Expression Quantitative Trait Loci (eQTL) Mapping in Korean Patients With Crohn's Disease and Identification of Potential Causal Genes Through Integration With Disease Associations.

Seulgi Jung,Jianjun Liu,Kyuyoung Song,Sang Hyoung Park,Buhm Han,Wenting Liu,Suk-Kyun Yang,Ho-Su Lee,Byong Duk Ye,Jung Won Moon,Jiwon Baek

doi:10.3389/fgene.2020.00486

Abstract

BackgroundExpression quantitative trait loci (eQTL) datasets have extensively been used to help interpret genome-wide association study signals. Most eQTL analyses have been conducted with populations of European ancestry.ObjectiveTo determine the most functionally relevant genes at the Crohn’s disease (CD) loci identified in genome-wide association studies (GWAS) involving Asian populations and to find novel disease-associated genes, we conducted an eQTL analysis.MethodseQTL analysis was performed using whole-blood RNA-sequencing of 101 Korean patients with CD. FastQTL was used for a pair-wise genome analysis of ∼ 6.5 M SNPs and ∼ 22 K transcripts.ResultsWe identified 135,164 cis-eQTL and 3,816 eGenes with a false discovery rate less than 0.05. A significant proportion of the genes identified in our study overlapped with those identified in previous studies. The significantly enriched pathways of these 3,816 eGenes included neutrophil degranulation and small molecule biosynthetic process. Integrated analysis of CD GWAS with Korean eQTL revealed two putative target genes, TNFSF15 and GPR35, at two previously reported loci, whereas TNFSF15 only with the whole blood data from the Genotype-Tissue Expression (GTEx) project, highlighting the utility of building a population-specific data set, even of modest size. The risk alleles of these genes were found to be associated with lower expression levels of TNFSF15 and GPR35, respectively. Our eQTL browser can be accessed at “http://asan.crohneqtl.com/”.ConclusionThis resource would be useful for studies that need to employ genome-wide association analyses involving Asian populations.

Highlights

Genome-wide association studies (GWAS) have identified >200 loci that are associated with inflammatory bowel diseases (IBD) (Liu et al, 2015; de Lange et al, 2017)
Our Expression quantitative trait locus (eQTL) browser can be accessed at “http://asan.crohneqtl.com/”. This resource would be useful for studies that need to employ genomewide association analyses involving Asian populations
Our dataset identified eQTL unique to our study population and confirmed the eQTL signals previously identified in other populations

Summary

Introduction

Genome-wide association studies (GWAS) have identified >200 loci that are associated with inflammatory bowel diseases (IBD) (Liu et al, 2015; de Lange et al, 2017). Summary-data-based Mendelian Randomization (SMR) integrates GWAS with eQTL data by testing if the eQTL occurs to be associated with the disease (Zhu et al, 2016) These methods allow determination of the most functionally relevant genes at the loci and identification of novel trait-associated loci via imputation of genotype correlated gene expression levels into GWAS datasets (Gusev et al, 2016; Zhu et al, 2016). Most eQTL analyses have been conducted with populations of European ancestry

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