Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/059329

RiVIERA-beta: Joint Bayesian inference of risk variants and tissue-specific epigenomic enrichments across multiple complex human diseases

Yue Li·Manolis Kellis
View original source ↗Export metadata ↓

Abstract

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.

Source connections

Explore related subjects

BioinformaticsPreprint

Keep this discovery

BibTeXRIS

Yue Li, Manolis Kellis. 2016-06-16. RiVIERA-beta: Joint Bayesian inference of risk variants and tissue-specific epigenomic enrichments across multiple complex human diseases. https://doi.org/10.1101/059329

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2016

iCARE: An R Package to Build and Apply Absolute Risk Models

This report describes a R package, called the Individualized Coherent Absolute Risk Estimation (iCARE) tool, that allows researchers to build and evaluate models for absolute risk and apply them to estimate an individuals risk of developing disease during a specified time interval based on a set of user defined input parameters. An attractive feature of the software is that it gives users flexibility to update models rapidly based on new knowledge on risk factors and tailor models to different populations by specifying three input arguments: (1) a model for relative risk, (2) an age-specific disease incidence rate, (3) the distribution of risk factors for the population of interest. The tool can handle missing information on risk factors for individuals for whom risks are to be predicted using a coherent approach where all estimates are derived from a single model after appropriate model averaging. The software allows single nucleotide polymorphisms (SNPs) to be incorporated into the model using published odds ratios and allele frequencies. The validation component of the software implements the methods for evaluation of model calibration, discrimination and risk-stratification based on independent validation datasets. We provide an illustration of the utility of iCARE for building, validating and applying absolute risk models using breast cancer as an example.

Bioinformatics↗
bioRxiv2016

deSPI: efficient classification of metagenomic reads with lightweight de Bruijn graph-based reference indexing

SummaryIn metagenomic studies, fast and effective tools are on wide demand to implement taxonomy classification for upto billions of reads. Herein, we propose deSPI, a novel read classification method that classifies reads by recognizing and analyzing the matches between reads and reference with de Bruijn graph-based lightweight reference indexing. deSPI has faster speed with relatively small memory footprint, meanwhile, it can also achieve higher or similar sensitivity and accuracy.\n\nAvailabilitythe C++ source code of deSPI is available at https://github.com/hitbc/deSPI\n\nContactydwang@hit.edu.cn\n\nSupplementary informationSupplementary data are available at Bioinformatics online.

Bioinformatics↗
bioRxiv2016

De novo assembly of viral quasispecies using overlap graphs

A viral quasispecies, the ensemble of viral strains populating an infected person, can be highly diverse. For optimal assessment of virulence, pathogenesis and therapy selection, determining the haplotypes of the individual strains can play a key role. As many viruses are subject to high mutation and recombination rates, high-quality reference genomes are often not available at the time of a new disease outbreak. We present SAVAGE, a computational tool for reconstructing individual haplotypes of intrahost virus strains without the need for a high-quality reference genome. SAVAGE makes use of either FM-index based data structures or ad-hoc consensus reference sequence for constructing overlap graphs from patient sample data. In this overlap graph, nodes represent reads and/or contigs, while edges reflect that two reads/contigs, based on sound statistical considerations, represent identical haplotypic sequence. Following an iterative scheme, a new overlap assembly algorithm that is based on the enumeration of statistically well-calibrated groups of reads/contigs then efficiently reconstructs the individual haplotypes from this overlap graph. In benchmark experiments on simulated and on real deep coverage data, SAV-AGE drastically outperforms generic de novo assemblers as well as the only specialized de novo viral quasispecies assembler available so far. When run on ad-hoc consensus reference sequence, SAVAGE performs very favorably in comparison with state-of-the-art reference genome guided tools. We also apply SAVAGE on two deep coverage samples of patients infected by the Zika and the hepatitis C virus, respectively, which sheds light on the genetic structures of the respective viral quasispecies.

Bioinformatics↗