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Blood Lipid GWAS Points to Trait-Related Loci, Architecture in Greenlanders

NEW YORK – A University of Copenhagen-led team has identified genetic loci linked to blood lipid levels in individuals from Greenland, including genetic variants that overlapped with, and were distinct from, those described in other populations.

As they reported in the European Journal of Human Genetics on Monday, the researchers began with a genome-wide association study involving nearly 4,500 individuals from Greenland, searching for variants with ties to half a dozen blood lipid traits: blood triglyceride levels, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, total blood cholesterol, and apolipoprotein A1 and apolipoprotein B levels.

"Perturbation of lipid homeostasis is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide," University of Copenhagen researchers Anders Albrechtsen, Torben Hansen, and Ida Moltke, the study's co-senior and co-corresponding authors, and their colleagues wrote. "We aimed to identify genetic variants affecting lipid levels, and thereby risk of CVD."

The participants included 3,115 Greenlanders from an "Inuit Health in Transition" study and more than 1,900 participants from the "Greenland Population Study," the team explained, which included 1,401 Greenlanders living in Greenland and 503 Greenlanders who reside in Denmark. Up to 4,473 individuals with available genetic and blood lipid data were available to assess each of the traits considered after accounting for participants found in multiple cohorts.

Using these data, the investigators narrowed in on 11 loci with genome-wide significant ties to one or more lipid traits, including previously unappreciated loci on chromosomes 2 and 7 that mainly coincided with enhanced LDL cholesterol and blood triglyceride levels, respectively.

Their analyses also highlighted a distinct chromosome 1 variant influencing expression of PCSK9, a gene previously linked to lipid levels via a distinct loss-of-function variant previously described in other populations.

In the Greenland population, the team flagged a predicted regulatory variant known as rs12117661 that appeared to correspond with reduced LDL cholesterol, total cholesterol, and ApoB levels, but enhanced HDL cholesterol levels.

When the researchers brought in expression quantitative locus data from GTEx and data for UK Biobank participants from Greenland or other parts of Europe, they found that the variant also corresponded with lower-than-usual levels of PCSK9 gene expression. They also saw hints that the variant tracks with reduced risk of certain cardiovascular conditions such as myocardial infarction or ischemic stroke, though the associations did not reach statistical significance.

"The suggested causal variant (rs12117661) in the PCSK9 locus colocalized with a predicted regulatory site and was strongly associated with lipid levels in Greenlanders, and lower expression of PCSK9 and lower risk of certain CVD outcomes in Europeans," the authors explained.

Along with follow-up analyses focused on finding other traits or conditions linked to the significant lipid loci from the GWAS, the team considered associations that appeared to be specific to Greenlanders relative to European populations.

In particular, the authors suggested that a relatively small set of common variants with outsized effects may influence circulating blood lipid levels in Greenlanders, compared to a broader set of low-effect variants accounting for predicted genetic variance of the traits in Europeans.

"Taken together, the genetic architecture of lipid traits in Greenlanders is similar to what has been reported for other metabolic traits, where few variants explain a large proportion of the variance," the authors wrote, noting that the findings "revealed a unique genetic architecture of lipid traits among Greenlanders, where few variants explained a large amount of the trait variance."