Biology subjects

Francesca Luca

Publications and source records attributed to Francesca Luca.

8 recordsLinked to original sources

bioRxiv2016

Integrating Molecular QTL Data into Genome-wide Genetic Association Analysis: Probabilistic Assessment of Enrichment and Colocalization

We propose a novel statistical framework for integrating genetic data from molecular quantitative trait loci (QTL) mapping into genome-wide genetic association analysis of complex traits, with the primary objectives of quantitatively assessing the enrichment of the molecular QTLs in complex trait-associated genetic variants and the colocalizations of the two types of association signals. We introduce a natural Bayesian hierarchical model that treats the latent association status of molecular QTLs as SNP-level annotations for candidate SNPs for complex traits. We detail a computational procedure to seamlessly perform enrichment, fine-mapping and colocalization analyses, which is a distinct feature compared to the existing colocalization analysis procedures in the literature. The proposed approach is computationally efficient and requires only summary-level statistics. We evaluate and demonstrate the proposed computational approach through extensive simulation studies and the analysis of blood lipid data and the whole blood eQTL data from the GTEx project. In addition, a useful utility from our proposed method enables the computation of expected colocalization signals, which is analogous to the power calculation in genetic association studies. Using this utility, we further illustrate the importance of enrichment analysis on the ability of discovering colocalized signals and the potential limitations of currently available molecular QTL data.

Genetics↗

bioRxiv2016

Genetic and transcriptional analysis of human host response to healthy gut microbiome

Many studies have demonstrated the importance of the gut microbiome in healthy and disease states. However, establishing the causality of host-microbiome interactions in humans is still challenging. Here, we describe a novel experimental system to define the transcriptional response induced by the microbiome in human cells and to shed light on the molecular mechanisms underlying host-gut microbiome interactions. In primary human colonic epithelial cells, we identified over 6,000 genes that change expression at various time points following co-culturing with the gut microbiome of a healthy individual. The differentially expressed genes are enriched for genes associated with several microbiome-related diseases, such as obesity and colorectal cancer. In addition, our experimental system allowed us to identify 87 host SNPs that show allele-specific expression in 69 genes. Furthermore, for 12 SNPs in 12 different genes, allele-specific expression is conditional on the exposure to the microbiome. Of these 12 genes, eight have been associated with diseases linked to the gut microbiome, specifically colorectal cancer, obesity and type 2 diabetes. Our study demonstrates a scalable approach to study host-gut microbiome interactions and can be used to identify putative mechanisms for the interplay between host genetics and microbiome in health and disease.

Genomics↗

bioRxiv2015

Efficient Integrative Multi-SNP Association Analysis using Deterministic Approximation of Posteriors

With the increasing availability of functional genomic data,1-3 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 association analysis incorporating genomic annotations for both traditional GWAS and emerging molecular QTL mapping studies. In particular, we propose an algorithm, named \"Deterministic Approximation of Posteriors\" (DAP), which enables highly efficient and accurate joint enrichment analysis and identification of multiple causal variants. We use a series of simulation studies to highlight the power and computational efficiency of our proposed approach and further demonstrate it by analyzing the cross-population eQTL data from the GEUVADIS project and the multi-tissue eQTL data from the GTEx project. In particular, we find that genetic variants predicted to disrupt transcription factor binding sites are enriched in cis-eQTLs across all tissues. Moreover, the enrichment estimates obtained across the tissues are correlated with the cell types for which the annotations are derived.

Genetics↗

bioRxiv2015

A high-throughput RNA-seq approach to profile transcriptional responses

In recent years, different technologies have been used to measure genome-wide gene expression levels across many types of tissues and in response to in vitro treatments. However, a full understanding of gene regulation in any given cellular and environmental context combination is still missing. This is partly because analyzing tissue/environment-specific gene expression generally implies screening a large number of cellular conditions and samples, without prior knowledge of which conditions are most informative (e.g. some cell types may not respond to certain treatments). To circumvent these challenges, we have established a new two-step high-throughput and cost-effective RNA-seq approach: the first step consists of gene expression screening of a large number of conditions, while the second step focuses on deep sequencing of the most relevant conditions (e.g. largest number of differentially expressed genes). This study design allows for a fast and economical screen in step one, with a more profitable allocation of resources for the deep sequencing of re-pooled libraries in step two. We have applied this approach to study the response to 26 treatments in three lymphoblastoid cell lines and we show that it is applicable for other high-throughput transcriptome profiling requiring iterative refinement or screening.

Genomics↗

bioRxiv2015

Bacterial Infection Remodels the DNA Methylation Landscape of Human Dendritic Cells

DNA methylation is thought to be robust to environmental perturbations on a short time scale. Here, we challenge that view by demonstrating that the infection of human dendritic cells (DCs) with a pathogenic bacteria is associated with rapid changes in methylation at thousands of loci. Infection-induced changes in methylation occur primarily at distal enhancer elements, including those associated with the activation of key immune-transcription factors and genes involved in the crosstalk between DCs and adaptive immunity. Active demethylation is associated with extensive epigenetic remodeling and is strongly predictive of changes in the expression levels of nearby genes. Collectively, our observations show that rapid changes in methylation play a previously unappreciated role in regulating the transcriptional response of DCs to infection.

Genomics↗

bioRxiv2014

Cross-population Joint Analysis of eQTLs: Fine Mapping and Functional Annotation

Mapping expression quantitative trait loci (eQTLs) has been shown as a powerful tool to uncover the genetic underpinnings of many complex traits at the molecular level. In this paper, we present an integrative analysis approach that leverages eQTL data collected from multiple population groups. In particular, our approach effectively identifies multiple independent cis-eQTL signals that are consistently presented across populations, accounting for heterogeneity in allele frequencies and patterns of linkage disequilibrium. Furthermore, our analysis framework enables integrating high-resolution functional annotations into analysis of eQTLs. We applied our statistical approach to analyze the GEUVADIS data consisting of samples from five population groups. From this analysis, we concluded that i) joint analysis across population groups greatly improves the power of eQTL discovery and the resolution of fine mapping of causal eQTLs; ii) many genes harbor multiple independent eQTLs in their cis regions; iii) genetic variants that disrupt transcription factor binding are significantly enriched in eQTLs (p-value = 4.93 x 10-22).\n\nAuthor SummaryExpression quantitative trait loci (eQTLs) are genetic variants associated with gene expression phenotypes. Mapping eQTLs enables us to study the genetic basis of gene expression variation across individuals. In this study, we introduce a statistical framework for analyzing genotype-expression data collected from multiple population groups. We show that our approach is particularly effective in identifying multiple independent eQTL signals that are consistently presented across populations in the proximity of a gene. In addition, our analysis framework allows effective integration of genomic annotations into eQTL analysis, which is helpful in dissecting the functional basis of eQTLs.

Genetics↗

bioRxiv2014

QuASAR: Quantitative Allele Specific Analysis of Reads

MotivationExpression quantitative trait loci (eQTL) studies have discovered thousands of genetic variants that regulate gene expression, enabling a better understanding of the functional role of non-coding sequences. However, eQTL studies are costly, requiring large sample sizes and genome-wide genotyping of each sample. In contrast, analysis of allele specific expression (ASE) is becoming a popular approach to detect the effect of genetic variation on gene expression, even within a single individual. This is typically achieved by counting the number of RNA-seq reads matching each allele at heterozygous sites and testing the null hypothesis of a 1:1 allelic ratio. In principle, when genotype information is not readily available it could be inferred from the RNA-seq reads directly. However, there are currently no existing methods that jointly infer genotypes and conduct ASE inference, while considering uncertainty in the genotype calls.\n\nResultsWe present QuASAR, Quantitative Allele Specific Analysis of Reads, a novel statistical learning method for jointly detecting heterozygous genotypes and inferring ASE. The proposed ASE inference step takes into consideration the uncertainty in the genotype calls while including parameters that model base-call errors in sequencing and allelic over-dispersion. We validated our method with experimental data for which high quality genotypes are available. Results for an additional dataset with multiple replicates at different sequencing depths demonstrate that QuASAR is a powerful tool for ASE analysis when genotypes are not available.\n\nAvailabilityhttp://github.com/piquelab/QuASAR\n\nContactfluca@wayne.edu; rpique@wayne.edu

Bioinformatics↗

bioRxiv2014

Which genetic variants in DNase I sensitive regions are functional?

Ongoing large experimental characterization is crucial to determine all regulatory sequences, yet we do not know which genetic variants in those regions are non-silent. Here, we present a novel analysis integrating sequence and DNase I footprinting data for 653 samples to predict the impact of a sequence change on transcription factor binding for a panel of 1,372 motifs. Most genetic variants in footprints (5,810,227) do not show evidence of allele-specific binding (ASB). In contrast, functional genetic variants predicted by our computational models are highly enriched for ASB (3,217 SNPs at 20% FDR). Comparing silent to functional non-coding genetic variants, the latter are 1.22-fold enriched for GWAS traits, have lower allele frequencies, and affect footprints more distal to promoters or active in fewer tissues. Finally, integration of the annotations into 18 GWAS meta-studies improves identification of likely causal SNPs and transcription factors relevant for complex traits.

Genomics↗