As with GWAS, achieving the long term objective of the complete articulation of the contribution of rare variation will ultimately require the analysis of tens of thousands of samples and a worldwide collaborative effort. We have begun HIESP with a series of projects that take advantage of established strategies to increase the power of genetic studies to discover high-impact variants, or which address specific questions of clinical importance over and above IBD risk. In the first year we have launched projects in the following areas:

Case-control samples from isolated/founder populations offer established advantages for the study of rare variation in medical genetics.  Specifically, the allele frequency spectrum and relationship of effect size and frequency is significantly more favorable in populations that have passed through a recent bottleneck, offering substantial efficiency and power in gene discovery efforts.  We have ongoing exome sequencing studies specifically targeting IBD in samples of Ashkenazi Jewish descent (where a higher rate of Crohn's disease is well-documented) as well as in Finland and the French-Canadian population of Quebec, all of which have well-established population bottlenecks influencing the architecture of rare, disease-causing variation.

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As commonly seen in all areas of medical genetics, infantile and early-onset cases are likely to harbor a heavier genetic load of IBD risk variants at all loci, including severe protein-coding mutations seen less frequently seen in adult patients.  As cases of IBD in infants and toddlers can be difficult to distinguish from severe Mendelian syndromes, we are broadly studying severe infantile diarrheal and other GI diseases beyond idiopathic IBD.


Severe adverse drug reactions are a major clinical challenge in IBD and several known examples (TPMT, NUDT15) have highlighted the potential utility of genetic testing in conjunction with drug administration.  We have initiated large-scale exome sequencing studies of thiopurine-induced myelosuppression, hepatotoxicity and pancreatitis and open to partnerships with many investigators to advance this important area of genetics with immediate potential clinical benefit to IBD patients.

Cohorts with deep longitudinal phenotyping, information on responses to therapeutics as well as those with extensive additional functional genomics data (e.g., microbiome sequencing, RNA sequencing from IBD-relevant cells and tissues) provide significant opportunity for discovery and biological insight and are prioritized for their potential clinical relevance.