Mining GWAS and eQTL data for CF lung disease modifiers by gene expression imputation.

Hong Dang,Deepika Polineni,Garry R Cutting,Harriet Corvol,Wanda K O’Neal,Michael R Knowles,Lisa J Strug,Rhonda G Pace,Mitchell L Drumm,Jaclyn R Stonebraker,Dylan Glubb

doi:10.1371/journal.pone.0239189

Abstract

Genome wide association studies (GWAS) have identified several genomic loci with candidate modifiers of cystic fibrosis (CF) lung disease, but only a small proportion of the expected genetic contribution is accounted for at these loci. We leveraged expression data from CF cohorts, and Genotype-Tissue Expression (GTEx) reference data sets from multiple human tissues to generate predictive models, which were used to impute transcriptional regulation from genetic variance in our GWAS population. The imputed gene expression was tested for association with CF lung disease severity. By comparing and combining results from alternative approaches, we identified 379 candidate modifier genes. We delved into 52 modifier candidates that showed consensus between approaches, and 28 of them were near known GWAS loci. A number of these genes are implicated in the pathophysiology of CF lung disease (e.g., immunity, infection, inflammation, HLA pathways, glycosylation, and mucociliary clearance) and the CFTR protein biology (e.g., cytoskeleton, microtubule, mitochondrial function, lipid metabolism, endoplasmic reticulum/Golgi, and ubiquitination). Gene set enrichment results are consistent with current knowledge of CF lung disease pathogenesis. HLA Class II genes on chr6, and CEP72, EXOC3, and TPPP near the GWAS peak on chr5 are most consistently associated with CF lung disease severity across the tissues tested. The results help to prioritize genes in the GWAS regions, predict direction of gene expression regulation, and identify new candidate modifiers throughout the genome for potential therapeutic development.

Highlights

The International Cystic Fibrosis Gene Modifier Consortium identified 5 genome-wide significant genetic loci associated with cystic fibrosis (OMIM: 219700) lung disease severity through Genome wide association studies (GWAS) of 6,365 CF patients, with a chr16 locus showing significance in some analyses [1, 2]
The GWAS signals point to genes in regions that may play a role in CF lung disease pathogenesis
Genotype-Tissue Expression (GTEx) models from 48 human tissues and a large data set from Depression Genes and Networks (DGN) whole blood [13] were downloaded from the PredictDB (PrediXcan) data repository [9], and Transcriptome-Wide Association Studies (TWAS) [10]

Summary

Introduction

The International Cystic Fibrosis Gene Modifier Consortium identified 5 genome-wide significant genetic loci associated with cystic fibrosis (OMIM: 219700) lung disease severity through GWAS of 6,365 CF patients, with a chr locus showing significance in some analyses [1, 2]. The most common scenario explaining genetic association to phenotype is through the effects of variants on gene expression [4, 5]. In a survey of 44 human tissues, the GTEx consortium found that most genetic regulation of gene expression is common across multiple tissues, acting through cis-SNPs at promoter and enhancer sites [5]. Genetic regulation of gene expression, or eQTL, can be informative regardless of tissue origin of the training data set [8], and can help overcome technical deficiencies, such as small sample sizes of certain tissue data, and potential biological limitations such as unsampled developmental stage and environmental and pathogenic masking of gene expression through reverse causality

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Conclusion