TY - JOUR T1 - RiVIERA-beta: Joint Bayesian inference of risk variants and tissue-specific epigenomic enrichments across multiple complex human diseases JF - bioRxiv DO - 10.1101/059329 SP - 059329 AU - Yue Li AU - Manolis Kellis Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/06/16/059329.abstract N2 - Genome wide association studies (GWAS) provide a powerful approach for uncovering disease-associated variants in human, but fine-mapping the causal variants remains a challenge. This is partly remedied by prioritization of disease-associated variants that overlap GWAS-enriched epigenomic annotations. Here, we introduce a new Bayesian model RiVIERA-beta (Risk Variant Inference using Epigenomic Reference Annotations) for inference of driver variants by modelling summary statistics p-values in Beta density function across multiple traits using hundreds of epigenomic annotations. In simulation, RiVIERA-beta promising power in detecting causal variants and causal annotations, the multi-trait joint inference further improved the detection power. We applied RiVIERA-beta to model the existing GWAS summary statistics of 9 autoimmune diseases and Schizophrenia by jointly harnessing the potential causal enrichments among 848 tissue-specific epigenomics annotations from ENCODE/Roadmap consortium covering 127 cell/tissue types and 8 major epigenomic marks. RiVIERA-beta identified meaningful tissue-specific enrichments for enhancer regions defined by H3K4me1 and H3K27ac for Blood T-Cell specifically in the 9 autoimmune diseases and Brain-specific enhancer activities exclusively in Schizophrenia. Moreover, the variants from the 95% credible sets exhibited high conservation and enrichments for GTEx whole-blood eQTLs located within transcription-factor-binding-sites and DNA-hypersensitive-sites. Furthermore, joint modeling the nine immune traits by simultaneously inferring and exploiting the underlying epigenomic correlation between traits further improved the functional enrichments compared to single-trait models. ER -