学术文献库

Genome-wide association studies (GWAS) have successfully identified a large number of genetic variants associated with traits and diseases. However, it still remains challenging to fully understand functional mechanisms underlying many associated variants. This is especially the case when we are interested in variants shared across multiple phenotypes. To address this challenge, we propose graph-GPA 2.0 (GGPA 2.0), a novel statistical framework to integrate GWAS datasets for multiple phenotypes and incorporate functional annotations within a unified framework. We conducted simulation studies to evaluate GGPA 2.0. The results indicate that incorporating functional annotation data using GGPA 2.0 does not only improve detection of disease-associated variants, but also allows to identify more accurate relationships among diseases. We analyzed five autoimmune diseases and five psychiatric disorders with the functional annotations derived from GenoSkyline and GenoSkyline-Plus and the prior disease graph generated by biomedical literature mining. For autoimmune diseases, GGPA 2.0 identified enrichment for blood, especially B cells and regulatory T cells across multiple diseases. Psychiatric disorders were enriched for brain, especially prefrontal cortex and inferior temporal lobe for bipolar disorder (BIP) and schizophrenia (SCZ), respectively. Finally, GGPA 2.0 successfully identified the pleiotropy between BIP and SCZ. These results demonstrate that GGPA 2.0 can be a powerful tool to identify associated variants associated with each phenotype or those shared across multiple phenotypes, while also promoting understanding of functional mechanisms underlying the associated variants.