Grant: CIHR Fellowship

The discovery of disease-causing genes is crucial to understand how diseases function and to design new drug targets. Over the past decade, researchers have performed large genetic studies, looking at DNA base pair differences that commonly occur in the population-single nucleotide polymorphisms (SNPs). Researchers ask whether a SNP occurs more than expected by chance in individuals with a specific disease, and then inspect the DNA near the SNP for which genes may be under its influence. This powerful approach, known as a genome-wide association study (GWAS), has uncovered several possible disease-causing genes, but exactly which gene is influenced by a GWAS-identified SNP, and how this results in disease, remains unknown. We urgently need new methods to study these SNPs and definitively uncover human disease-causing genes. To this end, I propose to develop and apply the CRISPR-GWAS method for functional dissection of multiple GWAS findings for any disease in a massively parallel fashion. My goal is to harness pooled genome editing screens with the CRISPR technology (e.g. 100s or 1000s of DNA edits in a single experiment) to introduce GWAS-identified SNPs in a cell sample, analyze edited cells, and identify causal genes. We are currently developing computational methods for identifying which SNPs to target, and a novel CRISPR editing protein variant to use, xCas9. The outcome of this work, the systematic identification of disease-causing genes, will be important across many fields. This work will benefit genetic epidemiology by realizing the promise of GWAS to identify human disease-causing genes. This work will also benefit genome engineering, because we will develop and optimize novel CRISPR methods for precise DNA editing. Finally, this work will benefit Canadians by uncovering new drug targets for diseases, allowing researchers, clinicians, and pharmaceutical companies to develop and administer preventative care or treatment options.