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

1 Citationer (Scopus)

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 (β SD(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 not available: see fulltext.].

OriginalsprogEngelsk
TidsskriftEuropean journal of human genetics : EJHG
Vol/bind32
Udgave nummer2
Sider (fra-til)215-223
Antal sider9
ISSN1018-4813
DOI
StatusUdgivet - feb. 2024

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