Integrative analysis of functional genomic annotations and sequencing data to identify rare causal variants via hierarchical modeling
نویسندگان
چکیده
Identifying the small number of rare causal variants contributing to disease has been a major focus of investigation in recent years, but represents a formidable statistical challenge due to the rare frequencies with which these variants are observed. In this commentary we draw attention to a formal statistical framework, namely hierarchical modeling, to combine functional genomic annotations with sequencing data with the objective of enhancing our ability to identify rare causal variants. Using simulations we show that in all configurations studied, the hierarchical modeling approach has superior discriminatory ability compared to a recently proposed aggregate measure of deleteriousness, the Combined Annotation-Dependent Depletion (CADD) score, supporting our premise that aggregate functional genomic measures can more accurately identify causal variants when used in conjunction with sequencing data through a hierarchical modeling approach.
منابع مشابه
Identification of Rare Causal Variants in Sequence-Based Studies: Methods and Applications to VPS13B, a Gene Involved in Cohen Syndrome and Autism
Pinpointing the small number of causal variants among the abundant naturally occurring genetic variation is a difficult challenge, but a crucial one for understanding precise molecular mechanisms of disease and follow-up functional studies. We propose and investigate two complementary statistical approaches for identification of rare causal variants in sequencing studies: a backward elimination...
متن کاملEfficient Integrative Multi-SNP QTL Mapping using Deterministic Approximation of Posteriors
With the increasing availability of functional genomic data (Consortium et al., 2012, Kundaje et al., 2015, Ardlie et al., 2015), incorporating genomic annotations into QTL mapping has become a standard analytical procedure. However, the existing analysis methods often lack rigor and/or computational efficiency. We present a novel algorithm to perform integrative multi-SNP QTL mapping in a prob...
متن کاملEfficient Integrative Multi-SNP Association Analysis via Deterministic Approximation of Posteriors.
With the increasing availability of functional genomic data, incorporating genomic annotations into genetic association analysis has become a standard procedure. However, the existing methods often lack rigor and/or computational efficiency and consequently do not maximize the utility of functional annotations. In this paper, we propose a rigorous inference procedure to perform integrative asso...
متن کاملDetecting functional rare variants by collapsing and incorporating functional annotation in Genetic Analysis Workshop 17 mini-exome data
Association studies using tag SNPs have been successful in detecting disease-associated common variants. However, common variants, with rare exceptions, explain only at most 5-10% of the heritability resulting from genetic factors, which leads to the common disease/rare variants assumption. Indeed, recent studies using sequencing technologies have demonstrated that common diseases can be due to...
متن کاملRare and Common Regulatory Variation in Population-Scale Sequenced Human Genomes
Population-scale genome sequencing allows the characterization of functional effects of a broad spectrum of genetic variants underlying human phenotypic variation. Here, we investigate the influence of rare and common genetic variants on gene expression patterns, using variants identified from sequencing data from the 1000 genomes project in an African and European population sample and gene ex...
متن کامل