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Study Links GWAS Risk Loci to Distant Gene Expression

NEW YORK (GenomeWeb News) – In a study appearing online yesterday in Nature Genetics, researchers sifted through thousands of genome-wide association study risk loci to find those influencing the expression of far-off genes.

Through a meta-analysis that included genotyping and gene expression profiles for thousands of individuals, an international team led by investigators in half a dozen countries catalogued expression quantitative trait loci, or eQTLs, at more than 100 loci linked to complex traits or conditions in past GWAS.

Each of these eQTLs appeared to affect the expression of genes not directly neighboring them. And many of the so-called trans-eQTLs seemed to influence the expression of multiple genes, including some genes known for showing disease-related expression changes.

"These trans eQTLs can provide insight into the pathogenesis of disease," corresponding author Lude Franke, a genetics researcher at the University of Groningen, and colleagues noted.

"Although RNA microarray studies have identified dysregulated pathways for many complex diseases," they added, "it is often unclear whether associated SNPs first cause defects in the pathways whose dysregulation ultimately leads to disease or vice-versa."

Franke and his colleagues reasoned that ongoing searches for SNPs affecting the expression of neighboring and more distant genes — "cis" and "trans" eQTLs, respectively — might help in untangling the biological pathways and processes behind GWAS associations described for some complex traits or diseases.

In an effort to track more of these eQTL players, particularly less-studied trans-eQTLs, the team began by analyzing genotype and gene expression profiles gleaned from peripheral blood samples for 5,311 participants from seven past studies.

Amongst more than 4,500 SNPs unearthed through past GWAS, the researchers saw several hundred variants that seemed to independently affect the expression of 430 genes not directly neighboring them.

Following replication testing using expression data for thousands more individuals, along with a meta-analysis focused on the 2,082 SNPs with genome-wide significant GWAS associations, the team was left with 233 authentic trans-eQTLs.

Over-represented among these SNPs, which fell at 103 independent loci, were variants in microRNA binding sites, histone enhancer regions, and the like, the study's authors noted.

A subset of the newly detected trans-eQTLs appeared to influence the expression of the same genes that are dialed up or down in concert with a particular trait or condition of interest — patterns that the researchers used to take a peek at disease-related biological pathways in some cases.

One of the trans-eQTLs detected in the study was a SNP called rs4917014 that's been implicated in systemic lupus erythematosus, for instance. The researchers found that rs4917014 influenced the expression of several distant genes known for SLE-related expression shifts.

Notably, the SLE-associated version of that variant seemed to dial up the expression of five type I interferon-alpha response genes and curb the expression of a protective lupus gene called C1QB.

A more in-depth analysis of that SLE risk SNP suggested that the rs4917014 SNP can act as a trans-eQTL for those and other genes, while at once influencing the expression of its neighboring transcription factor gene IKZF1 through cis-regulation.

The group also saw examples of multiple, independent eQTLs that could ramp up or decrease levels of the same genes. These included SNPs implicated in low-density lipoprotein cholesterol levels, a range of blood-related traits, and autoimmune conditions such as celiac disease, type 1 diabetes, and rheumatoid arthritis.

"Our analyses show that trans-eQTL mapping in blood for lipid-regulatory and immune-mediated disease variants yields insights into downstream pathways that are biologically meaningful," the study's authors concluded, adding that "[f]uture, larger-scale trans-eQTL analyses in blood will likely uncover many more of these regulatory relationships."