Abstract
Genome-wide association studies (GWAS) have identified numerous genetic variants in the human genome associated with diseases and traits. Nevertheless, for most loci the causative variant is still unknown. Expression quantitative trait loci (eQTL) in disease relevant tissues is an excellent approach to correlate genetic association with gene expression. While liver is the primary site of gene transcription for two pathways relevant to age-related macular degeneration (AMD), namely the complement system and cholesterol metabolism, we explored the contribution of AMD associated variants to modulate liver gene expression. We extracted publicly available data and computed the largest eQTL data set for liver tissue to date. Genotypes and expression data from all studies underwent rigorous quality control. Subsequently, Matrix eQTL was used to identify significant local eQTL. In total, liver samples from 588 individuals revealed 202,489 significant eQTL variants affecting 1,959 genes (Q-Value < 0.001). In addition, a further 101 independent eQTL signals were identified in 93 of the 1,959 eQTL genes. Importantly, our results independently reinforce the notion that high density lipoprotein metabolism plays a role in AMD pathogenesis. Taken together, our study generated a first comprehensive map reflecting the genetic regulatory landscape of gene expression in liver.
Highlights
Large genome-wide association studies (GWAS) have led to the identification of risk-associated variants with genome-wide significance for a multitude of diseases[1]
We show that two age-related macular degeneration (AMD) risk variants are significant expression quantitative trait locus (eQTL) in liver affecting the expression of two genes involved in high density lipoprotein (HDL) metabolism
Local eQTL were calculated by including all variants on the same chromosome that are located within 1,000,000 base pairs (1 Mbp) up- or downstream of the transcription start site or polyadenylation site of a gene locus, respectively
Summary
Large genome-wide association studies (GWAS) have led to the identification of risk-associated variants with genome-wide significance for a multitude of diseases[1]. Regions are often intergenic but can have an effect such as recruiting transcription factors, which in turn can influence expression of nearby genes[11] Such loci potentially harbour regulatory sequences in cis or trans to the gene regulated by the associated genetic variant. Gene products (e.g. proteins) of complement and of HDL metabolism expressed by the liver are frequently secreted into circulation where they exert various biological activities, and which could influence AMD through its systemic effect in the choriocapillaris.
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