Gene-gene and gene-environment interactions in ulcerative colitis

Ming Hsi Wang, Claudio Fiocchi, Xiaofeng Zhu, Stephan Ripke, M. Ilyas Kamboh, Nancy Rebert, Richard H. Duerr, Jean Paul Achkar

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Genome-wide association studies (GWAS) have identified at least 133 ulcerative colitis (UC) associated loci. The role of genetic factors in clinical practice is not clearly defined. The relevance of genetic variants to disease pathogenesis is still uncertain because of not characterized gene-gene and gene-environment interactions. We examined the predictive value of combining the 133 UC risk loci with genetic interactions in an ongoing inflammatory bowel disease (IBD) GWAS. The Wellcome Trust Case-Control Consortium (WTCCC) IBD GWAS was used as a replication cohort. We applied logic regression (LR), a novel adaptive regression methodology, to search for high-order interactions. Exploratory genotype correlations with UC sub-phenotypes [extent of disease, need of surgery, age of onset, extra-intestinal manifestations and primary sclerosing cholangitis (PSC)] were conducted. The combination of 133 UC loci yielded good UC risk predictability [area under the curve (AUC) of 0.86]. A higher cumulative allele score predicted higher UC risk. Through LR, several lines of evidence for genetic interactions were identified and successfully replicated in the WTCCC cohort. The genetic interactions combined with the gene-smoking interaction significantly improved predictability in the model (AUC, from 0.86 to 0.89, P = 3.26E-05). Explained UC variance increased from 37 to 42 % after adding the interaction terms. A within case analysis found suggested genetic association with PSC. Our study demonstrates that the LR methodology allows the identification and replication of high-order genetic interactions in UC GWAS datasets. UC risk can be predicted by a 133 loci and improved by adding gene-gene and gene-environment interactions.

Original languageEnglish (US)
Pages (from-to)547-558
Number of pages12
JournalHuman Genetics
Volume133
Issue number5
DOIs
StatePublished - 2014
Externally publishedYes

Fingerprint

Gene-Environment Interaction
Ulcerative Colitis
Genome-Wide Association Study
Genes
Sclerosing Cholangitis
Inflammatory Bowel Diseases
Area Under Curve
Genetic Loci
Age of Onset
Smoking
Alleles
Genotype
Phenotype

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Wang, M. H., Fiocchi, C., Zhu, X., Ripke, S., Kamboh, M. I., Rebert, N., ... Achkar, J. P. (2014). Gene-gene and gene-environment interactions in ulcerative colitis. Human Genetics, 133(5), 547-558. https://doi.org/10.1007/s00439-013-1395-z

Gene-gene and gene-environment interactions in ulcerative colitis. / Wang, Ming Hsi; Fiocchi, Claudio; Zhu, Xiaofeng; Ripke, Stephan; Kamboh, M. Ilyas; Rebert, Nancy; Duerr, Richard H.; Achkar, Jean Paul.

In: Human Genetics, Vol. 133, No. 5, 2014, p. 547-558.

Research output: Contribution to journalArticle

Wang, MH, Fiocchi, C, Zhu, X, Ripke, S, Kamboh, MI, Rebert, N, Duerr, RH & Achkar, JP 2014, 'Gene-gene and gene-environment interactions in ulcerative colitis', Human Genetics, vol. 133, no. 5, pp. 547-558. https://doi.org/10.1007/s00439-013-1395-z
Wang MH, Fiocchi C, Zhu X, Ripke S, Kamboh MI, Rebert N et al. Gene-gene and gene-environment interactions in ulcerative colitis. Human Genetics. 2014;133(5):547-558. https://doi.org/10.1007/s00439-013-1395-z
Wang, Ming Hsi ; Fiocchi, Claudio ; Zhu, Xiaofeng ; Ripke, Stephan ; Kamboh, M. Ilyas ; Rebert, Nancy ; Duerr, Richard H. ; Achkar, Jean Paul. / Gene-gene and gene-environment interactions in ulcerative colitis. In: Human Genetics. 2014 ; Vol. 133, No. 5. pp. 547-558.
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