Fine-mapping causal tissues at disease-associated loci to infer disease subtypes

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Project Summary (Abstract) Genome-wide association studies (GWAS) have been extremely successful in identifying genetic loci associated with complex diseases, but the causal tissue and functional mechanism underlying the association at each locus is generally unknown. Recent work has shown gene expression across tissues can be used as an intermediate phenotype to fill in these missing links between genotype and disease. An accurate mapping from disease locus to the causal tissue and gene mediating that disease locus would further our understanding of disease biology and provide novel insights into tissue-linked mechanisms of disease. However, accurate inference of the causal tissue and gene driving a disease locus can be obscured by genetic co-regulation (correlation among variant effects on gene expression) across tissues as well as genes. The first aim of this proposal is to develop a new statistical method to accurately infer the causal tissue and gene driving a disease locus, while explicitly modeling genetic co-regulation between tissues and genes. The second aim of this proposal is to infer disease subtypes linked to specific tissues using tissue-specific polygenic risk scores (PRS) generated by annotating disease loci according to their causal tissue type, utilizing the method developed in the first aim. I expect tissue-specific PRS to uncover patterns of tissue-specific genetic risk across individuals that correspond to different subtypes of the disease. If achieved, this work will refine our knowledge of causal tissues and genes underlying disease loci, as well as provide a new paradigm for inferring the disease subtype of each individual in a disease association study. More generally, this work has the potential to refine the set of drug target candidate disease genes and facilitate the development of patient care and treatments specific to disease subtypes. In addition, I propose an in-depth training plan that leverages the research community throughout Harvard to provide me with the training and skills necessary to advance my career from a post- doctoral fellow to an independent investigator.