06. February 2013 · Comments Off on Moving from common to rare · Categories: Conferences, Editorial · Tags: , , ,

One of the main research focuses of the Barrett group is to understand genetic associations with Inflammatory Bowel Disease (IBD), in particular with its two most common subtypes, Crohn’s disease and ulcerative colitis (UC).

Back in November 2012, in preparation for the ASHG meeting, I did a brief literature review on the development of IBD based on a number of selected publications. The motion chart below (created in R as used in the well-known Hans Rosling TED talk) shows an overview of the discovery of IBD disease loci since 2001, when three independent groups identified a CD risk gene on chromosome 16q12, NOD2, using linkage techniques.

MotionChartID17b62b2346c5
Plot: IBD Motion Chart
R version 2.15.2 (2012-10-26) • googleVis-0.2.17Google Terms of UseData Policy

The y-axis (in the default setting) shows the odds ratio for each IBD association reported at a certain time. The x-axis is the minor allele frequency of the risk variants. Viewers can customize the size and colour of the data points using the drop-down boxes in the top right corner.

If we play the timeline of the risk variant discovery, the number of disease loci can be seen to increase rapidly every year since we entered the era of genome-wide association studies (GWAS):

  • A risk variant was identified by a Japanese group in TNFSF15 – a gene encoding a cytokine belonging to the tumour necrosis factor (TNF) family using genome wide arrays which surveyed a small proportion of the genome in 2005.
  • The first full-scale IBD GWAS was led by Duerr et al. (2006). They observed highly significant association between CD and variants in the interleukin 23 receptor (IL23R) on chromosome 1p31.
  • The WTCCC (Wellcome Trust Case Control Consortium) added 9 more independent CD signals to the list in 2007.
  • Barrett et al. (2008) combined data from three studies on CD and increased the tally of susceptibility loci to more than 30.
  • Five new loci associated with early-onset IBD were reported by Imielinski et al. (2009).
  • Franke et al. (2010) increased the confirmed CD susceptibility loci to 71.
  • Anderson et al. (2011) identified 29 additional ulcerative colitis (UC) risk loci, increasing the total number of confirmed UC associations to 47.
  • Most recently, Jostins et al. (2012) added another 71 loci to the list, making 163 risk loci for IBD in total, the largest for any complex disease.

Following the notable successes of IBD GWAS – a joint effort by all the scientists in the IBD community – it has become increasingly clear that GWAS alone will not explain all of the disease’s heritability. As we observe in the motion chart, these GWAS discoveries have been limited almost completely to common variants (MAF > 0.1). Rarer variants, which may confer a relatively large effect size, may help us understand this missing heritability.

A hypothesis-free way of discovering low-frequency risk variation is to extend the genome-wide approach that has been so successful in GWAS by using next-generation sequencing. Two research groups from the Wellcome Trust Sanger Institute, in collaboration with the UK IBD Genetics Consortium (UKIBDGC), designed a large low-coverage sequencing project of IBD cases. The project is funded by the Wellcome Trust and the MRC, and will sequence 5,000 cases (3,000 CD and 2,000 UC). This data will be combined with the 4,000+ UK10K cohort controls to produce one of the largest whole-genome sequencing case-control datasets to date.

Our group is now focusing on analyzing this data, and together with our fellow researchers, we will be updating the chart as this exciting field develops. So add us to your RSS feed and check back here for the new genetic risk factors that will be added in 2013!

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