GWAS of lipids in Greenlanders finds association signals shared with Europeans and reveals an independent PCSK9 association signal

Ninna Karsbæk Senftleber, Mette K. Andersen, Emil Jørsboe, Frederik Filip Stæger, Anne Krogh Nøhr, Genis Garcia-Erill, Jonas Meisner, Cindy G. Santander, Renzo F. Balboa, Arthur Gilly, Peter Bjerregaard, Christina Viskum Lytken Larsen, Niels Grarup, Marit Eika Jørgensen, Eleftheria Zeggini, Ida Moltke, Torben Hansen, Anders Albrechtsen

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Perturbation of lipid homoeostasis is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. We aimed to identify genetic variants affecting lipid levels, and thereby risk of CVD, in Greenlanders. Genome-wide association studies (GWAS) of six blood lipids, triglycerides, LDL-cholesterol, HDL-cholesterol, total cholesterol, as well as apolipoproteins A1 and B, were performed in up to 4473 Greenlanders. For genome-wide significant variants, we also tested for associations with additional traits, including CVD events. We identified 11 genome-wide significant loci associated with lipid traits. Most of these loci were already known in Europeans, however, we found a potential causal variant near PCSK9 (rs12117661), which was independent of the known PCSK9 loss-of-function variant (rs11491147). rs12117661 was associated with lower LDL-cholesterol (βSD(SE) = −0.22 (0.03), p = 6.5 × 10−12) and total cholesterol (−0.17 (0.03), p = 1.1 × 10−8) in the Greenlandic study population. Similar associations were observed in Europeans from the UK Biobank, where the variant was also associated with a lower risk of CVD outcomes. Moreover, rs12117661 was a top eQTL for PCSK9 across tissues in European data from the GTEx portal, and was located in a predicted regulatory element, supporting a possible causal impact on PCSK9 expression. Combined, the 11 GWAS signals explained up to 16.3% of the variance of the lipid traits. This suggests that the genetic architecture of lipid levels in Greenlanders is different from Europeans, with fewer variants explaining the variance. (Figure presented.)

Original languageEnglish
Pages (from-to)215-223
Number of pages9
JournalEuropean Journal of Human Genetics
Volume32
Issue number2
DOIs
StatePublished - Feb 2024
Externally publishedYes

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