LPG: a four-groups probabilistic approach to leveraging pleiotropy in genome-wide association studies

To date, genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants among a variety of traits/diseases, shedding a light on the genetic architecture of complex diseases. Polygenicity of complex diseases, which refers to the phenomenon that a vast number of risk variants collectively contribute to the heritability of complex diseases with modest individual effects, have been widely accepted. This imposes a major challenge towards fully characterizing the genetic bases of complex diseases. An immediate implication of polygenicity is that a much larger sample size is required to detect risk variants with weak/moderate effects. Meanwhile, accumulating evidence suggests that different complex diseases can share genetic risk variants, a phenomenon known as pleiotropy. In this study, we propose a statistical framework for Leveraging Pleiotropic effects in large-scale GWAS data (LPG). LPG utilizes a variational Bayesian expectation-maximization (VBEM) algorithm, making it computationally efficient and scalable for genome-wide scale analysis. To demon- strate the advantage of LPG over existing methods that do not leverage pleiotropy, we conducted extensive simulation studies and also applied LPG to analyze three au- toimmune disorders (Crohn's disease, rheumatoid arthritis and Type 1 diabetes). The results indicate that LPG can improve the power of prioritization of risk variants and accuracy of risk prediction by leveraging pleiotropy. The software is available at http- s://github.com/Shufeyangyi2015310117/LPG.