Dissecting the molecular aetiology of complex traits using high dimensional omic data

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The discovery of genetic variants associated with complex traits is increasing at an exponential rate. It is now of vital importance to develop our understanding of the molecular mechanisms which can help explain these findings, in order to improve our capability to prevent and treat disease. Advancements in high-throughput sequencing technologies present an unprecedented opportunity to address this challenge and ascertain the biological and clinical relevance of results from genome-wide association studies (GWAS). However, there is an increasing abundance of data being generated on diverse types of molecular "omic" traits, accompanied by the rapid development of partially overlapping and often untested methodologies. To overcome this challenge, there needs to be focused research into the most appropriate and efficient manner to harness large-scale 'omic data to elucidate the molecular determinants of complex disease.The research outlined in this fellowship proposal can be delineated into five categories, with the overall aim of harnessing large-scale data to improve patient healthcare in-line with the UK's industrial strategy. The opportunity presented by HDR-UK will allow me to address some of the most crucial limitations in molecular aetiology. Specifically, there needs to be extensive research into tissue-specificity for 'omic traits, systematic frameworks to appropriately appraise molecular mediation and methods to improve causal inference in this paradigm. I also intend on applying novel, state-of-art-methods to available 'omic data to elucidate findings which have translational value for therapeutic evaluation. Finally, I will build publicly accessible computational tools to automate fundamental analyses in this paradigm and resources to disseminate the findings of this fellowship. Using health informatics to harness large-scale, high throughput data to develop our understanding of the causal pathway from genetic variation to complex disease is the overarching theme of this research project. This research will lead to several high impact publications to improve our understanding of the molecular determinants of disease, as well as web tools that should help disseminate the product of this project and also assist colleagues with their endeavors in this field. As such, this work most closely aligns with the HDR-UK priorities concerning health informatics and accelerating medicines discovery.