Integrative proteo-genomic analysis to investigative immune-mediated disease aetiology

Background: Familial genetic diseases (e.g., sickle cell anaemia) are monogenic (i.e., caused by a mutation in a single gene). However, most common diseases do not follow a Mendelian pattern of inheritance and are instead 'complex traits', resulting from a combination of genetic, environmental and stochastic factors. The advent of large-scale genome-wide association studies (GWAS) has revolutionised our understanding of the genetic architecture of complex traits, revealing that they are highly polygenic (i.e. influenced by many genes)1. The disease risk conferred by any particular genomic locus is typically small but nevertheless the cumulative load of risk alleles across a very large number of susceptibility loci probabilistically confers a substantial effect. This can be quantified using a polygenic risk score (PRS), which provides a measure of an individual's genetic predisposition to a particular disease2. The PRS is calculated by the summing the number of risk alleles, each weighted by its estimated effect size (log odds ratio) from GWAS. Individuals in a population typically form a Gaussian distribution in terms of their PRS for a given common disease.