Genetics and gene regulation in the inflammatory bowel diseases

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! ABSTRACT Genome-wide association studies have found 200 genetic loci associated with the inflammatory bowel diseases (IBD). With other colleagues, Dr. Hailiang Huang led the recent fine-mapping effort in the international IBD genetics consortium and convincingly mapped many of these disease associations to a small set of variants with high causal probabilities. Despite that a lot of these fine-mapped causal variants are near genes, few of them have well characterized functions. This four-year research plan is proposed to fill in this knowledge gap by developing and employing novel statistical genetics methods and analyses to systematically understand the connection between tissue-specific gene regulation and IBD genetics. With the planned training and mentoring, Dr. Huang will develop novel methods to identify cis-regulatory elements such as the expression quantitative trait loci and the splice quantitative trait loci using RNA sequencing. These methods take advantage of the allele specific information, but unlike existing methods, do not require the knowledge of phase. As a result, this study will identify previously missed cis-regulatory variants that are rare or distant to genes with limited linkage-disequilibrium for phasing. Epigenomic profiles will be used to empirically identify tissues that the disease associated cis-regulatory elements are likely to function in. Loss- of-function variants disrupting transcript isoforms specific to the disease relevant tissues will also be integrated in the analysis. Furthermore, Dr. Huang will perform fine-mapping for IBD associations using a novel method that combines individuals genotyped and sequenced on various platforms, and leverages the distinct linkage-disequilibrium patterns from worldwide populations. A Bayesian statistical method will be designed to understand the connection between these fine-mapped IBD associations and tissue specific cis-regulatory elements identified in this proposal. Knowledge from these analyses will greatly improve our understanding of the non-coding genome and their impact on IBD, and generate a short list of the best candidates, ranked with their causal probabilities, for further functional studies. Novel methods designed in this study will also be implemented in software packages and made widely available to the community. Successful completion of this work will provide Dr. Huang in-depth training in IBD biology, the biology of transcriptome and gene regulations. Dr. Huang will also gain practical experience with RNA sequencing, acquire skills and expertise in statistical genetics method development, and engage in professional and career development activities including presentation, manuscript preparation and grant writing. The proposed research plan will lead to future projects in the non-coding genome and IBD genetics in which Dr. Huang will be the principal investigator.