and NOD2) and confirmed a possible role in disease risk in a previously unreported gene (BIRC2). The identification of this novel gene provides a wider role for the inhibitor of apoptosis gene family in IBD pathogenesis.

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Image Figure 1. NOD pathway - Accepted Manuscript
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Image Figure 2_NOD2 gene and protein - Accepted Manuscript
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Image Figure 3_BIRC2 gene and protein structures - Accepted Manuscript
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Accepted/In Press date: 20 March 2017
e-pub ahead of print date: 19 April 2017
Published date: 2017
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 406935
URI: https://eprints.soton.ac.uk/id/eprint/406935
PURE UUID: 07ece817-f48a-4f18-82b4-0343dc47411d

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Date deposited: 28 Mar 2017 01:06
Last modified: 06 Oct 2018 04:11

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Contributors

Author: Gaia Andreoletti
Author: Valentina Shakhnovich
Author: Kathy Cristenson
Author: Tracy Coelho
Author: Rachel Haggarty
Author: Nadeem A. Afzal
Author: Akshay Batra
Author: Britt-Sabina Petersen
Author: Matthew Mort
Author: R.M. Beattie
Author: Sarah Ennis

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