Characterisation of the genetic architecture of immune-mediated disease through informed dimension reduction

Integration of genome-wide association study (GWAS) data has been used to generate new hypotheses of biological mechanism, aetiological relationships between traits, or test causality of one factor for another. However, such approaches have typically been limited to pairwise comparisons of traits. We propose a generally applicable method, that exploits ideas from Bayesian genetic fine mapping to define a "lens" that focuses relevant variants before dimension reduction of a set of related GWAS summary statistics. We applied this technique to immune-mediated diseases, deriving 13 components which summarise the multidimensional patterns of genetic risk. Projection of independent datasets demonstrated the specificity and accuracy of our reduced dimension basis, enabled us to functionally characterise individual components, identify disease-discriminating components and suggest novel associations in rare diseases where classical GWAS approaches are challenging. Our approach summarises the genetic architectures underlying any range of aetiologically-related traits in fewer dimensions, facilitating more nuanced multidimensional comparative analyses.