A New Liver Expression Quantitative Trait Locus Map From 1,183 Individuals Provides Evidence for Novel Expression Quantitative Trait Loci of Drug Response, Metabolic, and Sex‐Biased Phenotypes

Abstract

Expression quantitative trait locus (eQTL) studies in human liver are crucial for elucidating how genetic variation influences variability in disease risk and therapeutic outcomes and may help guide strategies to obtain maximal efficacy and safety of clinical interventions. Associations between expression microarray and genome-wide genotype data from four human liver eQTL studies (n = 1,183) were analyzed. More than 2.3 million cis-eQTLs for 15,668 genes were *

Genetic effects on liver chromatin accessibility identify disease regulatory variants

“…Finally, we identified caQTLs for which the lead variant exhibited high LD (r 2 > 0.8) with an eQTL lead variant for 15,418 autosomal genes from a liver tissue eQTL meta-analysis of 1,183 individuals. 11 Of 3,119 unique caQTL lead variants, 414 (13%) were in strong LD with at least 1 eQTL lead variant (Table S18), which is similar to the percentage reported in a previous caQTL study. 6 Among caQTL lead variants, 71 were in strong LD with more than one eQTL lead variant, suggesting that some ca-Peaks may affect expression of multiple genes.…”

“…Identification of a putative functional variant at the LITAF locus Near LITAF (MIM: 603795), which encodes lipopolysaccharide (LPS)-induced TNF factor, we identified a caQTL signal for caPeak75869 and tested variants for allelic differences in transcriptional activity and protein binding. This caQTL signal is potentially colocalized with a GWAS signal for LDL cholesterol 79 and an eQTL signal for LITAF 11 (Figures 6A, 6B, and S8). caPeak75869 loops to the promoter of LI-TAF in liver tissue promoter capture Hi-C 2 (Figure 6C).…”

“…We obtained liver tissue expression quantitative trait loci (eQTLs) for 15,668 genes (FDR < 5%) from a meta-analysis of 1,183 individuals 11 and restricted to the 15,418 eQTLs on autosomes. We calculated LD and haplotype phase between eQTL and caQTL lead variants using PLINK 20 v.1.9 and classified signals as colocalized if these lead variants exhibited strong pairwise LD (r 2 > 0.8, 1000G phase 3 Europeans).…”

“…10 Several studies have mapped eQTLs in liver tissue, and liver eQTLs are colocalized with GWAS loci for lipid, drug response, and other traits. [11][12][13] Lipid GWAS loci are enriched in regulatory chromatin states, including enhancers and promoters, in HepG2 hepatocytes. 14 QTLs for the active regulatory element histone marks H3K27ac and H3K4me3 have been identified in liver tissue, including a subset colocalized with liver eQTLs and GWAS loci.…”

Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model

“…Many vertebrate tissues, including non-reproductive tissues, show significant sex differences in their gene expression profiles, metabolic and physiological properties, and patterns of disease susceptibility [1][2][3]. Underlying regulatory mechanisms are best studied in the liver, where there is extensive transcriptomic and regulatory sex bias in fish [4,5], rats [6,7], mice [8][9][10] and humans [11,12]. In mouse liver, hundreds of genes are expressed in a sex-dependent manner, including protein-coding genes [13], miRNAs [14,15] and lncRNA genes [16][17][18].…”