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Epistasis01:39

Epistasis

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In addition to multiple alleles at the same locus influencing traits, numerous genes or alleles at different locations may interact and influence phenotypes in a phenomenon called epistasis. For example, rabbit fur can be black or brown depending on whether the animal is homozygous dominant or heterozygous at a TYRP1 locus. However, if the rabbit is also homozygous recessive at a locus on the tyrosinase gene (TYR), it will have an unshaded coat that appears white, regardless of its TYRP1...
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Inflammatory Bowel Disease I: Ulcerative Colitis01:27

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Introduction
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Ulcerative colitis is a chronic inflammatory condition primarily affecting the colon and rectum. The primary drugs used in the treatment of ulcerative colitis are aminosalicylates. They exhibit anti-inflammatory and immunosuppressive properties. They modulate inflammatory mediators and inhibit the activity of nuclear factor κB (NF-κB). Aminosalicylates also reduce inflammation by inhibiting prostaglandin and leukotriene production and decreasing neutrophil chemotaxis and superoxide...
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Epistasis Analysis01:09

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Although Mendel chose seven unrelated traits in peas to study gene segregation, most traits involve multiple gene interactions that create a spectrum of phenotypes. When the interaction of various genes or alleles at different locations influences a phenotype, this is called epistasis. Epistasis often involves one gene masking or interfering with the expression of another (antagonistic epistasis). Epistasis often occurs when different genes are part of the same biochemical pathway. The...
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The Concept of Multiple Allelism
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Peptic Ulcer Disease (PUD) is characterized by the development of ulcers in the stomach or duodenal mucosa. Its pathophysiology is complex, involving a balance between damaging and protective elements.
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Multiple Epistasis Interactions Within MHC Are Associated With Ulcerative Colitis.

Jie Zhang1,2, Zhi Wei1, Christopher J Cardinale3

  • 1Department of Computer Science, New Jersey Institute of Technology, Newark, NJ, United States.

Frontiers in Genetics
|April 20, 2019
PubMed
Summary

Detecting gene interactions (epistasis) is difficult but possible in large datasets. This study found significant epistatic signals within the MHC region for inflammatory bowel disease, with some replicated in a separate cohort.

Keywords:
epistasisgenome-wide association studyimmunochipmajor histocompatibility complexulcerative colitis

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Area of Science:

  • Genetics
  • Genomics
  • Computational Biology

Background:

  • Epistasis detection typically requires large sample sizes and dense genetic marker data.
  • Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a complex condition with genetic underpinnings.
  • Previous studies have faced challenges in identifying epistatic interactions due to these requirements.

Purpose of the Study:

  • To identify epistatic interactions in large cohorts of Crohn's disease and ulcerative colitis.
  • To leverage dense marker information and substantial sample sizes for robust epistasis analysis.
  • To investigate the role of epistasis within the Major Histocompatibility Complex (MHC) region in IBD.

Main Methods:

  • Utilized the largest available IBD datasets for CD (18,000 cases + 34,000 controls) and UC (14,000 cases + 34,000 controls).
  • Employed a two-step approach for exhaustive epistasis searching, considering marker dependencies.
  • Performed conditional analyses to assess the significance of epistatic signals independent of additive effects.

Main Results:

  • Detected numerous genome-wide significant epistatic signals (p < 1 × 10^-13), exclusively within the MHC region.
  • Nine epistatic interaction pairs remained significant at the Immunochip-wide level (P < 1.1 × 10^-8) for UC after accounting for additive effects.
  • These significant interactions explained approximately 0.15% of phenotypic variance on average and eight were successfully replicated.

Conclusions:

  • Epistasis analysis in large, dense-marker datasets is a promising strategy for uncovering genetic interactions in complex diseases.
  • Multiple, albeit weak, epistatic interactions independent of additive effects exist within the MHC region for UC.
  • The findings highlight the importance of considering epistasis in IBD genetic studies, particularly within the MHC region.