A systematic approach to understanding the biology underpinning GWAS hits. (360G-Wellcome-106130_Z_14_Z)

Genome-wide association studies have been extraordinarily successful in identifying DNA sequence variants associated with human diseases and phenotypes, with thousands of risk-loci identified across hundreds of traits. Each of these loci has the potential to reveal novel insights into human biology which can in turn underpin future translational advances. However GWAS loci frequently lie within regulatory sequences which complicates efforts to deliver actionable biological insights. To date, ch aracterisation of the molecular basis of predisposition to specific traits and diseases has been limited to a handful of the many thousands of non-coding GWAS signals. This lack of successful follow-up has impeded the GWAS approach from realising its huge potential. Recently, there have been major advances in our understanding of the regulatory architecture of the human genome, and, in particular, in the development of techniques for assessing the relationships between regulatory elements and t he genes they control. This application seeks funding for international leaders in GWAS, human gene regulation, human disease, and statistical genetics to exploit these recent advances by developing a systematic approach to the functional follow-up of GWAS loci and applying this across a series of diseases selected to represent increasingly complex challenges to biological inference.