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

• Published in: European Journal of Human Genetics
• Main Authors: Senftleber, Ninna Karsbæk, Andersen, Mette K., Jørsboe, Emil, Stæger, Frederik Filip, Nøhr, Anne Krogh, Garcia-Erill, Genis, Meisner, Jonas, Santander, Cindy G., Balboa, Renzo F., Gilly, Arthur, Bjerregaard, Peter, Larsen, Christina Viskum Lytken, Grarup, Niels, Jørgensen, Marit Eika, Zeggini, Eleftheria, Moltke, Ida, Hansen, Torben, Albrechtsen, Anders
• Format: Article in Journal/Newspaper
• Language: English
• Published: 2024
• Subjects: greenlander*; greenlandic
• Online Access: https://vbn.aau.dk/da/publications/e9eae316-fc05-49e0-a645-6e8ec53d478b; https://doi.org/10.1038/s41431-023-01485-8; https://vbn.aau.dk/ws/files/668790000/Senftleber_et_al_2024_GWAS_of_lipids_in_Greenlanders_finds_association_signals_shared_with_Europeans_and_reveals_an_independent_PCSK9_association_signal.pdf; http://www.scopus.com/inward/record.url?scp=85175247548&partnerID=8YFLogxK

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 presented.)