Beyond disease susceptibility-Leveraging genome-wide association studies for new insights into complex disease biology

HLA. 2017 Dec;90(6):329-334. doi: 10.1111/tan.13170.


Genetic studies in complex diseases have been highly successful, but have also been largely one-dimensional: predominantly focusing on the genetic contribution to disease susceptibility. While this is undoubtedly important-indeed it is a pre-requisite for understanding the mechanisms underlying disease development-there are many other important aspects of disease biology that have received comparatively little attention. In this review, I will discuss how existing genetic data can be leveraged to provide new insights into other aspects of disease biology, why such insights could change the way we think about complex disease, and how this could provide opportunities for better therapies and/or facilitate personalised medicine. To do this, I will use the example of Crohn's disease-a chronic form of inflammatory bowel disease that has been one of the main success stories in complex disease genetics. Indeed, thanks to genetic studies, we now have a much more detailed understanding of the processes involved in Crohn's disease development, but still know relatively little about what determines the subsequent disease course (prognosis) and why this differs so considerably between individuals. I will discuss how we came to realise that genetic variation plays an important role in determining disease prognosis and how this has changed the way we think about Crohn's disease genetics. This will illustrate how phenotypic data can be used to leverage new insights from genetic data and will provide a broadly applicable framework that could yield new insights into the biology of multiple diseases.

Keywords: Crohn's disease; GWAS; SNPs; prognosis; susceptibility.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Crohn Disease / diagnosis
  • Crohn Disease / genetics*
  • Crohn Disease / immunology
  • Crohn Disease / pathology
  • Forkhead Box Protein O3 / genetics
  • Forkhead Box Protein O3 / immunology
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / immunology
  • Gene Expression Regulation*
  • Genetic Loci
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genome, Human*
  • Genome-Wide Association Study
  • Humans
  • Nod2 Signaling Adaptor Protein / genetics
  • Nod2 Signaling Adaptor Protein / immunology
  • Prognosis
  • Severity of Illness Index
  • Smad3 Protein / genetics
  • Smad3 Protein / immunology
  • Toll-Like Receptor 10 / genetics
  • Toll-Like Receptor 10 / immunology


  • FOXO3 protein, human
  • Forkhead Box Protein O3
  • NOD2 protein, human
  • Nod2 Signaling Adaptor Protein
  • SMAD3 protein, human
  • Smad3 Protein
  • TLR10 protein, human
  • Toll-Like Receptor 10
  • GTP-Binding Proteins
  • IRGM protein, human