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.
Highlights
Since the discovery of NOD2 in 2001 as the first susceptibility gene for IBD3, over 200 loci have been associated with IBD risk in humans through genome wide association studies (GWAS)[4,5]
Pediatric onset IBD presents with unique phenotypic characteristics and pronounced severity compared to adult-onset disease[13]
principle component analysis (PCA) procedure removed 10 cases and 20 controls reducing the final number of cases to 136 and controls to 106 within the discovery cohort (Supplementary Figure 1)
Summary
Since the discovery of NOD2 in 2001 as the first susceptibility gene for IBD3, over 200 loci have been associated with IBD risk in humans through genome wide association studies (GWAS)[4,5]. Recent technological advances in DNA sequencing have made it possible to sequence large tracts of the genome in a cost-effective manner. This has enabled large-scale studies of the impact of rare variants on complex diseases[9]. It is estimated that ~85% of disease-causing mutations reside within the coding regions of the genome[11] Targeting these expressed regions of the genome represents the most cost-effective means to uncover causal disease genes[12]. Early-onset IBD has a stronger familial component than adult disease[1] These combined features indicate a stronger genetic component to pIBD compared to IBD diagnosed in adulthood.
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